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Rodriguez-Calvo T, Laiho JE, Oikarinen M, Akhbari P, Flaxman C, Worthington T, Apaolaza P, Kaddis JS, Kusmartseva I, Tauriainen S, Campbell-Thompson M, Atkinson MA, von Herrath M, Hyöty H, Morgan NG, Pugliese A, Richardson SJ. Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes. Diabetologia 2025; 68:1197-1210. [PMID: 40090995 PMCID: PMC12069150 DOI: 10.1007/s00125-025-06384-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 11/19/2024] [Indexed: 03/19/2025]
Abstract
AIMS/HYPOTHESIS Earlier studies of pancreases from donors with type 1 diabetes demonstrated enteroviral capsid protein VP1 in beta cells. In the context of a multidisciplinary approach undertaken by the nPOD-Virus group, we assessed VP1 positivity in pancreas and other tissues (spleen, duodenum and pancreatic lymph nodes) from 188 organ donors, including donors with type 1 diabetes and donors expressing autoantibody risk markers. We also investigated whether VP1 positivity is linked to the hyperexpression of HLA class I (HLA-I) molecules in islet cells. METHODS Organ donor tissues were collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) from donors without diabetes (ND, n=76), donors expressing a single or multiple diabetes-associated autoantibodies (AAb+, n=20; AAb++, n=9) and donors with type 1 diabetes with residual insulin-containing islets (T1D-ICIs, n=41) or only insulin-deficient islets (T1D-IDIs, n=42). VP1 was assessed using immunohistochemistry (IHC) and HLA-I using IHC and immunofluorescence, in two independent laboratories. We determined assay concordance across laboratories and overall occurrence of positive assays, on a case-by-case basis and between donor groups. RESULTS Islet cell VP1 positivity was detected in most T1D-ICI donors (77.5%) vs only 38.2% of ND donors (p<0.001). VP1 positivity was associated with HLA-I hyperexpression. Of those donors assessed for HLA-I and VP1, 73.7% had both VP1 immunopositivity and HLA-I hyperexpression (p<0.001 vs ND). Moreover, VP1+ cells were detected at higher frequency in donors with HLA-I hyperexpression (p<0.001 vs normal HLA-I). Among VP1+ donors, the proportion with HLA-I hyperexpression was significantly higher in the AAb++ and T1D-ICI groups (94.9%, p<0.001 vs ND); this was not restricted to individuals with recent-onset diabetes. Critically, for all donor groups combined, HLA-I hyperexpression occurred more frequently in VP1+ compared with VP1- donors (45.8% vs 16%, p<0.001). CONCLUSIONS/INTERPRETATION We report the most extensive analysis to date of VP1 and HLA-I in pancreases from donors with preclinical and diagnosed type 1 diabetes. We find an association of VP1 with residual beta cells after diagnosis and demonstrate VP1 positivity during the autoantibody-positive preclinical stage. For the first time, we show that VP1 positivity and HLA-I hyperexpression in islet cells are both present during the preclinical stage. While the study of tissues does not allow us to demonstrate causality, our data support the hypothesis that enterovirus infections may occur throughout the natural history of type 1 diabetes and may be one of multiple mechanisms driving islet cell HLA-I hyperexpression.
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Affiliation(s)
- Teresa Rodriguez-Calvo
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.
| | - Jutta E Laiho
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Maarit Oikarinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Pouria Akhbari
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Christine Flaxman
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Thomas Worthington
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Paola Apaolaza
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - John S Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Irina Kusmartseva
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | | | - Martha Campbell-Thompson
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Mark A Atkinson
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Matthias von Herrath
- Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, Miami, FL, USA
- Division of Endocrine, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
- Global Chief Medical Office, Novo Nordisk A/S, Søborg, Denmark
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
| | - Noel G Morgan
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Alberto Pugliese
- Department of Diabetes Immunology, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Sarah J Richardson
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK.
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Richardson SJ, Rodriguez-Calvo T, Laiho JE, Kaddis JS, Nyalwidhe JO, Kusmartseva I, Morfopoulou S, Petrosino JF, Plagnol V, Maedler K, Morris MA, Nadler JL, Atkinson MA, von Herrath M, Lloyd RE, Hyoty H, Morgan NG, Pugliese A. Joint analysis of the nPOD-Virus Group data: the association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue. Diabetologia 2025; 68:1226-1241. [PMID: 40090994 PMCID: PMC12069141 DOI: 10.1007/s00125-025-06401-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 12/03/2024] [Indexed: 03/19/2025]
Abstract
AIMS/HYPOTHESIS Previous pathology studies have associated enterovirus infections with type 1 diabetes by examining the enterovirus capsid protein 1 (VP1) in autopsy pancreases obtained near diabetes diagnosis. The Network for Pancreatic Organ Donors with Diabetes (nPOD) has since obtained pancreases from organ donors with type 1 diabetes (with broad age and disease duration) and donors with disease-associated autoantibodies (AAbs), the latter representing preclinical disease. Two accompanying manuscripts from the nPOD-Virus Group report primary data from a coordinated analysis of multiple enterovirus indices. We aimed to comprehensively assess the association of multiple enterovirus markers with type 1 diabetes. METHODS The nPOD-Virus Group examined pancreases from 197 donors, recovered between 2007 and 2019, classified into five groups: donors with type 1 diabetes, with residual insulin-containing islets (T1D-ICI group, n=41) or with only insulin-deficient islets (T1D-IDI, n=42); donors without diabetes who are AAb-negative (ND, n=83); and rare donors without diabetes expressing a single AAb (AAb+, n=22) or multiple AAbs (AAb++, n=9). We assessed the overall association of multiple indicators of enterovirus infection, case-by-case and between donor groups, as well as assay agreement and reproducibility, using various statistical methods. We examined data from 645 assays performed across 197 nPOD donors. RESULTS Detection of enterovirus indices by independent laboratories had high reproducibility, using both enterovirus-targeted and unbiased methods. T1D-ICI donors had significantly higher (p<0.001) proportions of positive assay outcomes (58.4%) vs T1D-IDI (10.3%), ND (17.8%) and AAb-positive donors (AAb+ 24.6%; AAb++ 35.0%). Head-to-head comparisons revealed increased proportions of donors positive in two independent assays among T1D-ICI vs ND donors (VP1/HLA class I [HLA-I], p<0.0001; VP1/enterovirus-specific RT-PCR (EV-PCR), p=0.076; EV-PCR/HLA-I, p=0.016; proteomics/HLA-I, p<0.0001; VP1/proteomics, p=0.06). Among 110 donors examined for three markers (VP1, EV-PCR and HLA-I), 83.3% of T1D-ICI donors were positive in two or more assays vs 0% of ND (p<0.001), 26.7% of AAb+ (p=0.006), 28.6% of AAb++ (p=0.023) and 0% of T1D-IDI (p<0.001) donors. CONCLUSIONS/INTERPRETATION The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb++ donors than in other groups. Their preferential detection of these indices in donors with residual beta cells and autoimmunity implicates enterovirus infections across disease progression stages and supports a contribution to beta cell loss, directly or indirectly, even after diagnosis. The relatively small number of infected cells and the low amount of viral RNA support the existence of non-acute, low level, possibly persistent enterovirus infections in the pancreas.
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Affiliation(s)
- Sarah J Richardson
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Teresa Rodriguez-Calvo
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Jutta E Laiho
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - John S Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Julius O Nyalwidhe
- Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Irina Kusmartseva
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Sofia Morfopoulou
- Division of Infection and Immunity, University College London, London, UK
| | | | | | - Kathrin Maedler
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany
| | - Margaret A Morris
- Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
- Autoimmunity and Primary Immunodeficiency Disease Section, Autoimmunity and Mucosal Immunology Branch, DAIT NIAD NIH DHHS, Rockville, MD, USA
| | - Jerry L Nadler
- UC Davis School of Medicine, Sacramento, CA, USA
- ACOS-Research Northern California VA Health System, Mather, CA, USA
| | - Mark A Atkinson
- Diabetes Institute, Department of Pathology, University of Florida, Gainesville, FL, USA
| | - Matthias von Herrath
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Heikki Hyoty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
- Department of Paediatrics, Tampere University Hospital, Tampere, Finland
| | - Noel G Morgan
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Alberto Pugliese
- Department of Diabetes Immunology, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA.
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Galipeau Y, Cooper C, Langlois MA. Autoantibodies in COVID-19: implications for disease severity and clinical outcomes. Front Immunol 2025; 15:1509289. [PMID: 39835117 PMCID: PMC11743527 DOI: 10.3389/fimmu.2024.1509289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/13/2024] [Indexed: 01/22/2025] Open
Abstract
Few pathogens have historically been subjected to as intense scientific and clinical scrutiny as SARS-CoV-2. The genetic, immunological, and environmental factors influencing disease severity and post-infection clinical outcomes, known as correlates of immunity, remain largely undefined. Clinical outcomes of SARS-CoV-2 infection vary widely, ranging from asymptomatic cases to those with life-threatening COVID-19 symptoms. While most infected individuals return to their former health and fitness within a few weeks, some develop debilitating chronic symptoms, referred to as long-COVID. Autoimmune responses have been proposed as one of the factors influencing long-COVID and the severity of SARS-CoV-2 infection. The association between viral infections and autoimmune pathologies is not new. Viruses such as Epstein-Barr virus and cytomegalovirus, among others, have been shown to induce the production of autoantibodies and the onset of autoimmune conditions. Given the extensive literature on SARS-CoV-2, here we review current evidence on SARS-CoV-2-induced autoimmune pathologies, with a focus on autoantibodies. We closely examine mechanisms driving autoantibody production, particularly their connection with disease severity and long-COVID.
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Affiliation(s)
- Yannick Galipeau
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Curtis Cooper
- The Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Marc-André Langlois
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
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Zeller I, Weiss A, Arnolds S, Schütte-Borkovec K, Arabi S, von dem Berge T, Casteels K, Hommel A, Kordonouri O, Larsson HE, Lundgren M, Rochtus A, Snape MD, Szypowka A, Vatish M, Winkler C, Bonifacio E, Ziegler AG. Infection episodes and islet autoantibodies in children at increased risk for type 1 diabetes before and during the COVID-19 pandemic. Infection 2024; 52:2465-2473. [PMID: 38874748 PMCID: PMC11621198 DOI: 10.1007/s15010-024-02312-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 05/29/2024] [Indexed: 06/15/2024]
Abstract
OBJECTIVES To determine the impact of the COVID-19 pandemic on the incidence rates of infection and islet autoimmunity in children at risk for type 1 diabetes. METHODS 1050 children aged 4 to 7 months with an elevated genetic risk for type 1 diabetes were recruited from Germany, Poland, Sweden, Belgium and the UK. Reported infection episodes and islet autoantibody development were monitored until age 40 months from February 2018 to February 2023. RESULTS The overall infection rate was 311 (95% Confidence Interval [CI], 304-318) per 100 person years. Infection rates differed by age, country, family history of type 1 diabetes, and period relative to the pandemic. Total infection rates were 321 per 100 person-years (95% CI 304-338) in the pre-pandemic period (until February 2020), 160 (95% CI 148-173) per 100 person-years in the first pandemic year (March 2020-February 2021; P < 0.001) and 337 (95% CI 315-363) per 100 person-years in subsequent years. Similar trends were observed for respiratory and gastrointestinal infections. Islet autoantibody incidence rates were 1.6 (95% CI 1.0-2.4) per 100 person-years in the pre-pandemic period, 1.2 (95% CI 0.8-1.9) per 100 person-years in the first pandemic year (P = 0.46), and 3.4 (95% CI 2.3-4.8) per 100 person-years in subsequent years (P = 0.005 vs. pre-pandemic year; P < 0.001 vs. first pandemic year). CONCLUSIONS The COVID-19 pandemic was associated with significantly altered infection patterns. Islet autoantibody incidence rates increased two-fold when infection rates returned to pre-pandemic levels.
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Affiliation(s)
- Ivo Zeller
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Heidemannstrasse 1, 80939, Munich, Germany
| | - Andreas Weiss
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Heidemannstrasse 1, 80939, Munich, Germany
| | - Stefanie Arnolds
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Heidemannstrasse 1, 80939, Munich, Germany
| | - Katharina Schütte-Borkovec
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Heidemannstrasse 1, 80939, Munich, Germany
| | - Sari Arabi
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
- Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | | | - Kristina Casteels
- Department of Pediatrics, University Hospitals Leuven, Louvain, Belgium
- Department of Development and Regeneration, KU Leuven, Louvain, Belgium
| | - Angela Hommel
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Olga Kordonouri
- Kinder- Und Jugendkrankenhaus AUF DER BULT, Hannover, Germany
| | - Helena Elding Larsson
- Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
- Department of Paediatrics, Skåne University Hospital, Malmö/Lund, Sweden
| | - Markus Lundgren
- Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
- Department of Pediatrics, Kristianstad Hospital, Kristianstad, Sweden
| | - Anne Rochtus
- Department of Pediatrics, University Hospitals Leuven, Louvain, Belgium
- Department of Development and Regeneration, KU Leuven, Louvain, Belgium
| | - Matthew D Snape
- Oxford Vaccine Group, University of Oxford Department of Paediatrics, NIHR Oxford Biomedical Research Centre, Oxford, UK
| | | | - Manu Vatish
- Nuffield Department of Women's & Reproductive Health, Oxford, UK
| | - Christiane Winkler
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Heidemannstrasse 1, 80939, Munich, Germany
| | - Ezio Bonifacio
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Munich at University Hospital Carl Gustav Carus, Faculty of Medicine, TU, Dresden, Germany
| | - Anette-Gabriele Ziegler
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Heidemannstrasse 1, 80939, Munich, Germany.
- Forschergruppe Diabetes E.V. at Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany.
- Forschergruppe Diabetes, School of Medicine, Klinikum Rechts Der Isar, Technical University Munich, Munich, Germany.
