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Nicholas CA, Tensun FA, Evans SA, Toole KP, Prendergast JE, Broncucia H, Hesselberth JR, Gottlieb PA, Wells KL, Smith MJ. Activated polyreactive B cells are clonally expanded in autoantibody positive and patients with recent-onset type 1 diabetes. Cell Rep 2025; 44:115425. [PMID: 40117290 PMCID: PMC12068228 DOI: 10.1016/j.celrep.2025.115425] [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] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 01/21/2025] [Accepted: 02/21/2025] [Indexed: 03/23/2025] Open
Abstract
Autoreactive B cells play an important but ill-defined role in autoimmune type 1 diabetes (T1D). We isolated pancreatic islet antigen-reactive B cells from the peripheral blood of non-diabetic autoantibody-negative first-degree relatives, autoantibody-positive, and recent-onset T1D donors. Single-cell RNA sequencing analysis revealed that islet antigen-reactive B cells from autoantibody-positive and T1D donors had altered gene expression in pathways associated with B cell signaling and inflammation. Additionally, BCR sequencing uncovered a similar shift in islet antigen-reactive B cell repertoires among autoantibody-positive and T1D donors where greater clonal expansion was also observed. Notably, a substantial fraction of islet antigen-reactive B cells in autoantibody-positive and T1D donors appeared to be polyreactive, which was corroborated by analysis of recombinant monoclonal antibodies. These results expand our understanding of autoreactive B cell phenotypes during T1D and identify unique BCR repertoire changes that may serve as biomarkers for increased disease risk.
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Affiliation(s)
- Catherine A Nicholas
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Molecular Biology Graduate Program, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Fatima A Tensun
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Spencer A Evans
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Kevin P Toole
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Jessica E Prendergast
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Hali Broncucia
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Jay R Hesselberth
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Molecular Biology Graduate Program, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Peter A Gottlieb
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Kristen L Wells
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
| | - Mia J Smith
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
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Hansen MS, Pokharel P, Piganelli J, Sussel L. The Chicken or the Egg Dilemma: Understanding the Interplay between the Immune System and the β Cell in Type 1 Diabetes. Cold Spring Harb Perspect Med 2025; 15:a041591. [PMID: 38951031 PMCID: PMC11960692 DOI: 10.1101/cshperspect.a041591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
In this review, we explore the complex interplay between the immune system and pancreatic β cells in the context of type 1 diabetes (T1D). While T1D is predominantly considered a T-cell-mediated autoimmune disease, the inability of human leukocyte antigen (HLA)-risk alleles alone to explain disease development suggests a role for β cells in initiating and/or propagating disease. This review delves into the vulnerability of β cells, emphasizing their susceptibility to endoplasmic reticulum (ER) stress and protein modifications, which may give rise to neoantigens. Additionally, we discuss the role of viral infections as contributors to T1D onset, and of genetic factors with dual impacts on the immune system and β cells. A greater understanding of the interplay between environmental triggers, autoimmunity, and the β cell will not only lead to insight as to why the islet β cells are specifically targeted by the immune system in T1D but may also reveal potential novel therapeutic interventions.
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Affiliation(s)
- Maria Skjøtt Hansen
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
| | - Pravil Pokharel
- Division of Endocrinology Diabetes and Metabolism, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Jon Piganelli
- Division of Endocrinology Diabetes and Metabolism, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
| | - Lori Sussel
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
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Cheng X, Yang J, Wang Z, Zhou K, An X, Xu ZZ, Lu H. Modulating intestinal viruses: A potential avenue for improving metabolic diseases with unresolved challenges. Life Sci 2025; 361:123309. [PMID: 39674267 DOI: 10.1016/j.lfs.2024.123309] [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: 09/13/2024] [Revised: 11/29/2024] [Accepted: 12/11/2024] [Indexed: 12/16/2024]
Abstract
The gut microbiome affects the occurrence and development of metabolic diseases, with a significant amount of research focused on intestinal bacteria. As an important part of the gut microbiome, gut viruses were studied recently, particularly through fecal virome transplantation (FVT), revealing manipulating the gut virus could reverse overweight and glucose intolerance in mice. And human cohort studies found gut virome changed significantly in patients with metabolic disease. By summarizing those studies, we compared the research and analytical methods, as well as the similarities and differences in their results, and analyzed the reasons for these discrepancies. FVT provided potential value to improve metabolic diseases, but the mechanisms involved and the effect of FVT on humans should be investigated further. The potential methods of regulating intestinal virome composition and the possible mechanisms of intestinal virome changes affecting metabolic diseases were also discussed.