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Butrym M, Byvald F, Blanter M, Ringqvist EE, Vasylovska S, Marjomäki V, Lau J, Stone VM, Flodström-Tullberg M. Vemurafenib inhibits the replication of diabetogenic enteroviruses in intestinal epithelial and pancreatic beta cells. Antiviral Res 2024; 231:106021. [PMID: 39419452 DOI: 10.1016/j.antiviral.2024.106021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/27/2024] [Accepted: 10/14/2024] [Indexed: 10/19/2024]
Abstract
Enteroviruses, which infect via the gut, have been implicated in type 1 diabetes (T1D) development. Prolonged faecal shedding of enterovirus has been associated with islet autoimmunity. Additionally, enteroviral proteins and viral RNA have been detected in the pancreatic islets of individuals with recent-onset T1D, implicating their possible role in beta cell destruction. Despite this, no approved antiviral drugs currently exist that specifically target enterovirus infections for utilisation in disease interventions. Drug repurposing allows for the discovery of new clinical uses for existing drugs and can expedite drug discovery. Previously, the cancer drug Vemurafenib demonstrated unprecedented antiviral activity against several enteroviruses. In the present study, we assessed the efficacy of Vemurafenib and an analogue thereof in preventing infection or reducing the replication of enteroviruses associated with T1D. We tested Vemurafenib in intestinal epithelial cells (IECs) and insulin-producing beta cells. Additionally, we established a protocol for infecting human stem cell-derived islets (SC-islets) and used Vemurafenib and its analogue in this model. Our studies revealed that Vemurafenib exhibited strong antiviral properties in IECs and a beta cell line. The antiviral effect was also seen with the Vemurafenib analogue. SC-islets expressed the viral receptors CAR and DAF, with their highest expression in insulin- and glucagon-positive cells, respectively. SC-islets were successfully infected by CVBs and the antiviral activity of Vemurafenib and its analogue was confirmed in most SC-islet batches. In summary, our observations suggest that Vemurafenib and its analogue warrant further exploration as potential antiviral agents for the treatment of enterovirus-induced diseases, including T1D.
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Affiliation(s)
- Marta Butrym
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
| | - Fabian Byvald
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
| | - Marfa Blanter
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
| | - Emma E Ringqvist
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
| | - Svitlana Vasylovska
- Department of Medical Cell Biology, Uppsala University, BOX 571, 751 23, Uppsala, Sweden.
| | - Varpu Marjomäki
- Department of Biological and Environmental Science, University of Jyväskylä, P.O. Box 35, FI-40014, Jyväskylä, Finland.
| | - Joey Lau
- Department of Medical Cell Biology, Uppsala University, BOX 571, 751 23, Uppsala, Sweden.
| | - Virginia M Stone
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
| | - Malin Flodström-Tullberg
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
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Fogarasi M, Dima S. Immunomodulatory Functions of TNF-Related Apoptosis-Inducing Ligand in Type 1 Diabetes. Cells 2024; 13:1676. [PMID: 39451194 PMCID: PMC11506310 DOI: 10.3390/cells13201676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/01/2024] [Accepted: 10/09/2024] [Indexed: 10/26/2024] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF protein superfamily and was initially identified as a protein capable of inducing apoptosis in cancer cells. In addition, TRAIL can promote pro-survival and proliferation signaling in various cell types. Subsequent studies have demonstrated that TRAIL plays several important roles in immunoregulation, immunosuppression, and immune effector functions. Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia due to the loss of insulin-producing β-cells, primarily driven by T-cell-mediated pancreatic islet inflammation. Various genetic, epigenetic, and environmental factors, in conjunction with the immune system, contribute to the initiation, development, and progression of T1D. Recent reports have highlighted TRAIL as an important immunomodulatory molecule with protective effects on pancreatic islets. Experimental data suggest that TRAIL protects against T1D by reducing the proliferation of diabetogenic T cells and pancreatic islet inflammation and restoring normoglycemia in animal models. In this review, we aimed to summarize the consequences of TRAIL action in T1D, focusing on and discussing its signaling mechanisms, role in the immune system, and protective effects in T1D.
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Affiliation(s)
- Marton Fogarasi
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Simona Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Liakou AI, Tsantes AG, Routsi E, Agiasofitou E, Kalamata M, Bompou EK, Tsante KA, Vladeni S, Chatzidimitriou E, Kotsafti O, Samonis G, Bonovas S, Stratigos AI. Could Vaccination against COVID-19 Trigger Immune-Mediated Inflammatory Diseases? J Clin Med 2024; 13:4617. [PMID: 39200759 PMCID: PMC11355883 DOI: 10.3390/jcm13164617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 07/29/2024] [Accepted: 08/04/2024] [Indexed: 09/02/2024] Open
Abstract
Exacerbations and new onset of immune-mediated inflammatory diseases, such as psoriasis and hidradenitis suppurativa, have been reported following COVID-19 vaccination. In patients with hidradenitis suppurativa, recent studies have shown that those who received mRNA vaccines were 3.5 times as likely to develop flares following vaccination compared to patients who received non-mRNA vaccines, indicating that mRNA COVID-19 vaccines are associated with hidradenitis suppurativa flares. Similar findings have been found in other studies evaluating the association between COVID-19 vaccines and other immune-mediated inflammatory diseases such as psoriasis, atopic dermatitis, lichen planus, and alopecia areata. However, further research is warranted in larger populations to validate these findings.
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Affiliation(s)
- Aikaterini I. Liakou
- 1st Department of Dermatology-Venereology, “Andreas Sygros” Hospital, National and Kapodistrian University of Athens Medical School, 16121 Athens, Greece; (E.R.); (E.A.); (M.K.); (E.-K.B.); (S.V.); (E.C.); (O.K.); (A.I.S.)
| | - Andreas G. Tsantes
- Laboratory of Haematology and Blood Bank Unit, “Attikon” Hospital, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece; (A.G.T.); (K.A.T.)
- Microbiology Department, “Saint Savvas” Oncology Hospital, 11522 Athens, Greece
| | - Eleni Routsi
- 1st Department of Dermatology-Venereology, “Andreas Sygros” Hospital, National and Kapodistrian University of Athens Medical School, 16121 Athens, Greece; (E.R.); (E.A.); (M.K.); (E.-K.B.); (S.V.); (E.C.); (O.K.); (A.I.S.)
| | - Efthymia Agiasofitou
- 1st Department of Dermatology-Venereology, “Andreas Sygros” Hospital, National and Kapodistrian University of Athens Medical School, 16121 Athens, Greece; (E.R.); (E.A.); (M.K.); (E.-K.B.); (S.V.); (E.C.); (O.K.); (A.I.S.)
| | - Magdalini Kalamata
- 1st Department of Dermatology-Venereology, “Andreas Sygros” Hospital, National and Kapodistrian University of Athens Medical School, 16121 Athens, Greece; (E.R.); (E.A.); (M.K.); (E.-K.B.); (S.V.); (E.C.); (O.K.); (A.I.S.)
| | - Evangelia-Konstantina Bompou
- 1st Department of Dermatology-Venereology, “Andreas Sygros” Hospital, National and Kapodistrian University of Athens Medical School, 16121 Athens, Greece; (E.R.); (E.A.); (M.K.); (E.-K.B.); (S.V.); (E.C.); (O.K.); (A.I.S.)
| | - Konstantina A. Tsante
- Laboratory of Haematology and Blood Bank Unit, “Attikon” Hospital, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece; (A.G.T.); (K.A.T.)
| | - Soultana Vladeni
- 1st Department of Dermatology-Venereology, “Andreas Sygros” Hospital, National and Kapodistrian University of Athens Medical School, 16121 Athens, Greece; (E.R.); (E.A.); (M.K.); (E.-K.B.); (S.V.); (E.C.); (O.K.); (A.I.S.)
| | - Eleni Chatzidimitriou
- 1st Department of Dermatology-Venereology, “Andreas Sygros” Hospital, National and Kapodistrian University of Athens Medical School, 16121 Athens, Greece; (E.R.); (E.A.); (M.K.); (E.-K.B.); (S.V.); (E.C.); (O.K.); (A.I.S.)
| | - Ourania Kotsafti
- 1st Department of Dermatology-Venereology, “Andreas Sygros” Hospital, National and Kapodistrian University of Athens Medical School, 16121 Athens, Greece; (E.R.); (E.A.); (M.K.); (E.-K.B.); (S.V.); (E.C.); (O.K.); (A.I.S.)
| | - George Samonis
- Department of Medicine, University of Crete, 71500 Heraklion, Greece;
- Department of Oncology, Metropolitan Hospital, 18547 Athens, Greece
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy;
- IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Alexander I. Stratigos
- 1st Department of Dermatology-Venereology, “Andreas Sygros” Hospital, National and Kapodistrian University of Athens Medical School, 16121 Athens, Greece; (E.R.); (E.A.); (M.K.); (E.-K.B.); (S.V.); (E.C.); (O.K.); (A.I.S.)
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8
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Jartti M, Flodström-Tullberg M, Hankaniemi MM. Enteroviruses: epidemic potential, challenges and opportunities with vaccines. J Biomed Sci 2024; 31:73. [PMID: 39010093 PMCID: PMC11247760 DOI: 10.1186/s12929-024-01058-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/23/2024] [Indexed: 07/17/2024] Open
Abstract
Enteroviruses (EVs) are the most prevalent viruses in humans. EVs can cause a range of acute symptoms, from mild common colds to severe systemic infections such as meningitis, myocarditis, and flaccid paralysis. They can also lead to chronic diseases such as cardiomyopathy. Although more than 280 human EV serotypes exist, only four serotypes have licenced vaccines. No antiviral drugs are available to treat EV infections, and global surveillance of EVs has not been effectively coordinated. Therefore, poliovirus still circulates, and there have been alarming epidemics of non-polio enteroviruses. Thus, there is a pressing need for coordinated preparedness efforts against EVs.This review provides a perspective on recent enterovirus outbreaks and global poliovirus eradication efforts with continuous vaccine development initiatives. It also provides insights into the challenges and opportunities in EV vaccine development. Given that traditional whole-virus vaccine technologies are not suitable for many clinically relevant EVs and considering the ongoing risk of enterovirus outbreaks and the potential for new emerging pathogenic strains, the need for new effective and adaptable enterovirus vaccines is emphasized.This review also explores the difficulties in translating promising vaccine candidates for clinical use and summarizes information from published literature and clinical trial databases focusing on existing enterovirus vaccines, ongoing clinical trials, the obstacles faced in vaccine development as well as the emergence of new vaccine technologies. Overall, this review contributes to the understanding of enterovirus vaccines, their role in public health, and their significance as a tool for future preparedness.
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Affiliation(s)
- Minne Jartti
- Virology and Vaccine Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Malin Flodström-Tullberg
- Department of Medicine Huddinge and Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Minna M Hankaniemi
- Virology and Vaccine Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
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9
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Tsay GJ, Zouali M. Cellular pathways and molecular events that shape autoantibody production in COVID-19. J Autoimmun 2024; 147:103276. [PMID: 38936147 DOI: 10.1016/j.jaut.2024.103276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 05/26/2024] [Accepted: 06/18/2024] [Indexed: 06/29/2024]
Abstract
A hallmark of COVID-19 is the variety of complications that follow SARS-CoV-2 infection in some patients, and that target multiple organs and tissues. Also remarkable are the associations with several auto-inflammatory disorders and the presence of autoantibodies directed to a vast array of antigens. The processes underlying autoantibody production in COVID-19 have not been completed deciphered. Here, we review mechanisms involved in autoantibody production in COVID-19, multisystem inflammatory syndrome in children, and post-acute sequelae of COVID19. We critically discuss how genomic integrity, loss of B cell tolerance to self, superantigen effects of the virus, and extrafollicular B cell activation could underly autoantibody proaction in COVID-19. We also offer models that may account for the pathogenic roles of autoantibodies in the promotion of inflammatory cascades, thromboembolic phenomena, and endothelial and vascular deregulations.
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Affiliation(s)
- Gregory J Tsay
- Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan
| | - Moncef Zouali
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
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10
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Vecchio F, Carré A, Korenkov D, Zhou Z, Apaolaza P, Tuomela S, Burgos-Morales O, Snowhite I, Perez-Hernandez J, Brandao B, Afonso G, Halliez C, Kaddis J, Kent SC, Nakayama M, Richardson SJ, Vinh J, Verdier Y, Laiho J, Scharfmann R, Solimena M, Marinicova Z, Bismuth E, Lucidarme N, Sanchez J, Bustamante C, Gomez P, Buus S, You S, Pugliese A, Hyoty H, Rodriguez-Calvo T, Flodstrom-Tullberg M, Mallone R. Coxsackievirus infection induces direct pancreatic β cell killing but poor antiviral CD8 + T cell responses. SCIENCE ADVANCES 2024; 10:eadl1122. [PMID: 38446892 PMCID: PMC10917340 DOI: 10.1126/sciadv.adl1122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 01/30/2024] [Indexed: 03/08/2024]
Abstract
Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β cell autoimmunity and type 1 diabetes. We investigated how CVB affects human β cells and anti-CVB T cell responses. β cells were efficiently infected by CVB in vitro, down-regulated human leukocyte antigen (HLA) class I, and presented few, selected HLA-bound viral peptides. Circulating CD8+ T cells from CVB-seropositive individuals recognized a fraction of these peptides; only another subfraction was targeted by effector/memory T cells that expressed exhaustion marker PD-1. T cells recognizing a CVB epitope cross-reacted with β cell antigen GAD. Infected β cells, which formed filopodia to propagate infection, were more efficiently killed by CVB than by CVB-reactive T cells. Our in vitro and ex vivo data highlight limited CD8+ T cell responses to CVB, supporting the rationale for CVB vaccination trials for type 1 diabetes prevention. CD8+ T cells recognizing structural and nonstructural CVB epitopes provide biomarkers to differentially follow response to infection and vaccination.