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Affiliation(s)
- Xiaoxiao Cheng
- Jiangxi Agricultural University, College of Bioscience and Bioengineering, Nanchang, PR China
| | - Jie Yang
- Jiangxi Agricultural University, College of Bioscience and Bioengineering, Nanchang, PR China
| | - Zhijie Wang
- Jiangxi Agricultural University, College of Bioscience and Bioengineering, Nanchang, PR China
| | - Kefan Zhou
- Jiangxi Agricultural University, College of Bioscience and Bioengineering, Nanchang, PR China
| | - Xuejiao An
- Jiangxi Agricultural University, College of Bioscience and Bioengineering, Nanchang, PR China
| | - Zhenjiang Zech Xu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, PR China
| | - Hui Lu
- Jiangxi Agricultural University, College of Bioscience and Bioengineering, Nanchang, PR China.
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Roy S, Pokharel P, Piganelli JD. Decoding the immune dance: Unraveling the interplay between beta cells and type 1 diabetes. Mol Metab 2024; 88:101998. [PMID: 39069156 PMCID: PMC11342121 DOI: 10.1016/j.molmet.2024.101998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 07/12/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is an autoimmune disease characterized by the specific destruction of insulin-producing beta cells in the pancreas by the immune system, including CD4 cells which orchestrate the attack and CD8 cells which directly destroy the beta cells, resulting in the loss of glucose homeostasis. SCOPE OF REVIEW This comprehensive document delves into the complex interplay between the immune system and beta cells, aiming to shed light on the mechanisms driving their destruction in T1D. Insights into the genetic predisposition, environmental triggers, and autoimmune responses provide a foundation for understanding the autoimmune attack on beta cells. From the role of viral infections as potential triggers to the inflammatory response of beta cells, an intricate puzzle starts to unfold. This exploration highlights the importance of beta cells in breaking immune tolerance and the factors contributing to their targeted destruction. Furthermore, it examines the potential role of autophagy and the impact of cytokine signaling on beta cell function and survival. MAJOR CONCLUSIONS This review collectively represents current research findings on T1D which offers valuable perspectives on novel therapeutic approaches for preserving beta cell mass, restoring immune tolerance, and ultimately preventing or halting the progression of T1D. By unraveling the complex dynamics between the immune system and beta cells, we inch closer to a comprehensive understanding of T1D pathogenesis, paving the way for more effective treatments and ultimately a cure.
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Affiliation(s)
- Saptarshi Roy
- Department of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States
| | - Pravil Pokharel
- Department of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States
| | - Jon D Piganelli
- Department of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States.
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Gay L, Desquiret-Dumas V, Nagot N, Rapenne C, Van de Perre P, Reynier P, Molès JP. Long-term persistence of mitochondrial dysfunctions after viral infections and antiviral therapies: A review of mechanisms involved. J Med Virol 2024; 96:e29886. [PMID: 39246064 DOI: 10.1002/jmv.29886] [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: 03/25/2024] [Revised: 07/26/2024] [Accepted: 08/13/2024] [Indexed: 09/10/2024]
Abstract
Mitochondria are vital for most cells' functions. Viruses hijack mitochondria machinery for misappropriation of energy supply or to bypass defense mechanisms. Many of these mitochondrial dysfunctions persist after recovery from treated or untreated viral infections, particularly when mitochondrial DNA is permanently damaged. Quantitative defects and structural rearrangements of mitochondrial DNA accumulate in post-mitotic tissues as recently reported long after SARS-CoV-2 or HIV infection, or following antiviral therapy. These observations are consistent with the "hit-and-run" concept proposed decades ago to explain viro-induced cell transformation and it could apply to delayed post-viral onsets of symptoms and advocate for complementary supportive care. Thus, according to this concept, following exposure to viruses or antiviral agents, mitochondrial damage could evolve into an autonomous clinical condition. It also establishes a pathogenic link between communicable and non-communicable chronic diseases.