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Affiliation(s)
- Federica Vecchio
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Alexia Carré
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Daniil Korenkov
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Zhicheng Zhou
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Paola Apaolaza
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Soile Tuomela
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | | | - Isaac Snowhite
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | | | - Barbara Brandao
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Georgia Afonso
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Clémentine Halliez
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
| | - John Kaddis
- Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Sally C. Kent
- Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical Chan School, Worcester, MA, USA
| | - Maki Nakayama
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Sarah J. Richardson
- Islet Biology Exeter (IBEx), Exeter Centre of Excellence for Diabetes Research (EXCEED), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Joelle Vinh
- ESPCI Paris, PSL University, Spectrométrie de Masse Biologique et Protéomique, CNRS UMR8249, Paris, France
| | - Yann Verdier
- ESPCI Paris, PSL University, Spectrométrie de Masse Biologique et Protéomique, CNRS UMR8249, Paris, France
| | - Jutta Laiho
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | | | - Michele Solimena
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Paul Langerhans Institute Dresden (PLID), Helmholtz Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Zuzana Marinicova
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Paul Langerhans Institute Dresden (PLID), Helmholtz Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Elise Bismuth
- Assistance Publique Hôpitaux de Paris, Service d’Endocrinologie Pédiatrique, Robert Debré Hospital, Paris, France
| | - Nadine Lucidarme
- Assistance Publique Hôpitaux de Paris, Service de Pédiatrie, Jean Verdier Hospital, Bondy, France
| | - Janine Sanchez
- Department of Pediatrics, Division of Pediatric Endocrinology, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Carmen Bustamante
- Department of Pediatrics, Division of Pediatric Endocrinology, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Patricia Gomez
- Department of Pediatrics, Division of Pediatric Endocrinology, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Soren Buus
- Department of Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - the nPOD-Virus Working Group
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
- Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical Chan School, Worcester, MA, USA
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
- Islet Biology Exeter (IBEx), Exeter Centre of Excellence for Diabetes Research (EXCEED), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
- ESPCI Paris, PSL University, Spectrométrie de Masse Biologique et Protéomique, CNRS UMR8249, Paris, France
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Paul Langerhans Institute Dresden (PLID), Helmholtz Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
- Assistance Publique Hôpitaux de Paris, Service d’Endocrinologie Pédiatrique, Robert Debré Hospital, Paris, France
- Assistance Publique Hôpitaux de Paris, Service de Pédiatrie, Jean Verdier Hospital, Bondy, France
- Department of Pediatrics, Division of Pediatric Endocrinology, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Indiana Biosciences Research Institute, Indianapolis, IN, USA
- Fimlab Laboratories, Tampere, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Sylvaine You
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Indiana Biosciences Research Institute, Indianapolis, IN, USA
| | - Alberto Pugliese
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Heikki Hyoty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Teresa Rodriguez-Calvo
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Malin Flodstrom-Tullberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Roberto Mallone
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
- Indiana Biosciences Research Institute, Indianapolis, IN, USA
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11
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Uribe FR, González VPI, Kalergis AM, Soto JA, Bohmwald K. Understanding the Neurotrophic Virus Mechanisms and Their Potential Effect on Systemic Lupus Erythematosus Development. Brain Sci 2024; 14:59. [PMID: 38248274 PMCID: PMC10813552 DOI: 10.3390/brainsci14010059] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/24/2023] [Accepted: 01/03/2024] [Indexed: 01/23/2024] Open
Abstract
Central nervous system (CNS) pathologies are a public health concern, with viral infections one of their principal causes. These viruses are known as neurotropic pathogens, characterized by their ability to infiltrate the CNS and thus interact with various cell populations, inducing several diseases. The immune response elicited by neurotropic viruses in the CNS is commanded mainly by microglia, which, together with other local cells, can secrete inflammatory cytokines to fight the infection. The most relevant neurotropic viruses are adenovirus (AdV), cytomegalovirus (CMV), enterovirus (EV), Epstein-Barr Virus (EBV), herpes simplex virus type 1 (HSV-1), and herpes simplex virus type 2 (HSV-2), lymphocytic choriomeningitis virus (LCMV), and the newly discovered SARS-CoV-2. Several studies have associated a viral infection with systemic lupus erythematosus (SLE) and neuropsychiatric lupus (NPSLE) manifestations. This article will review the knowledge about viral infections, CNS pathologies, and the immune response against them. Also, it allows us to understand the relevance of the different viral proteins in developing neuronal pathologies, SLE and NPSLE.
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Affiliation(s)
- Felipe R. Uribe
- Millennium Institute on Immunology and Immunotherapy, Laboratorio de Inmunología Traslacional, Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago 8370146, Chile; (F.R.U.); (V.P.I.G.)
| | - Valentina P. I. González
- Millennium Institute on Immunology and Immunotherapy, Laboratorio de Inmunología Traslacional, Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago 8370146, Chile; (F.R.U.); (V.P.I.G.)
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile;
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Jorge A. Soto
- Millennium Institute on Immunology and Immunotherapy, Laboratorio de Inmunología Traslacional, Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago 8370146, Chile; (F.R.U.); (V.P.I.G.)
| | - Karen Bohmwald
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma, Santiago 8910060, Chile
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12
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Haapakoski M, Emelianov A, Reshamwala D, Laajala M, Tienaho J, Kilpeläinen P, Liimatainen J, Jyske T, Pettersson M, Marjomäki V. Antiviral functionalization of cellulose using tannic acid and tannin-rich extracts. Front Microbiol 2023; 14:1287167. [PMID: 38125579 PMCID: PMC10731304 DOI: 10.3389/fmicb.2023.1287167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/13/2023] [Indexed: 12/23/2023] Open
Abstract
Due to seasonally appearing viruses and several outbreaks and present pandemic, we are surrounded by viruses in our everyday life. In order to reduce viral transmission, functionalized surfaces that inactivate viruses are in large demand. Here the endeavor was to functionalize cellulose-based materials with tannic acid (TA) and tannin-rich extracts by using different binding polymers to prevent viral infectivity of both non-enveloped coxsackievirus B3 (CVB3) and enveloped human coronavirus OC43 (HCoV-OC43). Direct antiviral efficacy of TA and spruce bark extract in solution was measured: EC50 for CVB3 was 0.12 and 8.41 μg/ml and for HCoV-OC43, 78.16 and 95.49 μg/ml, respectively. TA also led to an excellent 5.8- to 7-log reduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infectivity. TA functionalized materials reduced infectivity already after 5-min treatment at room temperature. All the tested methods to bind TA showed efficacy on paperboard with 0.1 to 1% (w/v) TA concentrations against CVB3 whereas material hydrophobicity decreased activities. Specific signatures for TA and HCoV-OC43 were discovered by Raman spectroscopy and showed clear co-localization on the material. qPCR study suggested efficient binding of CVB3 to the TA functionalized cellulose whereas HCoV-OC43 was flushed out from the surfaces more readily. In conclusion, the produced TA-materials showed efficient and broadly acting antiviral efficacy. Additionally, the co-localization of TA and HCoV-OC43 and strong binding of CVB3 to the functionalized cellulose demonstrates an interaction with the surfaces. The produced antiviral surfaces thus show promise for future use to increase biosafety and biosecurity by reducing pathogen persistence.
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Affiliation(s)
- Marjo Haapakoski
- Department of Biological and Environmental Sciences/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Aleksei Emelianov
- Department of Chemistry/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Dhanik Reshamwala
- Department of Biological and Environmental Sciences/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Mira Laajala
- Department of Biological and Environmental Sciences/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Jenni Tienaho
- Production Systems Unit, Natural Resources Institute Finland (Luke), Helsinki, Finland
| | - Petri Kilpeläinen
- Production Systems Unit, Natural Resources Institute Finland (Luke), Helsinki, Finland
| | - Jaana Liimatainen
- Production Systems Unit, Natural Resources Institute Finland (Luke), Helsinki, Finland
| | - Tuula Jyske
- Production Systems Unit, Natural Resources Institute Finland (Luke), Helsinki, Finland
| | - Mika Pettersson
- Department of Chemistry/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Varpu Marjomäki
- Department of Biological and Environmental Sciences/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
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13
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Gomaa AF, Elghmary RM, Sharafeddin MA, Mohamed SY, Elsayed AF. COVID-19 Infection and Diabetes. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2023; 31:1-6. [DOI: 10.1097/ipc.0000000000001295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Abstract
Background
Hyperglycemia is one of the most important independent risk factors that affect the prognosis and outcome of COVID-19 patients. Coronavirus disease 2019 infection is associated with poor glycemic control. This study's objectives were to determine the effect of hyperglycemia on the prognosis and outcome of COVID-19 patients and to detect whether COVID-19 infection can induce new-onset diabetes.
Patients and Methods
This cohort study was carried out on 240 hospitalized Egyptian COVID-19 patients, at Zagazig University Hospital isolation intensive care unit, between March 2020 and March 2021. They compared patients with diabetes and uncontrolled hyperglycemia against each other and COVID-19 patients without diabetes or uncontrolled hyperglycemia. Baseline demographic data, clinical features, and laboratory analysis were collected. Clinical outcome was evaluated via hospital stay and survival rate. Patients with uncontrolled hyperglycemia and nondiabetic patients were followed up 1 year after the hospital discharge to detect the development of new-onset diabetes.
Result
The diabetic group had the highest creatinine level, and the nondiabetic group had a minor C-reactive protein and D-dimer. The difference is significant between diabetic and nondiabetic groups concerning hospital stay. The nondiabetic group had the shortest hospital stay. There is a statistically substantial relationship between mortality and the glycosylated hemoglobin, serum creatinine, C-reactive protein, D-dimer, and serum ferritin. A total of 46.6% of survivors in the uncontrolled hyperglycemic group and 3.4% in the nondiabetic group developed diabetes mellitus during follow-up. There is a statistically significant relationship between new-onset diabetes mellitus and D-dimer.
Conclusions
Coronavirus disease 2019 can induce diabetes mellitus in vulnerable patients (presented with uncontrolled hyperglycemia at admission). In addition, COVID-19 patients with diabetes or uncontrolled hyperglycemia have worse outcomes and poor prognoses.
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Affiliation(s)
| | - Reda M. Elghmary
- Pulmonology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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14
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Lugar M, Eugster A, Achenbach P, von dem Berge T, Berner R, Besser REJ, Casteels K, Elding Larsson H, Gemulla G, Kordonouri O, Lindner A, Lundgren M, Müller D, Oltarzewski M, Rochtus A, Scholz M, Szypowska A, Todd JA, Ziegler AG, Bonifacio E. SARS-CoV-2 Infection and Development of Islet Autoimmunity in Early Childhood. JAMA 2023; 330:1151-1160. [PMID: 37682551 PMCID: PMC10523173 DOI: 10.1001/jama.2023.16348] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 08/07/2023] [Indexed: 09/09/2023]
Abstract
Importance The incidence of diabetes in childhood has increased during the COVID-19 pandemic. Elucidating whether SARS-CoV-2 infection is associated with islet autoimmunity, which precedes type 1 diabetes onset, is relevant to disease etiology and future childhood diabetes trends. Objective To determine whether there is a temporal relationship between SARS-CoV-2 infection and the development of islet autoimmunity in early childhood. Design, Setting, and Participants Between February 2018 and March 2021, the Primary Oral Insulin Trial, a European multicenter study, enrolled 1050 infants (517 girls) aged 4 to 7 months with a more than 10% genetically defined risk of type 1 diabetes. Children were followed up through September 2022. Exposure SARS-CoV-2 infection identified by SARS-CoV-2 antibody development in follow-up visits conducted at 2- to 6-month intervals until age 2 years from April 2018 through June 2022. Main Outcomes and Measures The development of multiple (≥2) islet autoantibodies in follow-up in consecutive samples or single islet antibodies and type 1 diabetes. Antibody incidence rates and risk of developing islet autoantibodies were analyzed. Results Consent was obtained for 885 (441 girls) children who were included in follow-up antibody measurements from age 6 months. SARS-CoV-2 antibodies developed in 170 children at a median age of 18 months (range, 6-25 months). Islet autoantibodies developed in 60 children. Six of these children tested positive for islet autoantibodies at the same time as they tested positive for SARS-CoV-2 antibodies and 6 at the visit after having tested positive for SARS-CoV-2 antibodies. The sex-, age-, and country-adjusted hazard ratio for developing islet autoantibodies when the children tested positive for SARS-CoV-2 antibodies was 3.5 (95% CI, 1.6-7.7; P = .002). The incidence rate of islet autoantibodies was 3.5 (95% CI, 2.2-5.1) per 100 person-years in children without SARS-CoV-2 antibodies and 7.8 (95% CI, 5.3-19.0) per 100 person-years in children with SARS-CoV-2 antibodies (P = .02). Islet autoantibody risk in children with SARS-CoV-2 antibodies was associated with younger age (<18 months) of SARS-CoV-2 antibody development (HR, 5.3; 95% CI, 1.5-18.3; P = .009). Conclusion and relevance In young children with high genetic risk of type 1 diabetes, SARS-CoV-2 infection was temporally associated with the development of islet autoantibodies.
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Affiliation(s)
- Marija Lugar
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Anne Eugster
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Peter Achenbach
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
- Forschergruppe Diabetes, School of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
- Forschergruppe Diabetes e.V. at Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | | | - Reinhard Berner
- Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Rachel E. J. Besser
- Department of Pediatrics, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, Oxford University, Oxford, United Kingdom
| | - Kristina Casteels
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Helena Elding Larsson
- Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
- Department of Paediatrics, Skåne University Hospital, Malmö, Sweden
| | - Gita Gemulla
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
- Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Olga Kordonouri
- Kinder-und Jugendkrankenhaus AUF DER BULT, Hannover, Germany
| | - Annett Lindner
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Markus Lundgren
- Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
- Department of Pediatrics, Kristianstad Hospital, Kristianstad, Sweden
| | - Denise Müller
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | | | - Anne Rochtus
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Marlon Scholz
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
- Forschergruppe Diabetes, School of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
- Forschergruppe Diabetes e.V. at Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | | | - John A. Todd
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, Oxford University, Oxford, United Kingdom
| | - Anette-Gabriele Ziegler
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
- Forschergruppe Diabetes, School of Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
- Forschergruppe Diabetes e.V. at Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | - Ezio Bonifacio
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Germany
- Institute for Diabetes and Obesity, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
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15
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Perakakis N, Harb H, Hale BG, Varga Z, Steenblock C, Kanczkowski W, Alexaki VI, Ludwig B, Mirtschink P, Solimena M, Toepfner N, Zeissig S, Gado M, Abela IA, Beuschlein F, Spinas GA, Cavelti-Weder C, Gerber PA, Huber M, Trkola A, Puhan MA, Wong WWL, Linkermann A, Mohan V, Lehnert H, Nawroth P, Chavakis T, Mingrone G, Wolfrum C, Zinkernagel AS, Bornstein SR. Mechanisms and clinical relevance of the bidirectional relationship of viral infections with metabolic diseases. Lancet Diabetes Endocrinol 2023; 11:675-693. [PMID: 37524103 DOI: 10.1016/s2213-8587(23)00154-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 05/09/2023] [Accepted: 05/19/2023] [Indexed: 08/02/2023]
Abstract
Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany.
| | - Hani Harb
- Medical Microbiology and Virology, Technische Universität Dresden, Dresden 01307, Germany
| | - Benjamin G Hale
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland
| | - Zsuzsanna Varga
- Department of Pathology and Molecular Pathology, University of Zürich, Zürich, Switzerland
| | - Charlotte Steenblock
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany
| | - Waldemar Kanczkowski
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany
| | - Vasileia Ismini Alexaki
- Institute for Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany
| | - Barbara Ludwig
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Peter Mirtschink
- Institute for Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany
| | - Michele Solimena
- Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; Department of Molecular Diabetology, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Nicole Toepfner
- Department of Pediatrics, Technische Universität Dresden, Dresden 01307, Germany
| | - Sebastian Zeissig
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden 01307, Germany; Department of Medicine I, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany
| | - Manuel Gado
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Irene Alma Abela
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland; Department of Infectious Diseases and Hospital Epidemiology, University of Zürich, Zürich, Switzerland
| | - Felix Beuschlein
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland; Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Giatgen A Spinas
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Claudia Cavelti-Weder
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Philipp A Gerber
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Michael Huber
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland
| | - Alexandra Trkola
- Institute of Medical Virology, University of Zürich, Zürich, Switzerland
| | - Milo A Puhan
- Epidemiology, Biostatistics and Prevention Institute, University of Zürich, Zürich, Switzerland
| | - Wendy Wei-Lynn Wong
- and Department of Molecular Life Science, University of Zürich, Zürich, Switzerland
| | - Andreas Linkermann
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Viswanathan Mohan
- Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Chennai, Tamil Nadu, India
| | - Hendrik Lehnert
- Presidential Office, Paris Lodron Universität Salzburg, Salzburg, Austria
| | - Peter Nawroth
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany
| | - Triantafyllos Chavakis
- Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; Institute for Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Geltrude Mingrone
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; Division of Diabetes and Nutritional Sciences, School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Christian Wolfrum
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland
| | - Annelies S Zinkernagel
- Department of Infectious Diseases and Hospital Epidemiology, University of Zürich, Zürich, Switzerland
| | - Stefan R Bornstein
- Department of Internal Medicine III, Technische Universität Dresden, Dresden 01307, Germany; Paul Langerhans Institute Dresden, Helmholtz Munich, Technische Universität Dresden, Dresden 01307, Germany; German Center for Diabetes Research, Neuherberg, Germany; Division of Diabetes and Nutritional Sciences, School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
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16
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González‐Moro I, Garcia‐Etxebarria K, Mendoza LM, Fernández‐Jiménez N, Mentxaka J, Olazagoitia‐Garmendia A, Arroyo MN, Sawatani T, Moreno‐Castro C, Vinci C, Op de Beek A, Cnop M, Igoillo‐Esteve M, Santin I. LncRNA ARGI Contributes to Virus-Induced Pancreatic β Cell Inflammation Through Transcriptional Activation of IFN-Stimulated Genes. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300063. [PMID: 37382191 PMCID: PMC10477904 DOI: 10.1002/advs.202300063] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 05/30/2023] [Indexed: 06/30/2023]
Abstract
Type 1 diabetes (T1D) is a complex autoimmune disease that develops in genetically susceptible individuals. Most T1D-associated single nucleotide polymorphisms (SNPs) are located in non-coding regions of the human genome. Interestingly, SNPs in long non-coding RNAs (lncRNAs) may result in the disruption of their secondary structure, affecting their function, and in turn, the expression of potentially pathogenic pathways. In the present work, the function of a virus-induced T1D-associated lncRNA named ARGI (Antiviral Response Gene Inducer) is characterized. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic β cells and binds to CTCF to interact with the promoter and enhancer regions of IFNβ and interferon-stimulated genes, promoting their transcriptional activation in an allele-specific manner. The presence of the T1D risk allele in ARGI induces a change in its secondary structure. Interestingly, the T1D risk genotype induces hyperactivation of type I IFN response in pancreatic β cells, an expression signature that is present in the pancreas of T1D patients. These data shed light on the molecular mechanisms by which T1D-related SNPs in lncRNAs influence pathogenesis at the pancreatic β cell level and opens the door for the development of therapeutic strategies based on lncRNA modulation to delay or avoid pancreatic β cell inflammation in T1D.
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Affiliation(s)
- Itziar González‐Moro
- Department of Biochemistry and Molecular BiologyUniversity of the Basque CountryLeioa48940Spain
- Biocruces Bizkaia Health Research InstituteBarakaldo48903Spain
| | - Koldo Garcia‐Etxebarria
- Biodonostia Health Research InstituteGastrointestinal Genetics GroupSan Sebastián20014Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)Barcelona08036Spain
| | - Luis Manuel Mendoza
- Department of Biochemistry and Molecular BiologyUniversity of the Basque CountryLeioa48940Spain
| | - Nora Fernández‐Jiménez
- Biocruces Bizkaia Health Research InstituteBarakaldo48903Spain
- Department of GeneticsPhysical Anthropology and Animal PhysiologyUniversity of the Basque CountryLeioa48940Spain
| | - Jon Mentxaka
- Department of Biochemistry and Molecular BiologyUniversity of the Basque CountryLeioa48940Spain
- Biocruces Bizkaia Health Research InstituteBarakaldo48903Spain
| | - Ane Olazagoitia‐Garmendia
- Department of Biochemistry and Molecular BiologyUniversity of the Basque CountryLeioa48940Spain
- Biocruces Bizkaia Health Research InstituteBarakaldo48903Spain
| | - María Nicol Arroyo
- ULB Center for Diabetes ResearchUniversité Libre de BruxellesBrussels1070Belgium
| | - Toshiaki Sawatani
- ULB Center for Diabetes ResearchUniversité Libre de BruxellesBrussels1070Belgium
| | | | - Chiara Vinci
- ULB Center for Diabetes ResearchUniversité Libre de BruxellesBrussels1070Belgium
| | - Anne Op de Beek
- ULB Center for Diabetes ResearchUniversité Libre de BruxellesBrussels1070Belgium
| | - Miriam Cnop
- ULB Center for Diabetes ResearchUniversité Libre de BruxellesBrussels1070Belgium
- Division of EndocrinologyErasmus HospitalUniversité Libre de BruxellesBrussels1070Belgium
| | | | - Izortze Santin
- Department of Biochemistry and Molecular BiologyUniversity of the Basque CountryLeioa48940Spain
- Biocruces Bizkaia Health Research InstituteBarakaldo48903Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)Instituto de Salud Carlos IIIMadrid28029Spain
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17
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Vecchio F, Carré A, Korenkov D, Zhou Z, Apaolaza P, Tuomela S, Burgos-Morales O, Snowhite I, Perez-Hernandez J, Brandao B, Afonso G, Halliez C, Kaddis J, Kent SC, Nakayama M, Richardson SJ, Vinh J, Verdier Y, Laiho J, Scharfmann R, Solimena M, Marinicova Z, Bismuth E, Lucidarme N, Sanchez J, Bustamante C, Gomez P, Buus S, You S, Pugliese A, Hyoty H, Rodriguez-Calvo T, Flodstrom-Tullberg M, Mallone R. Coxsackievirus infection induces direct pancreatic β-cell killing but poor anti-viral CD8+ T-cell responses. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.19.553954. [PMID: 37662376 PMCID: PMC10473604 DOI: 10.1101/2023.08.19.553954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β-cell autoimmunity. We investigated how CVB impacts human β cells and anti-CVB T-cell responses. β cells were efficiently infected by CVB in vitro, downregulated HLA Class I and presented few, selected HLA-bound viral peptides. Circulating CD8+ T cells from CVB-seropositive individuals recognized only a fraction of these peptides, and only another sub-fraction was targeted by effector/memory T cells that expressed the exhaustion marker PD-1. T cells recognizing a CVB epitope cross-reacted with the β-cell antigen GAD. Infected β cells, which formed filopodia to propagate infection, were more efficiently killed by CVB than by CVB-reactive T cells. Thus, our in-vitro and ex-vivo data highlight limited T-cell responses to CVB, supporting the rationale for CVB vaccination trials for type 1 diabetes prevention. CD8+ T cells recognizing structural and non-structural CVB epitopes provide biomarkers to differentially follow response to infection and vaccination.
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Affiliation(s)
- Federica Vecchio
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Alexia Carré
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Daniil Korenkov
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Zhicheng Zhou
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Paola Apaolaza
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Soile Tuomela
- Center for Infectious Medicine, Department of medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | | | - Isaac Snowhite
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, FL, USA
- Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | | | - Barbara Brandao
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Georgia Afonso
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | | | - John Kaddis
- Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Sally C. Kent
- University of Massachusetts Medical Chan School, Diabetes Center of Excellence, Department of Medicine, Worcester, MA, USA
| | - Maki Nakayama
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Sarah J. Richardson
- Islet Biology Exeter (IBEx), Exeter Centre of Excellence for Diabetes Research (EXCEED), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Joelle Vinh
- ESPCI Paris, PSL University, Spectrométrie de Masse Biologique et Protéomique, CNRS UMR8249, Paris, France
| | - Yann Verdier
- ESPCI Paris, PSL University, Spectrométrie de Masse Biologique et Protéomique, CNRS UMR8249, Paris, France
| | - Jutta Laiho
- Tampere University, Faculty of Medicine and Health Technology and Fimlab Laboratories, Tampere, Finland
| | | | - Michele Solimena
- Paul Langerhans Institute, Technical University Dresden, Germany
| | | | - Elise Bismuth
- Assistance Publique Hôpitaux de Paris, Service d’Endocrinologie Pédiatrique, Robert Debré Hospital, Paris, France
| | - Nadine Lucidarme
- Assistance Publique Hôpitaux de Paris, Service de Pédiatrie, Jean Verdier Hospital, Bondy, France
| | - Janine Sanchez
- Department of Pediatrics, Division of pediatric Endocrinology, Leonard Miller School of Medicine, University of Miami, FL, USA
| | - Carmen Bustamante
- Department of Pediatrics, Division of pediatric Endocrinology, Leonard Miller School of Medicine, University of Miami, FL, USA
| | - Patricia Gomez
- Department of Pediatrics, Division of pediatric Endocrinology, Leonard Miller School of Medicine, University of Miami, FL, USA
| | - Soren Buus
- Panum Institute, Department of International Health, Immunology and Microbiology, Copenhagen, Denmark
| | | | - Sylvaine You
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Indiana Biosciences Research Institute, Indianapolis, IN, USA
| | - Alberto Pugliese
- Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, FL, USA
- Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Heikki Hyoty
- Tampere University, Faculty of Medicine and Health Technology and Fimlab Laboratories, Tampere, Finland
| | - Teresa Rodriguez-Calvo
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Malin Flodstrom-Tullberg
- Center for Infectious Medicine, Department of medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Roberto Mallone
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Indiana Biosciences Research Institute, Indianapolis, IN, USA
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
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18
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Laajala M, Zwaagstra M, Martikainen M, Nekoua MP, Benkahla M, Sane F, Gervais E, Campagnola G, Honkimaa A, Sioofy-Khojine AB, Hyöty H, Ojha R, Bailliot M, Balistreri G, Peersen O, Hober D, Van Kuppeveld F, Marjomäki V. Vemurafenib Inhibits Acute and Chronic Enterovirus Infection by Affecting Cellular Kinase Phosphatidylinositol 4-Kinase Type IIIβ. Microbiol Spectr 2023; 11:e0055223. [PMID: 37436162 PMCID: PMC10433971 DOI: 10.1128/spectrum.00552-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 06/14/2023] [Indexed: 07/13/2023] Open
Abstract
Enteroviruses are one of the most abundant viruses causing mild to serious acute infections in humans and also contributing to chronic diseases like type 1 diabetes. Presently, there are no approved antiviral drugs against enteroviruses. Here, we studied the potency of vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAFV600E mutant-related melanoma, as an antiviral against enteroviruses. We showed that vemurafenib prevented enterovirus translation and replication at low micromolar dosage in an RAF/MEK/ERK-independent manner. Vemurafenib was effective against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect was related to a cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevented infection efficiently in acute cell models, eradicated infection in a chronic cell model, and lowered virus amounts in pancreas and heart in an acute mouse model. Altogether, instead of acting through the RAF/MEK/ERK pathway, vemurafenib affects the cellular PI4KB and, hence, enterovirus replication, opening new possibilities to evaluate further the potential of vemurafenib as a repurposed drug in clinical care. IMPORTANCE Despite the prevalence and medical threat of enteroviruses, presently, there are no antivirals against them. Here, we show that vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAFV600E mutant-related melanoma, prevents enterovirus translation and replication. Vemurafenib shows efficacy against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect acts through cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevents infection efficiently in acute cell models, eradicates infection in a chronic cell model, and lowers virus amounts in pancreas and heart in an acute mouse model. Our findings open new possibilities to develop drugs against enteroviruses and give hope for repurposing vemurafenib as an antiviral drug against enteroviruses.
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Affiliation(s)
- Mira Laajala
- Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Marleen Zwaagstra
- Section of Virology, Division of Infectious Diseases & Immunology, Department of Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands
| | - Mari Martikainen
- Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | | | - Mehdi Benkahla
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, Lille, France
| | - Famara Sane
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, Lille, France
| | - Emily Gervais
- Department of Biochemistry & Molecular Biology, Colorado State University, Fort Collins, Colorado, USA
| | - Grace Campagnola
- Department of Biochemistry & Molecular Biology, Colorado State University, Fort Collins, Colorado, USA
| | - Anni Honkimaa
- Department of Virology, Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland
| | - Amir-Babak Sioofy-Khojine
- Department of Virology, Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland
| | - Heikki Hyöty
- Department of Virology, Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
| | - Ravi Ojha
- Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Marie Bailliot
- Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Giuseppe Balistreri
- Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Olve Peersen
- Department of Biochemistry & Molecular Biology, Colorado State University, Fort Collins, Colorado, USA
| | - Didier Hober
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, Lille, France
| | - Frank Van Kuppeveld
- Section of Virology, Division of Infectious Diseases & Immunology, Department of Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands
| | - Varpu Marjomäki
- Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
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19
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Zhang M, Xu D, Liu Y, Wang X, Xu L, Gao N, Feng C, Guo W, Ma S. Screening of a new candidate coxsackievirus B1 vaccine strain based on its biological characteristics. Front Microbiol 2023; 14:1172349. [PMID: 37502400 PMCID: PMC10369069 DOI: 10.3389/fmicb.2023.1172349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/19/2023] [Indexed: 07/29/2023] Open
Abstract
Coxsackievirus B1 (CVB1) is one of the significant pathogens causing viral myocarditis, hand, foot, and mouth disease (HFMD), and aseptic meningitis, and it has been associated with type 1 diabetes (T1DM). No effective antiviral drugs against CVB1 infection or preventive vaccines are available. Due to the success of two inactivated vaccines against enterovirus 71 and poliovirus, an inactivated Vero cell-based CVB1 vaccine could be developed. In this study, we isolated a high-growth CVB1 virus strain KM7 in Vero cells and developed a Vero-adapted vaccine candidate strain KM7-X29 via three rounds of plaque purification and serial passages. The KM7-X29 strain was grouped into the GII sub-genotype, which belonged to the Chinese epidemic strain and grew to a titer of more than 107 CCID50/ml in Vero cells. The inactivated CVB1 vaccine produced by the KM7-X29 strain induced an effective neutralizing antibody response in BALB/c mice, and maternal antibodies were able to provide a 100% protective effect against lethal challenges with a CVB1 strain in suckling BALB/c mice. Thus, the KM7-X29 strain might be used as a new candidate coxsackievirus B1 vaccine strain. The neonatal murine model of CVB1 infection will contribute to the development of the CVB1 vaccine.