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Affiliation(s)
- Laetitia Gay
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, Etablissement Français du Sang, University of Antilles, Montpellier, France
| | - Valérie Desquiret-Dumas
- Department of Biochemistry and Molecular Biology, University Hospital of Angers, Angers, France
- MITOVASC Research Unit, CNRS 6015, INSERM U1083, University of Angers, Angers, France
| | - Nicolas Nagot
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, Etablissement Français du Sang, University of Antilles, Montpellier, France
| | - Clara Rapenne
- Department of Biochemistry and Molecular Biology, University Hospital of Angers, Angers, France
- MITOVASC Research Unit, CNRS 6015, INSERM U1083, University of Angers, Angers, France
| | - Philippe Van de Perre
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, Etablissement Français du Sang, University of Antilles, Montpellier, France
| | - Pascal Reynier
- Department of Biochemistry and Molecular Biology, University Hospital of Angers, Angers, France
- MITOVASC Research Unit, CNRS 6015, INSERM U1083, University of Angers, Angers, France
| | - Jean-Pierre Molès
- Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, INSERM, Etablissement Français du Sang, University of Antilles, Montpellier, France
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Dwyer AJ, Shaheen ZR, Fife BT. Antigen-specific T cell responses in autoimmune diabetes. Front Immunol 2024; 15:1440045. [PMID: 39211046 PMCID: PMC11358097 DOI: 10.3389/fimmu.2024.1440045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Autoimmune diabetes is a disease characterized by the selective destruction of insulin-secreting β-cells of the endocrine pancreas by islet-reactive T cells. Autoimmune disease requires a complex interplay between host genetic factors and environmental triggers that promote the activation of such antigen-specific T lymphocyte responses. Given the critical involvement of self-reactive T lymphocyte in diabetes pathogenesis, understanding how these T lymphocyte populations contribute to disease is essential to develop targeted therapeutics. To this end, several key antigenic T lymphocyte epitopes have been identified and studied to understand their contributions to disease with the aim of developing effective treatment approaches for translation to the clinical setting. In this review, we discuss the role of pathogenic islet-specific T lymphocyte responses in autoimmune diabetes, the mechanisms and cell types governing autoantigen presentation, and therapeutic strategies targeting such T lymphocyte responses for the amelioration of disease.
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Affiliation(s)
- Alexander J. Dwyer
- Center for Immunology, Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Zachary R. Shaheen
- Center for Immunology, Department of Pediatrics, Pediatric Rheumatology, Allergy, & Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Brian T. Fife
- Center for Immunology, Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota Medical School, Minneapolis, MN, United States
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Jeremiah SS, Moin ASM, Butler AE. Virus-induced diabetes mellitus: revisiting infection etiology in light of SARS-CoV-2. Metabolism 2024; 156:155917. [PMID: 38642828 DOI: 10.1016/j.metabol.2024.155917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/14/2024] [Accepted: 04/14/2024] [Indexed: 04/22/2024]
Abstract
Diabetes mellitus (DM) is comprised of two predominant subtypes: type 1 diabetes mellitus (T1DM), accounting for approximately 5 % of cases worldwide and resulting from autoimmune destruction of insulin-producing β-cells, and type 2 (T2DM), accounting for approximately 95 % of cases globally and characterized by the inability of pancreatic β-cells to meet the demand for insulin due to a relative β-cell deficit in the setting of peripheral insulin resistance. Both types of DM involve derangement of glucose metabolism and are metabolic diseases generally considered to be initiated by a combination of genetic and environmental factors. Viruses have been reported to play a role as infectious etiological factors in the initiation of both types of DM in predisposed individuals. Among the reported viral infections causing DM in humans, the most studied include coxsackie B virus, cytomegalovirus and hepatitis C virus. The recent COVID-19 pandemic has highlighted the diabetogenic potential of SARS-CoV-2, rekindling interest in the field of virus-induced diabetes (VID). This review discusses the reported mechanisms of viral-induced DM, addressing emerging concepts in VID, as well as highlighting areas where knowledge is lacking, and further investigation is warranted.
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Affiliation(s)
| | - Abu Saleh Md Moin
- Royal College of Surgeons in Ireland - Medical University of Bahrain, Busaiteen, Kingdom of Bahrain.
| | - Alexandra E Butler
- Royal College of Surgeons in Ireland - Medical University of Bahrain, Busaiteen, Kingdom of Bahrain.
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Alves Abrantes JJP, Veríssimo de Azevedo JC, Fernandes FL, Duarte Almeida V, Custódio De Oliveira LA, Ferreira de Oliveira MT, Galvão De Araújo JM, Lanza DCF, Bezerra FL, Andrade VS, Araújo de Medeiros Fernandes TA, Fernandes JV. Viruses as a potential environmental trigger of type 1 diabetes mellitus (Review). Biomed Rep 2024; 20:81. [PMID: 38628629 PMCID: PMC11019645 DOI: 10.3892/br.2024.1770] [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: 06/14/2023] [Accepted: 09/07/2023] [Indexed: 04/19/2024] Open
Abstract
The etiopathogenesis of type 1 diabetes mellitus (T1DM) is a complex multifactorial process that involves an intricate network of genetic, epigenetic, immunological, and environmental factors. Despite the advances in recent years, some aspects of the mechanisms involved in triggering the disease are still unclear. Infections with certain viruses have been suggested as possible environmental triggers for the autoimmune process that leads to selective and progressive destruction of pancreatic β-cells and insufficiency of insulin production, which is its hallmark. In this review, advances in knowledge and evidence that suggest the participation of certain viruses in the mechanisms of disease initiation and progression are described. It has been accepted that environmental factors, including viruses, can initiate and possibly sustain, accelerate, or slow down the autoimmune process and consequently damage insulin-producing pancreatic β-cells. Although the role of these agents, especially human enteroviruses, has been exhaustively studied as the most likely triggers of the activation of autoimmunity that destroys pancreatic islets and leads to T1DM, certain doubts remain. Clinical epidemiological and experimental studies in humans and animals provide consistent and increasing evidence that persistent viral infections, especially with human enteroviruses and rotavirus infections, are associated with an increased risk of the disease in individuals genetically predisposed to autoimmunity.
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Affiliation(s)
| | | | - Fernando Liberalino Fernandes
- Department of Biomedical Sciences, Rio Grande do Norte State University, Mossoró, Rio Grande do Norte 59607-360, Brazil
| | - Valéria Duarte Almeida
- Department of Biomedical Sciences, Rio Grande do Norte State University, Mossoró, Rio Grande do Norte 59607-360, Brazil
| | | | | | - Josélio Maria Galvão De Araújo
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte 59078-970, Brazil
| | - Daniel Carlos Ferreira Lanza
- Laboratory of Applied Molecular Biology, Department of Biochemistry, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte 59078-970, Brazil
| | - Fabiana Lima Bezerra
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte 59078-970, Brazil
| | - Vania Sousa Andrade
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte 59078-970, Brazil
| | | | - José Veríssimo Fernandes
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte 59078-970, Brazil
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Janse van Rensburg M, Mans J, Mafuyeka RT, Strydom KA, Myburgh M, van Zyl WB. Diversity of enteroviruses in cerebrospinal fluid specimens collected from hospitalised patients in the private and public sector in South Africa. J Med Virol 2024; 96:e29514. [PMID: 38488486 DOI: 10.1002/jmv.29514] [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: 10/09/2023] [Revised: 02/13/2024] [Accepted: 02/26/2024] [Indexed: 03/19/2024]
Abstract
Enteroviruses cause a wide range of neurological illnesses such as encephalitis, meningitis, and acute flaccid paralysis. Two types of enteroviruses, echovirus E4 and E9, have recently been detected in South Africa and are known to be associated with meningitis and encephalitis. The objective of this study was to characterize enterovirus strains detected in cerebrospinal fluid specimens of hospitalized patients in the private and public sector to identify genotypes associated with meningitis and encephalitis. From January 2019 to June 2021 enterovirus positive nucleic acid samples were obtained from a private (n = 116) and a public sector (n = 101) laboratory. These enteroviruses were typed using a nested set of primers targeting the VP1 region of the enterovirus genome, followed by Sanger sequencing and BLASTn analysis. Forty-two percent (91/217) of the strains could be genotyped. Enterovirus B species was the major species detected in 95% (86/91) of the specimens, followed by species C in 3% (3/91) and species A in 2% (2/91) of the specimens. Echovirus E4 and E9 were the two major types identified in this study and were detected in 70% (64/91) and in 10% (9/91) of specimens, respectively. Echovirus E11 has previously been identified in sewage samples from South Africa, but this study is the first to report Echovirus E11 in cerebrospinal fluid specimens from South African patients. The genotypes identified during this study are known to be associated with encephalitis and meningitis. The predominant detection of echovirus E4 followed by E9 corresponds with other studies conducted in South Africa.