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Affiliation(s)
- Ming Zhang
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China
- Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Disease, Kunming, China
| | - Danhan Xu
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China
- Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Disease, Kunming, China
| | - Yuhan Liu
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China
- Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Disease, Kunming, China
| | - Xiaohui Wang
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China
- Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Disease, Kunming, China
| | - Lilan Xu
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China
- Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Disease, Kunming, China
| | - Na Gao
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China
- Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Disease, Kunming, China
| | - Changzeng Feng
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China
- Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Disease, Kunming, China
| | - Wei Guo
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China
- Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Disease, Kunming, China
| | - Shaohui Ma
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China
- Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Disease, Kunming, China
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20
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Ingrosso DMF, Quarta MT, Quarta A, Chiarelli F. Prevention of Type 1 Diabetes in Children: A Worthy Challenge? INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:5962. [PMID: 37297566 PMCID: PMC10252671 DOI: 10.3390/ijerph20115962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/19/2023] [Accepted: 05/21/2023] [Indexed: 06/12/2023]
Abstract
Nowadays, the development of new immuno-therapeutic drugs has made it possible to alter the course of many autoimmune diseases. Type 1 diabetes is a chronic disease with a progressive dependence on exogenous insulin administration. The ability to intercept individuals at high risk of developing type 1 diabetes is the first step toward the development of therapies that can delay the process of β-cell destruction, thus permitting a better glycemic control and reducing the incidence of ketoacidosis. The knowledge of the main pathogenetic mechanisms underlying the three stages of the disease may be helpful to identify the best immune therapeutic approach. In this review, we aim to give an overview of the most important clinical trials conducted during the primary, secondary and tertiary phases of prevention.
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Affiliation(s)
| | | | | | - Francesco Chiarelli
- Department of Pediatrics, University of Chieti, Via dei Vestini, 66100 Chieti, Italy
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21
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Rajamanickam A, Venkataraman A, Kumar NP, Sasidaran R, Pandiarajan AN, Selvaraj N, Mittal R, Gowshika K, Putlibai S, Lakshan Raj S, Ramanan PV, Babu S. Alterations of adipokines, pancreatic hormones and incretins in acute and convalescent COVID-19 children. BMC Pediatr 2023; 23:156. [PMID: 37013538 PMCID: PMC10068212 DOI: 10.1186/s12887-023-03971-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 03/24/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes. METHODS We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19. RESULTS Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1β, IFNα, IFNβ, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1β, IFNα, IFNβ, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines. CONCLUSION Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.
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Affiliation(s)
- Anuradha Rajamanickam
- National Institutes of Health-National Institute for Research in Tuberculosis - International Center for Excellence in Research, Chennai, India.
| | | | | | - R Sasidaran
- Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India
| | - Arul Nancy Pandiarajan
- National Institutes of Health-National Institute for Research in Tuberculosis - International Center for Excellence in Research, Chennai, India
| | - Nandhini Selvaraj
- National Institutes of Health-National Institute for Research in Tuberculosis - International Center for Excellence in Research, Chennai, India
| | - Ruchi Mittal
- Sri Ramachandra Institute of Higher Education & Research, Chennai, India
| | - K Gowshika
- Sri Ramachandra Institute of Higher Education & Research, Chennai, India
| | | | - S Lakshan Raj
- Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India
| | | | - Subash Babu
- National Institutes of Health-National Institute for Research in Tuberculosis - International Center for Excellence in Research, Chennai, India
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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22
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Laajala M, Kalander K, Consalvi S, Amamuddy OS, Bishop ÖT, Biava M, Poce G, Marjomäki V. Antiviral Mechanisms of N-Phenyl Benzamides on Coxsackie Virus A9. Pharmaceutics 2023; 15:pharmaceutics15031028. [PMID: 36986888 PMCID: PMC10058015 DOI: 10.3390/pharmaceutics15031028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Enteroviruses are one of the most abundant groups of viruses infecting humans, and yet there are no approved antivirals against them. To find effective antiviral compounds against enterovirus B group viruses, an in-house chemical library was screened. The most effective compounds against Coxsackieviruses B3 (CVB3) and A9 (CVA9) were CL212 and CL213, two N-phenyl benzamides. Both compounds were more effective against CVA9 and CL213 gave a better EC50 value of 1 µM with high a specificity index of 140. Both drugs were most effective when incubated directly with viruses suggesting that they mainly bound to the virions. A real-time uncoating assay showed that the compounds stabilized the virions and radioactive sucrose gradient as well as TEM confirmed that the viruses stayed intact. A docking assay, taking into account larger areas around the 2-and 3-fold axes of CVA9 and CVB3, suggested that the hydrophobic pocket gives the strongest binding to CVA9 but revealed another binding site around the 3-fold axis which could contribute to the binding of the compounds. Together, our data support a direct antiviral mechanism against the virus capsid and suggest that the compounds bind to the hydrophobic pocket and 3-fold axis area resulting in the stabilization of the virion.
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Affiliation(s)
- Mira Laajala
- Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, 40014 Jyväskylä, Finland
| | - Kerttu Kalander
- Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, 40014 Jyväskylä, Finland
| | - Sara Consalvi
- Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy
| | - Olivier Sheik Amamuddy
- Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa
| | - Özlem Tastan Bishop
- Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa
| | - Mariangela Biava
- Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy
| | - Giovanna Poce
- Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy
| | - Varpu Marjomäki
- Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, 40014 Jyväskylä, Finland
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23
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Strachan E, Clemente-Casares X, Tsai S. Maternal provisions in type 1 diabetes: Evidence for both protective & pathogenic potential. Front Immunol 2023; 14:1146082. [PMID: 37033940 PMCID: PMC10073710 DOI: 10.3389/fimmu.2023.1146082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/08/2023] [Indexed: 04/11/2023] Open
Abstract
Maternal influences on the immune health and development of an infant begin in utero and continue well into the postnatal period, shaping and educating the child's maturing immune system. Two maternal provisions include early microbial colonizers to initiate microbiota establishment and the transfer of antibodies from mother to baby. Maternal antibodies are a result of a lifetime of antigenic experience, reflecting the infection history, health and environmental exposure of the mother. These same factors are strong influencers of the microbiota, inexorably linking the two. Together, these provisions help to educate the developing neonatal immune system and shape lymphocyte repertoires, establishing a role for external environmental influences even before birth. In the context of autoimmunity, the transfer of maternal autoantibodies has the potential to be harmful for the child, sometimes targeting tissues and cells with devastating consequences. Curiously, this does not seem to apply to maternal autoantibody transfer in type 1 diabetes (T1D). Moreover, despite the rising prevalence of the disease, little research has been conducted on the effects of maternal dysbiosis or antibody transfer from an affected mother to her offspring and thus their relevance to disease development in the offspring remains unclear. This review seeks to provide a thorough evaluation of the role of maternal microorganisms and antibodies within the context of T1D, exploring both their pathogenic and protective potential. Although a definitive understanding of their significance in infant T1D development remains elusive at present, we endeavor to present what has been learned with the goal of spurring further interest in this important and intriguing question.
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Affiliation(s)
| | | | - Sue Tsai
- Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB, Canada
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24
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Mone K, Lasrado N, Sur M, Reddy J. Vaccines against Group B Coxsackieviruses and Their Importance. Vaccines (Basel) 2023; 11:vaccines11020274. [PMID: 36851152 PMCID: PMC9961666 DOI: 10.3390/vaccines11020274] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
The group B coxsackieviruses (CVBs) exist in six serotypes (CVB1 to CVB6). Disease associations have been reported for most serotypes, and multiple serotypes can cause similar diseases. For example, CVB1, CVB3, and CVB5 are generally implicated in the causation of myocarditis, whereas CVB1 and CVB4 could accelerate the development of type 1 diabetes (T1D). Yet, no vaccines against these viruses are currently available. In this review, we have analyzed the attributes of experimentally tested vaccines and discussed their merits and demerits or limitations, as well as their impact in preventing infections, most importantly myocarditis and T1D.
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Affiliation(s)
- Kiruthiga Mone
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Ninaad Lasrado
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Meghna Sur
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Jay Reddy
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
- Correspondence: ; Tel.: +1-(402)-472-8541
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25
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Blum SI, Taylor JP, Barra JM, Burg AR, Shang Q, Qiu S, Shechter O, Hayes AR, Green TJ, Geurts AM, Chen YG, Tse HM. MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance. JCI Insight 2023; 8:e157929. [PMID: 36512407 PMCID: PMC9977297 DOI: 10.1172/jci.insight.157929] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5-dependent (MDA5-dependent) antiviral responses are linked with T1D development. Mutations within IFIH1, coding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing nonobese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice, which may be partly due to a concomitant increase in myeloid-derived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared with NOD mice. Whereas NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I IFNs, pancreatic infiltrating TNF+ macrophages, IFN-γ+CD4+ T cells, and perforin+CD8+ T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared with wild-type MDA5. Our results suggest that dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D.
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Affiliation(s)
- Samuel I. Blum
- Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jared P. Taylor
- Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jessie M. Barra
- Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Ashley R. Burg
- Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Qiao Shang
- Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Shihong Qiu
- Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Oren Shechter
- Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Aleah R. Hayes
- Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Todd J. Green
- Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | - Yi-Guang Chen
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Hubert M. Tse
- Department of Microbiology, Comprehensive Diabetes Center, The University of Alabama at Birmingham, Birmingham, Alabama, USA
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26
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A Monovalent Mt10-CVB3 Vaccine Prevents CVB4-Accelerated Type 1 Diabetes in NOD Mice. Vaccines (Basel) 2022; 11:vaccines11010076. [PMID: 36679922 PMCID: PMC9864234 DOI: 10.3390/vaccines11010076] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 12/27/2022] [Accepted: 12/27/2022] [Indexed: 12/30/2022] Open
Abstract
Enteroviruses, which include Coxsackieviruses, are a common cause of virus infections in humans, and multiple serotypes of the group B Coxsackievirus (CVB) can induce similar diseases. No vaccines are currently available to prevent CVB infections because developing serotype-specific vaccines is not practical. Thus, developing a vaccine that induces protective immune responses for multiple serotypes is desired. In that direction, we created a live-attenuated CVB3 vaccine virus, designated mutant (Mt)10, that offers protection against myocarditis and pancreatitis induced by CVB3 and CVB4 in disease-susceptible A/J mice. Here, we report that the Mt10 vaccine protected against CVB4-triggered type 1 diabetes (T1D) in non-obese diabetic (NOD) mice but the expected subsequent development of spontaneous T1D in these genetically predisposed NOD mice was not altered. We noted that Mt10 vaccine induced significant amounts of neutralizing antibodies, predominantly of the IgG2c isotype, and the virus was not detected in vaccine-challenged animals. Furthermore, monitoring blood glucose levels-and to a lesser extent, insulin antibodies-was found to be helpful in predicting vaccine responses. Taken together, our data suggest that the monovalent Mt10 vaccine has the potential to prevent infections caused by multiple CVB serotypes, as we have demonstrated in various pre-clinical models.
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27
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Libman I, Haynes A, Lyons S, Pradeep P, Rwagasor E, Tung JYL, Jefferies CA, Oram RA, Dabelea D, Craig ME. ISPAD Clinical Practice Consensus Guidelines 2022: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes 2022; 23:1160-1174. [PMID: 36537527 DOI: 10.1111/pedi.13454] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/09/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Ingrid Libman
- Division of Pediatric Endocrinology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Aveni Haynes
- Children's Diabetes Centre, Telethon Kids Institute, Perth, Western Australia, Australia
| | - Sarah Lyons
- Pediatric Diabetes and Endocrinology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Praveen Pradeep
- Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India
| | - Edson Rwagasor
- Rwanda Biomedical Center, Rwanda Ministry of Health, Kigali, Rwanda
| | - Joanna Yuet-Ling Tung
- Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong, Hong Kong
| | - Craig A Jefferies
- Starship Children's Health, Te Whatu Ora Health New Zealand, Auckland, New Zealand
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Dana Dabelea
- Department of Epidemiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Maria E Craig
- The Children's Hospital at Westmead, Sydney, New South Wales (NSW), Australia.,University of Sydney Children's Hospital Westmead Clinical School, Sydney, NEW, Australia.,Discipline of Paediatrics & Child Health, School of Clinical Medicine, University of NSW Medicine & Health, Sydney, NSW, Australia
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28
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Serum 25-hydroxyvitamin D and fatty acids in relation to the risk of microbial infections in children: The TRIGR Divia study. Clin Nutr 2022; 41:2729-2739. [PMID: 36368258 DOI: 10.1016/j.clnu.2022.10.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 10/03/2022] [Accepted: 10/23/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND & AIMS Nutrient status may affect the risk of microbial infections and play a role in modulating the immune response against such infections. The aim of this study was to determine whether serum 25-hydroxyvitamin D [25(OH)D] and serum fatty acids in infancy are associated with microbial infections by the age of 18 months. METHODS Altogether 576 newborn infants from Trial to Reduce IDDM in the Genetically at Risk (TRIGR) born between 2002 and 2007 were included. The concentration of 25(OH)D vitamin and proportions of 26 fatty acids (presented as % of total fatty acids) were analyzed in cord blood serum and in sera taken at 6, 12, and 18 months of age. The cord blood samples and mean of 6-18-month values were used as exposures. Infections were detected by screening IgG antibodies against 10 microbes using enzyme immunoassay and antibodies against 6 coxsackievirus B serotypes by plaque neutralization assay in serum samples taken at 18 months of age. RESULTS A higher proportion of n-3 polyunsaturated fatty acids (PUFAs) and especially long-chain n-3 PUFAs at birth and at the age of 6-18 months was associated with decreased risk of coxsackievirus B2 infection unadjusted and adjusted for region, case-control status, and maternal type 1 diabetes. Higher proportion of docosapentaenoic acid (DPA, 22:5 n-3) at birth was associated with a decreased risk of respiratory syncytial virus infection. 25(OH)D vitamin concentration was not consistently associated with the risk of infections. When only infected children were included docosahexaenoic acid (DHA, 22:6 n-3) and arachidonic acid (20:4 n-6) proportions were positively associated with IgG antibody levels against influenza A virus. 25(OH)D vitamin concentration showed an inverse association with rotavirus IgG levels among children with rotavirus seropositivity. CONCLUSIONS In young children with increased susceptibility to type 1 diabetes, long-chain n-3 PUFAs may influence the risk of viral infections and immune response against the infections. However, this association may depend on the type of virus suggesting virus-specific effects.