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Affiliation(s)
| | - Janet Mans
- Department of Medical Virology, University of Pretoria, Pretoria, South Africa
| | - Rendani T Mafuyeka
- Department of Medical Virology, University of Pretoria, Pretoria, South Africa
- National Health Laboratory Service, Tshwane Academic Division, Pretoria, South Africa
| | | | | | - Walda B van Zyl
- Department of Medical Virology, University of Pretoria, Pretoria, South Africa
- National Health Laboratory Service, Tshwane Academic Division, Pretoria, South Africa
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10
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Størdal K, Tapia G, Lund-Blix NA, Stene LC. Genotypes predisposing for celiac disease and autoimmune diabetes and risk of infections in early childhood. J Pediatr Gastroenterol Nutr 2024; 78:295-303. [PMID: 38374560 DOI: 10.1002/jpn3.12078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/28/2023] [Accepted: 11/28/2023] [Indexed: 02/21/2024]
Abstract
OBJECTIVES Infections in early childhood have been associated with risk of celiac disease (CD) and type 1 diabetes (T1D). We investigated whether this is driven by susceptibility genes for autoimmune disease by comparing infection frequency by genetic susceptibility variants for CD or T1D. METHODS We genotyped 373 controls and 384 children who developed CD or T1D in the population-based Norwegian Mother, Father and Child Cohort study (MoBa) study for human leukocyte antigen (HLA)-DQ, FUT2, SH2B3, and PTPN22, and calculated a weighted non-HLA genetic risk score (GRS) for CD and T1D based on over 40 SNPs. Parents reported infections in questionnaires when children were 6 and 18 months old. We used negative binomial regression to estimate incidence rate ratio (IRR) for infections by genotype. RESULTS HLA genotypes for CD and T1D or non-HLA GRS for T1D were not associated with infections. The non-HLA GRS for CD was associated with a nonsignificantly lower frequency of infections (aIRR: 0.95, 95% CI: 0.87-1.03 per weighted allele score), and significantly so when restricting to healthy controls (aIRR: 0.89, 0.81-0.99). Participants homozygous for rs601338(A;A) at FUT2, often referred to as nonsecretors, had a nonsignificantly lower risk of infections (aIRR: 0.91, 95% CI: 0.83-1.01). SH2B3 and PTPN22 genotypes were not associated with infections. The association between infections and risk of CD (OR: 1.15 per five infections) was strengthened after adjustment for HLA genotype and non-HLA GRS (OR: 1.24). CONCLUSIONS HLA variants and non-HLA GRS conferring susceptibility for CD were not associated with increased risk of infections in early childhood and is unlikely to drive the observed association between infections and risk of CD or T1D in many studies.