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29
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Stone VM, Utorova R, Butrym M, Sioofy-Khojine AB, Hankaniemi MM, Ringqvist EE, Blanter M, Parajuli A, Pincikova T, Fischler B, Karpati F, Hytönen VP, Hyöty H, Hjelte L, Flodström-Tullberg M. Coxsackievirus B infections are common in Cystic Fibrosis and experimental evidence supports protection by vaccination. iScience 2022; 25:105070. [PMID: 36157581 PMCID: PMC9490033 DOI: 10.1016/j.isci.2022.105070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 08/10/2022] [Accepted: 08/30/2022] [Indexed: 11/05/2022] Open
Abstract
Viral respiratory tract infections exacerbate airway disease and facilitate life-threatening bacterial colonization in cystic fibrosis (CF). Annual influenza vaccination is recommended and vaccines against other common respiratory viruses may further reduce pulmonary morbidity risk. Enteroviruses have been found in nasopharyngeal samples from CF patients experiencing pulmonary exacerbations. Using serology tests, we found that infections by a group of enteroviruses, Coxsackievirus Bs (CVBs), are prevalent in CF. We next showed that a CVB vaccine, currently undergoing clinical development, prevents infection and CVB-instigated lung damage in a murine model of CF. Finally, we demonstrate that individuals with CF have normal vaccine responses to a similar, commonly used enterovirus vaccine (inactivated poliovirus vaccine). Our study demonstrates that CVB infections are common in CF and provides experimental evidence indicating that CVB vaccines could be efficacious in the CF population. The role of CVB infections in contributing to pulmonary exacerbations in CF should be further studied.
CVB infections are common in CF A CVB vaccine prevents infection and tissue damage in a model of CF Most people with CF have robust antibody responses to a similar enterovirus vaccine
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Affiliation(s)
- Virginia M Stone
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden
| | - Renata Utorova
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden
| | - Marta Butrym
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden
| | | | - Minna M Hankaniemi
- Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland
| | - Emma E Ringqvist
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden
| | - Marfa Blanter
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden
| | - Anirudra Parajuli
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden
| | - Terezia Pincikova
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden.,Stockholm CF Center, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.,Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Department of Pediatrics, Karolinska University Hospital, 141 86 Stockholm, Sweden
| | - Björn Fischler
- Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Department of Pediatrics, Karolinska University Hospital, 141 86 Stockholm, Sweden
| | - Ferenc Karpati
- Stockholm CF Center, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.,Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Department of Pediatrics, Karolinska University Hospital, 141 86 Stockholm, Sweden
| | - Vesa P Hytönen
- Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland.,Fimlab Laboratories, 33520 Tampere, Finland
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland.,Fimlab Laboratories, 33520 Tampere, Finland
| | - Lena Hjelte
- Stockholm CF Center, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.,Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Department of Pediatrics, Karolinska University Hospital, 141 86 Stockholm, Sweden
| | - Malin Flodström-Tullberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital Huddinge, 141 52 Stockholm, Sweden
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30
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Maslinska M, Kostyra-Grabczak K. The role of virus infections in Sjögren’s syndrome. Front Immunol 2022; 13:823659. [PMID: 36148238 PMCID: PMC9488556 DOI: 10.3389/fimmu.2022.823659] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 08/09/2022] [Indexed: 11/26/2022] Open
Abstract
Primary Sjögren’s syndrome (pSS) is an autoimmune disease with a clinical picture of not only mainly exocrine gland involvement, with dryness symptoms, but also internal organ and systems involvement. The epithelial damage and releasing of antigens, which, in some circumstances, become autoantigens, underlay the pathogenesis of pSS. The activation of autoimmune processes in pSS leads to the hyperactivation of B cells with autoantibody production and other immunological phenomena such as hypergammaglobulinemia, production of cryoglobulins, or formation of extra-nodal lymphoid tissue. Among the risk factors for the development of this disease are viral infections, which themselves can activate autoimmune reactions and influence the host’s immune response. It is known that viruses, through various mechanisms, can influence the immune system and initiate autoimmune reactions. These mechanisms include molecular mimicry, bystander activation, production of superantigens—proteins encoded by viruses—or a programming to produce viral cytokines similar to host cytokines such as, e.g., interleukin-10. Of particular importance for pSS are viruses which not only, as expected, activate the interferon pathway but also play a particular role, directly or indirectly, in B cell activation or present tropism to organs also targeted in the course of pSS. This article is an attempt to present the current knowledge of the influence specific viruses have on the development and course of pSS.
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31
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Abstract
Diabetes is a chronic metabolic disease affecting an increasing number of people. Although diabetes has negative health outcomes for diagnosed individuals, a population at particular risk are pregnant women, as diabetes impacts not only a pregnant woman's health but that of her child. In this review, we cover the current knowledge and unanswered questions on diabetes affecting an expectant mother, focusing on maternal and fetal outcomes.
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Affiliation(s)
- Cecilia González Corona
- Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, One Baylor Plaza, Houston, TX 77030, USA
| | - Ronald J. Parchem
- Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, One Baylor Plaza, Houston, TX 77030, USA,Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
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Abstract
PURPOSE OF REVIEW Epidemiological research on type 1 diabetes (T1D) has traditionally focussed on the paediatric age group, but recent data in adults has confirmed it to be a disease of all ages with a wide clinical spectrum. We review the epidemiology and clinical features of T1D across the lifespan. RECENT FINDINGS While the peak incidence of T1D is still in early adolescence, T1D is now diagnosed more commonly in adulthood than childhood due to increasing recognition of adult-onset T1D and the length of the adult lifespan. It still follows the known geographic variations in incidence, being highest in Northern Europe and lowest in Asia. The onset of T1D in adulthood is usually less acute than in childhood and confers a lower, although still substantial, risk of complications and early mortality. Interventions to delay T1D onset are emerging and screening for those at risk at birth is increasingly available. Type 1 diabetes can develop at any age and may not present with ketosis or an immediate insulin requirement in adults. Macro- and microvascular complications are the greatest cause of excess morbidity and mortality in this population.
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Nekoua MP, Alidjinou EK, Hober D. Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol 2022; 18:503-516. [PMID: 35650334 PMCID: PMC9157043 DOI: 10.1038/s41574-022-00688-1] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/28/2022] [Indexed: 12/15/2022]
Abstract
Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.
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Affiliation(s)
| | | | - Didier Hober
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, Lille, France.
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Exposomic determinants of immune-mediated diseases. Environ Epidemiol 2022; 6:e212. [PMID: 35702504 PMCID: PMC9187189 DOI: 10.1097/ee9.0000000000000212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 05/04/2022] [Indexed: 11/25/2022] Open
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Savedchuk S, Raslan R, Nystrom S, Sparks MA. Emerging Viral Infections and the Potential Impact on Hypertension, Cardiovascular Disease, and Kidney Disease. Circ Res 2022; 130:1618-1641. [PMID: 35549373 DOI: 10.1161/circresaha.122.320873] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Viruses are ubiquitous in the environment and continue to have a profound impact on human health and disease. The COVID-19 pandemic has highlighted this with impressive morbidity and mortality affecting the world's population. Importantly, the link between viruses and hypertension, cardiovascular disease, and kidney disease has resulted in a renewed focus and attention on this potential relationship. The virus responsible for COVID-19, SARS-CoV-2, has a direct link to one of the major enzymatic regulatory systems connected to blood pressure control and hypertension pathogenesis, the renin-angiotensin system. This is because the entry point for SARS-CoV-2 is the ACE2 (angiotensin-converting enzyme 2) protein. ACE2 is one of the main enzymes responsible for dampening the primary effector peptide Ang II (angiotensin II), metabolizing it to Ang-(1-7). A myriad of clinical questions has since emerged and are covered in this review. Several other viruses have been linked to hypertension, cardiovascular disease, and kidney health. Importantly, patients with high-risk apolipoprotein L1 (APOL1) alleles are at risk for developing the kidney lesion of collapsing glomerulopathy after viral infection. This review will highlight several emerging viruses and their potential unique tropisms for the kidney and cardiovascular system. We focus on SARS-CoV-2 as this body of literature in regards to cardiovascular disease has advanced significantly since the COVID-19 pandemic.
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Affiliation(s)
- Solomiia Savedchuk
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC (S.S., S.N., M.A.S.)
| | - Rasha Raslan
- Internal Medicine, Virginia Commonwealth University, Richmond (R.R.)
| | - Sarah Nystrom
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC (S.S., S.N., M.A.S.)
| | - Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC (S.S., S.N., M.A.S.)
- Renal Section, Durham VA Health Care System, NC (M.A.S.)
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Qeadan F, Tingey B, Egbert J, Pezzolesi MG, Burge MR, Peterson KA, Honda T. The associations between COVID-19 diagnosis, type 1 diabetes, and the risk of diabetic ketoacidosis: A nationwide cohort from the US using the Cerner Real-World Data. PLoS One 2022; 17:e0266809. [PMID: 35439266 PMCID: PMC9017888 DOI: 10.1371/journal.pone.0266809] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 03/28/2022] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE To assess the risk of new-onset type 1 diabetes mellitus (T1D) diagnosis following COVID-19 diagnosis and the impact of COVID-19 diagnosis on the risk of diabetic ketoacidosis (DKA) in patients with prior T1D diagnosis. RESEARCH DESIGN AND METHODS Retrospective data consisting of 27,292,879 patients from the Cerner Real-World Data were used. Odds ratios, overall and stratified by demographic predictors, were calculated to assess associations between COVID-19 and T1D. Odds ratios from multivariable logistic regression models, adjusted for demographic and clinical predictors, were calculated to assess adjusted associations between COVID-19 and DKA. Multiple imputation with multivariate imputation by chained equations (MICE) was used to account for missing data. RESULTS The odds of developing new-onset T1D significantly increased in patients with COVID-19 diagnosis (OR: 1.42, 95% CI: 1.38, 1.46) compared to those without COVID-19. Risk varied by demographic groups, with the largest risk among pediatric patients ages 0-1 years (OR: 6.84, 95% CI: 2.75, 17.02) American Indian/Alaskan Natives (OR: 2.30, 95% CI: 1.86, 2.82), Asian or Pacific Islanders (OR: 2.01, 95% CI: 1.61, 2.53), older adult patients ages 51-65 years (OR: 1.77, 95% CI: 1.66, 1.88), those living in the Northeast (OR: 1.71, 95% CI: 1.61, 1.81), those living in the West (OR: 1.65, 95% CI: 1.56, 1.74), and Black patients (OR: 1.59, 95% CI: 1.47, 1.71). Among patients with diagnosed T1D at baseline (n = 55,359), 26.7% (n = 14,759) were diagnosed with COVID-19 over the study period. The odds of developing DKA for those with COVID-19 were significantly higher (OR 2.26, 95% CI: 2.04, 2.50) than those without COVID-19, and the largest risk was among patients with higher Elixhauser Comorbidity Index. CONCLUSIONS COVID-19 diagnosis is associated with significantly increased risk of new-onset T1D, and American Indian/Alaskan Native, Asian/Pacific Islander, and Black populations are disproportionately at risk. In patients with pre-existing T1D, the risk of developing DKA is significantly increased following COVID-19 diagnosis.
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Affiliation(s)
- Fares Qeadan
- Parkinson School of Health Sciences and Public Health, Loyola Univesity Chicago, Maywood, Illinois, United States of America
- * E-mail:
| | - Benjamin Tingey
- Parkinson School of Health Sciences and Public Health, Loyola Univesity Chicago, Maywood, Illinois, United States of America
| | - Jamie Egbert
- Parkinson School of Health Sciences and Public Health, Loyola Univesity Chicago, Maywood, Illinois, United States of America
| | - Marcus G. Pezzolesi
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Mark R. Burge
- Department of Internal Medicine, University of New Mexico Hospital, Albuquerque, New Mexico, United States of America
| | - Kathryn A. Peterson
- Department of Gastroenterology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Trenton Honda
- School of Clinical and Rehabilitation Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, United States of America
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Trier NH, Valdarnini N, Fanelli I, Rovero P, Hansen PR, Schafer-Nielsen C, Ciplys E, Slibinskas R, Pociot F, Friis T, Houen G. Peptide Antibody Reactivity to Homologous Regions in Glutamate Decarboxylase Isoforms and Coxsackievirus B4 P2C. Int J Mol Sci 2022; 23:ijms23084424. [PMID: 35457242 PMCID: PMC9028130 DOI: 10.3390/ijms23084424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/10/2022] [Accepted: 04/14/2022] [Indexed: 12/04/2022] Open
Abstract
Two isoforms of the glutamate decarboxylase (GAD) enzyme exist, GAD65 and GAD67, which are associated with type 1 diabetes (T1D) and stiff-person syndrome (SPS), respectively. Interestingly, it has been reported that T1D patients seldom develop SPS, whereas patients with SPS occasionally develop T1D. In addition, coxsackievirus B4 (CVB4) has previously been proposed to be involved in the onset of T1D through molecular mimicry. On this basis, we aimed to examine antibody cross-reactivity between a specific region of GAD65 and GAD67, which has high sequence homology to the nonstructural P2C protein of CVB4 to determine potential correlations at antibody level. Monoclonal peptide antibodies generated in mice specific for a region with high similarity in all three proteins were screened for reactivity along with human sera in immunoassays. In total, six antibodies were generated. Two of the antibodies reacted to both GAD isoforms. However, none of the antibodies were cross-reactive to CVB, suggesting that antibody cross-reactivity between GAD65 and CVB, and GAD67 and CVB may not contribute to the onset of T1D and SPS, respectively.