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Affiliation(s)
- Ketil Størdal
- Department of Pediatric Research, Faculty of Medicine, University of Oslo, Oslo, Norway
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - German Tapia
- Norwegian Institute of Public Health, Oslo, Norway
| | | | - Lars C Stene
- Norwegian Institute of Public Health, Oslo, Norway
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11
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Bhagchandani T, Nikita, Verma A, Tandon R. Exploring the Human Virome: Composition, Dynamics, and Implications for Health and Disease. Curr Microbiol 2023; 81:16. [PMID: 38006423 DOI: 10.1007/s00284-023-03537-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 10/24/2023] [Indexed: 11/27/2023]
Abstract
Humans are colonized by large number of microorganisms-bacteria, fungi, and viruses. The overall genome of entire viruses that either lives on or inside the human body makes up the human virome and is indeed an essential fraction of the human metagenome. Humans are constantly exposed to viruses as they are ubiquitously present on earth. The human virobiota encompasses eukaryotic viruses, bacteriophages, retroviruses, and even giant viruses. With the advent of Next-generation sequencing (NGS) and ongoing development of numerous bioinformatic softwares, identification and taxonomic characterization of viruses have become easier. The viruses are abundantly present in humans; these can be pathogenic or commensal. The viral communities occupy various niches in the human body. The viruses start colonizing the infant gut soon after birth in a stepwise fashion and the viral composition diversify according to their feeding habits. Various factors such as diet, age, medications, etc. influence and shape the human virome. The viruses interact with the host immune system and these interactions have beneficial or detrimental effects on their host. The virome composition and abundance change during the course of disease and these alterations impact the immune system. Hence, the virome population in healthy and disease conditions influences the human host in numerous ways. This review presents an overview of assembly and composition of the human virome in healthy asymptomatic individuals, changes in the virome profiles, and host-virome interactions in various disease states.
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Affiliation(s)
- Tannu Bhagchandani
- Laboratory of AIDS Research and Immunology, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Nikita
- Laboratory of AIDS Research and Immunology, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Anjali Verma
- Laboratory of AIDS Research and Immunology, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Ravi Tandon
- Laboratory of AIDS Research and Immunology, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
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12
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García E. Two putative glutamate decarboxylases of Streptococcus pneumoniae as possible antigens for the production of anti-GAD65 antibodies leading to type 1 diabetes mellitus. Int Microbiol 2023; 26:675-690. [PMID: 37154976 PMCID: PMC10165594 DOI: 10.1007/s10123-023-00364-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: 01/11/2023] [Revised: 04/13/2023] [Accepted: 04/21/2023] [Indexed: 05/10/2023]
Abstract
Type 1 diabetes mellitus (T1DM) has been increasing in prevalence in the last decades and has become a global burden. Autoantibodies against human glutamate decarboxylase (GAD65) are among the first to be detected at the onset of T1DM. Diverse viruses have been proposed to be involved in the triggering of T1DM because of molecular mimicry, i.e., similarity between parts of some viral proteins and one or more epitopes of GAD65. However, the possibility that bacterial proteins might also be responsible for GAD65 mimicry has been seldom investigated. To date, many genomes of Streptococcus pneumoniae (the pneumococcus), a prominent human pathogen particularly prevalent among children and the elderly, have been sequenced. A dataset of more than 9000 pneumococcal genomes was mined and two different (albeit related) genes (gadA and gadB), presumably encoding two glutamate decarboxylases similar to GAD65, were found. The various gadASpn alleles were present only in serotype 3 pneumococci belonging to the global lineage GPSC83, although some homologs have also been discovered in two subspecies of Streptococcus constellatus (pharyngis and viborgensis), an isolate of the group B streptococci, and several strains of Lactobacillus delbrueckii. Besides, gadBSpn alleles are present in > 10% of the isolates in our dataset and represent 16 GPSCs with 123 sequence types and 20 different serotypes. Sequence analyses indicated that gadA- and gadB-like genes have been mobilized among different bacteria either by prophage(s) or by integrative and conjugative element(s), respectively. Substantial similarities appear to exist between the putative pneumococcal glutamate decarboxylases and well-known epitopes of GAD65. In this sense, the use of broader pneumococcal conjugate vaccines such as PCV20 would prevent the majority of serotypes expressing those genes that might potentially contribute to T1DM. These results deserve upcoming studies on the possible involvement of S. pneumoniae in the etiopathogenesis and clinical onset of T1DM.
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Affiliation(s)
- Ernesto García
- Departamento de Biotecnología Microbiana y de Plantas, Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
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13
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Hu J, Ding J, Li X, Li J, Zheng T, Xie L, Li C, Tang Y, Guo K, Huang J, Liu S, Yan J, Peng W, Hou C, Wen L, Xu A, Zhou Z, Xiao Y. Distinct signatures of gut microbiota and metabolites in different types of diabetes: a population-based cross-sectional study. EClinicalMedicine 2023; 62:102132. [PMID: 37593224 PMCID: PMC10430172 DOI: 10.1016/j.eclinm.2023.102132] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 07/08/2023] [Accepted: 07/17/2023] [Indexed: 08/19/2023] Open
Abstract
BACKGROUND Patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) present intestinal disturbances. Recent epidemiological data have showed that, worldwide, over half of newly diagnosed T1D patients were adults. However, the gut microbial alterations in adult-onset T1D are unclear. We aimed to identify the signatures of gut microbiota and metabolites in patients with adult-onset T1D systematically, comparing with T2D patients and healthy controls (HCs). METHODS This study enrolled 218 subjects from February 2019 to April 2022 (discovery cohort: 36 HCs, 51 patients with adult-onset T1D and 56 patients with T2D; validation cohort: 28 HCs, 27 patients with adult-onset T1D and 20 patients with T2D). Gut microbial profiles of the study subjects were investigated by metagenomic sequencing, and their faecal and serum metabolites were measured with targeted metabolomics. The study was registered on ClinicalTrials.gov (NCT05252728). FINDINGS Patients with adult-onset T1D had significant differences in the composition of bacteria and their metabolites, characterized by notable depletion of short-chain fatty acid-producing bacteria, especially Eubacterium rectale. This was associated with a severe loss of phenolic acids and their derivatives, including gallic acid (associated with glucose metabolism) and 3,4-dihydroxyhydrocinnamic acid (linked with glucose metabolism and pancreatic beta cell autoimmunity). A predictive model based on six bacteria and six metabolites simultaneously discriminated adult-onset T1D from T2D and HCs with high accuracy. Interestingly, bacterial-viral or bacterial-fungal trans-kingdom relationships, especially positive correlations between bacteriophages and beneficial bacteria, were significantly reduced in adult-onset T1D compared to HCs. INTERPRETATION Adult-onset T1D patients exhibit unique changes in host-microbiota-metabolite interactions. Gut microbiota and metabolite-based algorithms could be used as additional tools for differential diagnosis of different types of diabetes and beyond. FUNDING National Key Research and Development Program of China, the National Natural Science Foundation of China.
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Affiliation(s)
- Jingyi Hu
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jin Ding
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xia Li
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jun Li
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
- School of Data Science, City University of Hong Kong, Hong Kong, China
| | - Tingting Zheng
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
| | - Lingxiang Xie
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Chenyu Li
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yingxin Tang
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Keyu Guo
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Juan Huang
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shanshan Liu
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jianru Yan
- Department of Endocrinology, The First People's Hospital of Pingjiang, Pingjiang, Hunan, China
| | - Weijun Peng
- Department of Integrated Traditional Chinese and Western Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Can Hou
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Li Wen
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
- Department of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Zhiguang Zhou
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yang Xiao
- National Clinical Research Centre for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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14
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Wu R, Mumtaz M, Maxwell AJ, Isaacs SR, Laiho JE, Rawlinson WD, Hyöty H, Craig ME, Kim KW. Respiratory infections and type 1 diabetes: Potential roles in pathogenesis. Rev Med Virol 2023; 33:e2429. [PMID: 36790804 PMCID: PMC10909571 DOI: 10.1002/rmv.2429] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/13/2023] [Accepted: 01/29/2023] [Indexed: 02/16/2023]
Abstract
Among the environmental factors associated with type 1 diabetes (T1D), viral infections of the gut and pancreas has been investigated most intensely, identifying enterovirus infections as the prime candidate trigger of islet autoimmunity (IA) and T1D development. However, the association between respiratory tract infections (RTI) and IA/T1D is comparatively less known. While there are significant amounts of epidemiological evidence supporting the role of respiratory infections in T1D, there remains a paucity of data characterising infectious agents at the molecular level. This gap in the literature precludes the identification of the specific infectious agents driving the association between RTI and T1D. Furthermore, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on the development of IA/T1D remains undeciphered. Here, we provide a comprehensive overview of the evidence to date, implicating RTIs (viral and non-viral) as potential risk factors for IA/T1D.