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Affiliation(s)
- Nicole Hartwig Trier
- Department of Neurology, Rigshospitalet Glostrup, Valdemar Hansens vej 13, 2600 Glostrup, Denmark
- Correspondence: (N.H.T.); (G.H.)
| | - Niccolo Valdarnini
- Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, Department of NeuroFarBa, University of Florence, Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Italy; (N.V.); (I.F.); (P.R.)
| | - Ilaria Fanelli
- Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, Department of NeuroFarBa, University of Florence, Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Italy; (N.V.); (I.F.); (P.R.)
| | - Paolo Rovero
- Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, Department of NeuroFarBa, University of Florence, Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Italy; (N.V.); (I.F.); (P.R.)
| | - Paul Robert Hansen
- Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark;
| | | | - Evaldas Ciplys
- Life Sciences Center, Institute of Biotechnology, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, Lithuania; (E.C.); (R.S.)
| | - Rimantas Slibinskas
- Life Sciences Center, Institute of Biotechnology, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, Lithuania; (E.C.); (R.S.)
| | - Flemming Pociot
- Steno Diabetes Center, Borgmester Ib Juuls Vej 83, 2730 Hellerup, Denmark;
| | - Tina Friis
- Department of Autoimmunity and Biomarkers, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark;
| | - Gunnar Houen
- Department of Neurology, Rigshospitalet Glostrup, Valdemar Hansens vej 13, 2600 Glostrup, Denmark
- Department Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark
- Correspondence: (N.H.T.); (G.H.)
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Buchacher T, Honkimaa A, Välikangas T, Lietzén N, Hirvonen MK, Laiho JE, Sioofy-Khojine AB, Eskelinen EL, Hyöty H, Elo LL, Lahesmaa R. Persistent coxsackievirus B1 infection triggers extensive changes in the transcriptome of human pancreatic ductal cells. iScience 2022; 25:103653. [PMID: 35024587 PMCID: PMC8728469 DOI: 10.1016/j.isci.2021.103653] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/02/2021] [Accepted: 12/15/2021] [Indexed: 02/07/2023] Open
Abstract
Enteroviruses, particularly the group B coxsackieviruses (CVBs), have been associated with the development of type 1 diabetes. Several CVB serotypes establish chronic infections in human cells in vivo and in vitro. However, the mechanisms leading to enterovirus persistency and, possibly, beta cell autoimmunity are not fully understood. We established a carrier-state-type persistent infection model in human pancreatic cell line PANC-1 using two distinct CVB1 strains and profiled the infection-induced changes in cellular transcriptome. In the current study, we observed clear changes in the gene expression of factors associated with the pancreatic microenvironment, the secretory pathway, and lysosomal biogenesis during persistent CVB1 infections. Moreover, we found that the antiviral response pathways were activated differently by the two CVB1 strains. Overall, our study reveals extensive transcriptional responses in persistently CVB1-infected pancreatic cells with strong opposite but also common changes between the two strains.
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Affiliation(s)
- Tanja Buchacher
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Anni Honkimaa
- Faculty of Medicine and Health Technology, Tampere University, Tampere FI-33014, Finland
| | - Tommi Välikangas
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Niina Lietzén
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland
| | - M. Karoliina Hirvonen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Jutta E. Laiho
- Faculty of Medicine and Health Technology, Tampere University, Tampere FI-33014, Finland
| | | | | | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere FI-33014, Finland
- Fimlab Laboratories, Pirkanmaa Hospital District, Tampere FI-33520, Finland
| | - Laura L. Elo
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku FI-20014, Finland
| | - Riitta Lahesmaa
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
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Välikangas T, Lietzén N, Jaakkola MK, Krogvold L, Eike MC, Kallionpää H, Tuomela S, Mathews C, Gerling IC, Oikarinen S, Hyöty H, Dahl-Jorgensen K, Elo LL, Lahesmaa R. Pancreas Whole Tissue Transcriptomics Highlights the Role of the Exocrine Pancreas in Patients With Recently Diagnosed Type 1 Diabetes. Front Endocrinol (Lausanne) 2022; 13:861985. [PMID: 35498413 PMCID: PMC9044038 DOI: 10.3389/fendo.2022.861985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/09/2022] [Indexed: 11/16/2022] Open
Abstract
Although type 1 diabetes (T1D) is primarily a disease of the pancreatic beta-cells, understanding of the disease-associated alterations in the whole pancreas could be important for the improved treatment or the prevention of the disease. We have characterized the whole-pancreas gene expression of patients with recently diagnosed T1D from the Diabetes Virus Detection (DiViD) study and non-diabetic controls. Furthermore, another parallel dataset of the whole pancreas and an additional dataset from the laser-captured pancreatic islets of the DiViD patients and non-diabetic organ donors were analyzed together with the original dataset to confirm the results and to get further insights into the potential disease-associated differences between the exocrine and the endocrine pancreas. First, higher expression of the core acinar cell genes, encoding for digestive enzymes, was detected in the whole pancreas of the DiViD patients when compared to non-diabetic controls. Second, In the pancreatic islets, upregulation of immune and inflammation related genes was observed in the DiViD patients when compared to non-diabetic controls, in line with earlier publications, while an opposite trend was observed for several immune and inflammation related genes at the whole pancreas tissue level. Third, strong downregulation of the regenerating gene family (REG) genes, linked to pancreatic islet growth and regeneration, was observed in the exocrine acinar cell dominated whole-pancreas data of the DiViD patients when compared with the non-diabetic controls. Fourth, analysis of unique features in the transcriptomes of each DiViD patient compared with the other DiViD patients, revealed elevated expression of central antiviral immune response genes in the whole-pancreas samples, but not in the pancreatic islets, of one DiViD patient. This difference in the extent of antiviral gene expression suggests different statuses of infection in the pancreas at the time of sampling between the DiViD patients, who were all enterovirus VP1+ in the islets by immunohistochemistry based on earlier studies. The observed features, indicating differences in the function, status and interplay between the exocrine and the endocrine pancreas of recent onset T1D patients, highlight the importance of studying both compartments for better understanding of the molecular mechanisms of T1D.
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Affiliation(s)
- Tommi Välikangas
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Niina Lietzén
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Maria K. Jaakkola
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Department of Mathematics and Statistics, University of Turku, Turku, Finland
| | - Lars Krogvold
- Pediatric Department, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Dentistry, Faculty of Dentistry, University of Oslo, Oslo, Norway
| | - Morten C. Eike
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Henna Kallionpää
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Soile Tuomela
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Clayton Mathews
- Department of Pathology, University of Florida, Gainesville, FL, United States
| | - Ivan C. Gerling
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Sami Oikarinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
| | - Knut Dahl-Jorgensen
- Pediatric Department, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Laura L. Elo
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
- *Correspondence: Riitta Lahesmaa, ; Laura L. Elo,
| | - Riitta Lahesmaa
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
- *Correspondence: Riitta Lahesmaa, ; Laura L. Elo,
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40
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Houeiss P, Luce S, Boitard C. Environmental Triggering of Type 1 Diabetes Autoimmunity. Front Endocrinol (Lausanne) 2022; 13:933965. [PMID: 35937815 PMCID: PMC9353023 DOI: 10.3389/fendo.2022.933965] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/20/2022] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic islet β cells are destroyed by immune cells, ultimately leading to overt diabetes. The progressive increase in T1D incidence over the years points to the role of environmental factors in triggering or accelerating the disease process which develops on a highly multigenic susceptibility background. Evidence that environmental factors induce T1D has mostly been obtained in animal models. In the human, associations between viruses, dietary habits or changes in the microbiota and the development of islet cell autoantibodies or overt diabetes have been reported. So far, prediction of T1D development is mostly based on autoantibody detection. Future work should focus on identifying a causality between the different environmental risk factors and T1D development to improve prediction scores. This should allow developing preventive strategies to limit the T1D burden in the future.
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Affiliation(s)
- Pamela Houeiss
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Sandrine Luce
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Christian Boitard
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
- *Correspondence: Christian Boitard,
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41
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Stone VM, Butrym M, Hankaniemi MM, Sioofy-Khojine AB, Hytönen VP, Hyöty H, Flodström-Tullberg M. Coxsackievirus B Vaccines Prevent Infection-Accelerated Diabetes in NOD Mice and Have No Disease-Inducing Effect. Diabetes 2021; 70:2871-2878. [PMID: 34497136 PMCID: PMC8660981 DOI: 10.2337/db21-0193] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 08/30/2021] [Indexed: 01/11/2023]
Abstract
Enteroviruses, including the Coxsackievirus Bs (CVB), have been implicated as causal agents in human type 1 diabetes. Immunization of at-risk individuals with a CVB vaccine provides an attractive strategy for elucidating the role of CVBs in the disease etiology. Previously, we have shown that an inactivated whole-virus vaccine covering all CVB serotypes (CVB1-6) is safe to administer and highly immunogenic in preclinical models, including nonhuman primates. Before initiating clinical trials with this type of vaccine, it was also important to address 1) whether the vaccine itself induces adverse immune reactions, including accelerating diabetes onset in a diabetes-prone host, and 2) whether the vaccine can prevent CVB-induced diabetes in a well-established disease model. Here, we present results from studies in which female NOD mice were left untreated, mock-vaccinated, or vaccinated with CVB1-6 vaccine and monitored for insulitis occurrence or diabetes development. We demonstrate that vaccination induces virus-neutralizing antibodies without altering insulitis scores or the onset of diabetes. We also show that NOD mice vaccinated with a CVB1 vaccine are protected from CVB-induced accelerated disease onset. Taken together, these studies show that CVB vaccines do not alter islet inflammation or accelerate disease progression in an animal model that spontaneously develops autoimmune type 1 diabetes. However, they can prevent CVB-mediated disease progression in the same model.
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Affiliation(s)
- Virginia M Stone
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Marta Butrym
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Minna M Hankaniemi
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | | | - Vesa P Hytönen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
| | - Malin Flodström-Tullberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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42
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Mt10-CVB3 Vaccine Virus Protects against CVB4 Infection by Inducing Cross-Reactive, Antigen-Specific Immune Responses. Microorganisms 2021; 9:microorganisms9112323. [PMID: 34835449 PMCID: PMC8622534 DOI: 10.3390/microorganisms9112323] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/05/2021] [Accepted: 11/06/2021] [Indexed: 12/29/2022] Open
Abstract
Group B coxsackieviruses (CVB) containing six serotypes, B1–B6, affect various organs, and multiple serotypes can induce similar diseases such as myocarditis and pancreatitis. Yet, no vaccines are currently available to prevent these infections. Translationally, the derivation of vaccines that offer protection against multiple serotypes is highly desired. In that direction, we recently reported the generation of an attenuated strain of CVB3, termed Mt10, which completely protects against both myocarditis and pancreatitis induced by the homologous wild-type CVB3 strain. Here, we report that the Mt10 vaccine can induce cross-protection against multiple CVB serotypes as demonstrated with CVB4. We note that the Mt10 vaccine could induce cross-reactive neutralizing antibodies (nABs) against both CVB1 and CVB4. In challenge studies with CVB4, the efficacy of the Mt10 vaccine was found to be 92%, as determined by histological evaluation of the heart and pancreas. Antibody responses induced in Mt10/CVB4 challenged animals indicated the persistence of cross-reactive nABs against CVB1, CVB3, and CVB4. Evaluation of antigen-specific immune responses revealed viral protein 1 (VP1)-reactive antibodies, predominantly IgG2a, IgG2b, IgG3, and IgG1. Similarly, by using major histocompatibility complex class II tetramers, we noted induction of VP1-specific CD4 T cells capable of producing multiple T cell cytokines, with interferon-γ being predominant. Finally, none of the vaccine recipients challenged with CVB4 revealed the presence of viral nucleic acid in the heart or pancreas. Taken together, our data suggest that the Mt10 vaccine can prevent infections caused by multiple CVB serotypes, paving the way for the development of monovalent CVB vaccines to prevent heart and pancreatic diseases of enteroviral origin.
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Palmu T, Lehtonen J, Korhonen L, Virtanen SM, Niemelä O, Toppari J, Ilonen J, Veijola R, Knip M, Laitinen OH, Lönnrot M, Hyöty H. Association of different enteroviruses with atopy and allergic diseases in early childhood. Pediatr Allergy Immunol 2021; 32:1629-1636. [PMID: 34219290 DOI: 10.1111/pai.13577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/24/2021] [Accepted: 05/31/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Enterovirus (EV) infections, being among the most prevalent viruses worldwide, have been associated with reduced risk of allergic diseases. We sought to determine the association between EVs and allergic sensitization and disease in early childhood. METHODS The study was carried out in a nested case-control setting within a prospective birth cohort in Finland. We included 138 case children who had specific IgE (s-IgE) sensitization at the age of 5 years and 138 control children without s-IgE sensitization. Allergic disease was recorded at study visits and identified with the ISAAC questionnaire. We screened for the presence of serotype-specific antibodies against 41 EVs at 1-5 years of age and assessed their association with allergic sensitization and disease. RESULTS The overall number of EV infections did not differ between s-IgE-sensitized children and non-sensitized control children. However, there was a tendency of case children with an allergic disease having less EV infections than their controls. This observation was statistically significant for species A EVs in case children with atopic dermatitis vs. control children: OR 0.6 (95% CI 0.36-0.99), p = .048. CONCLUSION This study supports the evidence that EV exposure and development of allergic disease are inversely associated. Interestingly, the inverse association was not observed for bare atopic IgE sensitization, but for IgE sensitization coupled with clinical atopic disease. This suggests that environmental factors influencing IgE sensitization may differ from those influencing progression to clinical allergic disease.
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Affiliation(s)
- Tiina Palmu
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Department of Dermatology and Allergology, The Hospital District of South Ostrobothnia, Seinäjoki, Finland
| | - Jussi Lehtonen
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Laura Korhonen
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Department of Dermatology, Tampere University Hospital, Tampere, Finland
| | - Suvi M Virtanen
- Health and Well-Being Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland.,Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland.,Tampere University Hospital, Research, Development and Innovation Center, Tampere, Finland.,Center for Child Health Research, Tampere University and Tampere University Hospital, Tampere, Finland
| | - Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and Tampere University, Seinäjoki/Tampere, Finland
| | - Jorma Toppari
- Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland.,Department of Pediatrics, Turku University Hospital, Turku, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Riitta Veijola
- Department of Pediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Mikael Knip
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Olli H Laitinen
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Maria Lönnrot
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Department of Dermatology, Tampere University Hospital, Tampere, Finland
| | - Heikki Hyöty
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
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Oikarinen S, Krogvold L, Edwin B, Buanes T, Korsgren O, Laiho JE, Oikarinen M, Ludvigsson J, Skog O, Anagandula M, Frisk G, Hyöty H, Dahl-Jørgensen K. Characterisation of enterovirus RNA detected in the pancreas and other specimens of live patients with newly diagnosed type 1 diabetes in the DiViD study. Diabetologia 2021; 64:2491-2501. [PMID: 34390364 PMCID: PMC8494699 DOI: 10.1007/s00125-021-05525-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/22/2021] [Indexed: 02/05/2023]
Abstract
AIMS/HYPOTHESIS The Diabetes Virus Detection (DiViD) study is the first study to laparoscopically collect pancreatic tissue and purified pancreatic islets together with duodenal mucosa, serum, peripheral blood mononuclear cells (PBMCs) and stools from six live adult patients (age 24-35 years) with newly diagnosed type 1 diabetes. The presence of enterovirus (EV) in the pancreatic islets of these patients has previously been reported. METHODS In the present study we used reverse transcription quantitative real-time PCR (RT-qPCR) and sequencing to characterise EV genomes present in different tissues to understand the nature of infection in these individuals. RESULTS All six patients were found to be EV-positive by RT-qPCR in at least one of the tested sample types. Four patients were EV-positive in purified islet culture medium, three in PBMCs, one in duodenal biopsy and two in stool, while serum was EV-negative in all individuals. Sequencing the 5' untranslated region of these EVs suggested that all but one belonged to enterovirus B species. One patient was EV-positive in all these sample types except for serum. Sequence analysis revealed that the virus strain present in the isolated islets of this patient was different from the strain found in other sample types. None of the islet-resident viruses could be isolated using EV-permissive cell lines. CONCLUSIONS/INTERPRETATION EV RNA can be frequently detected in various tissues of patients with type 1 diabetes. At least in some patients, the EV strain in the pancreatic islets may represent a slowly replicating persisting virus.
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Affiliation(s)
- Sami Oikarinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
| | - Lars Krogvold
- Paediatric Department, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Bjørn Edwin
- Paediatric Department, Oslo University Hospital, Oslo, Norway
- The Intervention Centre, Department of HPB Surgery, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Trond Buanes
- Paediatric Department, Oslo University Hospital, Oslo, Norway
- Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo University Hospital, Oslo, Norway
- Division of Cancer, Surgery and Transplantation, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Jutta E Laiho
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Maarit Oikarinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Johnny Ludvigsson
- Crown Princess Victoria Children's Hospital and Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Oskar Skog
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Mahesh Anagandula
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Gun Frisk
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
| | - Knut Dahl-Jørgensen
- Paediatric Department, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
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Abstract
This article summarizes clinical observations and management strategies in pediatric type 1 diabetes (T1D) during the coronavirus disease 2019 (COVID-19) pandemic. Despite initial fears that children with diabetes would, similar to adults with diabetes, be at risk for severe COVID-19, most pediatric patients with a history of T1D who developed COVID-19 had mild disease or were asymptomatic similar to their peers without diabetes. The article also summarizes the use of telemedicine to provide ongoing care for pediatric patients with T1D during the COVID-19 pandemic. Finally, the article highlights important lessons learned about management of pediatric diabetes during the COVID-19 pandemic.
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Faulkner CL, Luo YX, Isaacs S, Rawlinson WD, Craig ME, Kim KW. The virome in early life and childhood and development of islet autoimmunity and type 1 diabetes: A systematic review and meta-analysis of observational studies. Rev Med Virol 2021; 31:1-14. [PMID: 33378601 PMCID: PMC8518965 DOI: 10.1002/rmv.2209] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 12/15/2022]
Abstract
Viruses are postulated as primary candidate triggers of islet autoimmunity (IA) and type 1 diabetes (T1D), based on considerable epidemiological and experimental evidence. Recent studies have investigated the association between all viruses (the 'virome') and IA/T1D using metagenomic next-generation sequencing (mNGS). Current associations between the early life virome and the development of IA/T1D were analysed in a systematic review and meta-analysis of human observational studies from Medline and EMBASE (published 2000-June 2020), without language restriction. Inclusion criteria were as follows: cohort and case-control studies examining the virome using mNGS in clinical specimens of children ≤18 years who developed IA/T1D. The National Health and Medical Research Council level of evidence scale and Newcastle-Ottawa scale were used for study appraisal. Meta-analysis for exposure to specific viruses was performed using random-effects models, and the strength of association was measured using odds ratios (ORs) and 95% confidence intervals (CIs). Eligible studies (one case-control, nine nested case-control) included 1,425 participants (695 cases, 730 controls) and examined IA (n = 1,023) or T1D (n = 402). Meta-analysis identified small but significant associations between IA and number of stool samples positive for all enteroviruses (OR 1.14, 95% CI 1.00-1.29, p = 0.05; heterogeneity χ2 = 1.51, p = 0.68, I2 = 0%), consecutive positivity for enteroviruses (1.55, 1.09-2.20, p = 0.01; χ2 = 0.19, p = 0.91, I2 = 0%) and number of stool samples positive specifically for enterovirus B (1.20, 1.01-1.42, p = 0.04; χ2 = 0.03, p = 0.86, I2 = 0%). Virome analyses to date have demonstrated associations between enteroviruses and IA that may be clinically significant. However, larger prospective mNGS studies with more frequent sampling and follow-up from pregnancy are required to further elucidate associations between early virus exposure and IA/T1D.
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Affiliation(s)
- Clare L. Faulkner
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
| | - Yi Xuan Luo
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
| | - Sonia Isaacs
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
| | - William D. Rawlinson
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
- School of Medical SciencesUniversity of New South WalesSydneyNew South WalesAustralia
- Faculty of ScienceSchool of Biotechnology and Biomolecular SciencesUniversity of New South WalesSydneyNew South WalesAustralia
| | - Maria E. Craig
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
- Institute of Endocrinology and DiabetesChildren's Hospital at WestmeadSydneyNew South WalesAustralia
- Discipline of Child and Adolescent HealthUniversity of SydneySydneyNew South WalesAustralia
| | - Ki Wook Kim
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
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Secretory Carrier Membrane Protein 3 Interacts with 3A Viral Protein of Enterovirus and Participates in Viral Replication. Microbiol Spectr 2021; 9:e0047521. [PMID: 34378951 PMCID: PMC8552740 DOI: 10.1128/spectrum.00475-21] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Picornaviruses are a diverse and major cause of human disease, and their genomes replicate with intracellular membranes. The functionality of these replication organelles depends on the activities of both viral nonstructural proteins and co-opted host proteins. The mechanism by which viral-host interactions generate viral replication organelles and regulate viral RNA synthesis is unclear. To elucidate this mechanism, enterovirus A71 (EV-A71) was used here as a virus model to investigate how these replication organelles are formed and to identify the cellular components that are critical in this process. An immunoprecipitation assay was combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to identify 172 cellular proteins and four viral proteins associating with viral 3A protein. Secretory carrier membrane protein 3 (SCAMP3) was one of the host proteins we selected for further investigation. Here, we demonstrate by immunoprecipitation assay that SCAMP3 associates with 3A protein and colocalizes with 3A protein during virus infection. SCAMP3 knockdown or knockout in infected cells decreases synthesis of EV-A71 viral RNA, viral proteins, and viral growth. Furthermore, the viral 3A protein associates with SCAMP3 and phosphatidylinositol-4-kinase type III β (PI4KIIIβ) as shown by immunoprecipitation assay and colocalizes to the replication complex. Upon infection of cells with a SCAMP3 knockout construct, PI4KIIIβ and phosphatidylinositol-4-phosphate (PI4P) colocalization with EV-A71 3A protein decreases; viral RNA synthesis also decreases. SCAMP3 is also involved in the extracellular signal-regulated kinase (ERK) signaling pathway to regulate viral replication. The 3A and SCAMP3 interaction is also important for the replication of coxsackievirus B3 (CVB3). SCAMP3 also associates with 3A protein of CVB3 and enhances viral replication but does not regulate dengue virus 2 (DENV2) replication. Taken together, the results suggest that enterovirus 3A protein, SCAMP3, PI4KIIIβ, and PI4P form a replication complex and positively regulate enterovirus replication. IMPORTANCE Virus-host interaction plays an important role in viral replication. 3A protein of enterovirus A71 (EV-A71) recruits other viral and host factors to form a replication complex, which is important for viral replication. In this investigation, we utilized immunoprecipitation combined with proteomics approaches to identify 3A-interacting factors. Our results demonstrate that secretory carrier membrane protein 3 (SCAMP3) is a novel host factor that associates with enterovirus 3A protein, phosphatidylinositol-4-kinase type III β (PI4KIIIβ), and phosphatidylinositol-4-phosphate (PI4P) to form a replication complex and positively regulates viral replication. SCAMP3 is also involved in the extracellular signal-regulated kinase (ERK) signaling pathway to regulate viral replication.
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Marjomäki V, Kalander K, Hellman M, Permi P. Enteroviruses and coronaviruses: similarities and therapeutic targets. Expert Opin Ther Targets 2021; 25:479-489. [PMID: 34253126 PMCID: PMC8330013 DOI: 10.1080/14728222.2021.1952985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Introduction: Enteroviruses are common viruses causing a huge number of acute and chronic infections and producing towering economic costs. Similarly, coronaviruses cause seasonal mild infections, epidemics, and even pandemics and can lead to severe respiratory symptoms. It is important to develop broadly acting antiviral molecules to efficiently tackle the infections caused by thes.Areas covered: This review illuminates the differences and similarities between enteroviruses and coronaviruses and examines the most appealing therapeutic targets to combat both virus groups. Publications of both virus groups and deposited structures discovered through PubMed to March 2021 for viral proteases have been evaluated.Expert opinion: The main protease of coronaviruses and enteroviruses share similarities in their structure and function. These proteases process their viral polyproteins and thus drugs that bind to the active site have potential to target both virus groups. It is important to develop drugs that target more evolutionarily conserved processes and proteins. Moreover, it is a wise strategy to concentrate on processes that are similar between several virus families.
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Affiliation(s)
- Varpu Marjomäki
- Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Kerttu Kalander
- Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Maarit Hellman
- Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Perttu Permi
- Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
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Shih WL, Tung YC, Chang LY, Fang CT, Tsai WY. Increased Incidence of Pediatric Type 1 Diabetes With Novel Association With Coxsackievirus A Species in Young Children but Declined Incidence in Adolescents in Taiwan. Diabetes Care 2021; 44:1579-1585. [PMID: 34083323 PMCID: PMC8323190 DOI: 10.2337/dc20-1092] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 04/24/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Type 1 diabetes (T1D) has been linked to enterovirus infection in small population-based epidemiological studies. We investigated the secular relationship of T1D incidence with enterovirus infection and enterovirus species using nationwide population-based analysis. RESEARCH DESIGN AND METHODS We accessed the National Health Insurance Research Database of Taiwan to identify T1D and enterovirus infection cases from 2001 to 2015. Enterovirus serotype isolation rates were obtained from the nationwide laboratory surveillance systems. Negative binomial regression models assessed the incidence trend, and extended Cox proportional hazards models analyzed the association of enterovirus infection with T1D incidence. Spearman correlation coefficients evaluated the correlation between T1D incidence and circulating enterovirus species. RESULTS T1D incidence rates in youth younger than 20 years were 6.30 and 5.02 per 100,000 person-years in 2001 and 2015 (P = 0.287), respectively. T1D incidence increased significantly in children aged 0-6 years (P < 0.001) but decreased in adolescents aged 13-19 years (P = 0.011). The T1D risk in children aged 0-6 years with enterovirus infection was significantly higher than that in noninfected subjects (hazard ratio 1.46; 95% CI 1.35-1.58; P < 0.001). Additionally, TID incidence in children aged 0-6 years was significantly correlated with the isolation rates of coxsackievirus A species (r = 0.60; P = 0.017), but no association was found beyond the age of 7. CONCLUSIONS We demonstrated that T1D incidence increased in children aged 0-6 years but decreased in adolescents aged 13-19 years in Taiwan. Enterovirus-infected subjects younger than 7 years had a higher risk of T1D than noninfected subjects.
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Affiliation(s)
- Wei-Liang Shih
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.,Infectious Diseases Research and Education Center, Ministry of Health and Welfare and National Taiwan University, Taipei, Taiwan
| | - Yi-Ching Tung
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Luan-Yin Chang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan .,Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chi-Tai Fang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Yu Tsai
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
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50
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Pearson JA, Wong FS, Wen L. Inflammasomes and Type 1 Diabetes. Front Immunol 2021; 12:686956. [PMID: 34177937 PMCID: PMC8219953 DOI: 10.3389/fimmu.2021.686956] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/17/2021] [Indexed: 01/10/2023] Open
Abstract
Microbiota have been identified as an important modulator of susceptibility in the development of Type 1 diabetes in both animal models and humans. Collectively these studies highlight the association of the microbiota composition with genetic risk, islet autoantibody development and modulation of the immune responses. However, the signaling pathways involved in mediating these changes are less well investigated, particularly in humans. Importantly, understanding the activation of signaling pathways in response to microbial stimulation is vital to enable further development of immunotherapeutics, which may enable enhanced tolerance to the microbiota or prevent the initiation of the autoimmune process. One such signaling pathway that has been poorly studied in the context of Type 1 diabetes is the role of the inflammasomes, which are multiprotein complexes that can initiate immune responses following detection of their microbial ligands. In this review, we discuss the roles of the inflammasomes in modulating Type 1 diabetes susceptibility, from genetic associations to the priming and activation of the inflammasomes. In addition, we also summarize the available inhibitors for therapeutically targeting the inflammasomes, which may be of future use in Type 1 diabetes.
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Affiliation(s)
- James Alexander Pearson
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - F Susan Wong
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Li Wen
- Section of Endocrinology, Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States
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