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Affiliation(s)
- Roy Wu
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
| | - Mohsin Mumtaz
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
| | - Anna J. Maxwell
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
| | - Sonia R. Isaacs
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
| | - Jutta E. Laiho
- Department of VirologyFaculty of Medicine and Health TechnologyTampere UniversityTampereFinland
| | - William D. Rawlinson
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
- School of Biomedical SciencesFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- School of Biotechnology and Biomolecular SciencesFaculty of ScienceUniversity of New South WalesRandwickNew South WalesAustralia
| | - Heikki Hyöty
- Department of VirologyFaculty of Medicine and Health TechnologyTampere UniversityTampereFinland
- Fimlab LaboratoriesTampereFinland
| | - Maria E. Craig
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
- Institute of Endocrinology and DiabetesChildren's Hospital at WestmeadSydneyNew South WalesAustralia
- Faculty of Medicine and HealthDiscipline of Child and Adolescent HealthUniversity of SydneySydneyNew South WalesAustralia
| | - Ki Wook Kim
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
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15
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Alhazmi A, Nekoua MP, Mercier A, Vergez I, Sane F, Alidjinou EK, Hober D. Combating coxsackievirus B infections. Rev Med Virol 2023; 33:e2406. [PMID: 36371612 DOI: 10.1002/rmv.2406] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/11/2022] [Accepted: 10/27/2022] [Indexed: 11/15/2022]
Abstract
Coxsackieviruses B (CVB) are small, non-enveloped, single-stranded RNA viruses belonging to the Enterovirus genus of the Picornaviridae family. They are common worldwide and cause a wide variety of human diseases ranging from those having relatively mild symptoms to severe acute and chronic pathologies such as cardiomyopathy and type 1 diabetes. The development of safe and effective strategies to combat these viruses remains a challenge. The present review outlines current approaches to control CVB infections and associated diseases. Various drugs targeting viral or host proteins involved in viral replication as well as vaccines have been developed and shown potential to prevent or combat CVB infections in vitro and in vivo in animal models. Repurposed drugs and alternative strategies targeting miRNAs or based on plant extracts and probiotics and their derivatives have also shown antiviral effects against CVB. In addition, clinical trials with vaccines and drugs are underway and offer hope for the prevention or treatment of CVB-induced diseases.
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Affiliation(s)
- Abdulaziz Alhazmi
- Laboratoire de Virologie ULR3610, Université de Lille et CHU de Lille, Lille, France.,Microbiology and Parasitology Department, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia
| | | | - Ambroise Mercier
- Laboratoire de Virologie ULR3610, Université de Lille et CHU de Lille, Lille, France
| | - Ines Vergez
- Laboratoire de Virologie ULR3610, Université de Lille et CHU de Lille, Lille, France
| | - Famara Sane
- Laboratoire de Virologie ULR3610, Université de Lille et CHU de Lille, Lille, France
| | | | - Didier Hober
- Laboratoire de Virologie ULR3610, Université de Lille et CHU de Lille, Lille, France
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16
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Ottmann M. [These viruses that inhabit and visit us: The human virome]. Med Sci (Paris) 2022; 38:1028-1038. [PMID: 36692282 DOI: 10.1051/medsci/2022161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Recent advances in new sequencing technologies have opened the way to the deciphering of human virome. So far, human virome is defined as the complete list of viruses found in human body. Those viruses could be endogenous, prokaryotic, archaeal and eukaryotic. In addition, each compartment of the human body constitutes a different microenvironment with its own virome. Viral infections can be categorized according to the outcome of the acute phase and until recently, only symptomatic and pathological infections were studied. It is now well established that a healthy person has an extremely diverse virome. This review summarizes the current state of our knowledge and also proposes another classification of the human virome based on principles of ecology.
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Affiliation(s)
- Michèle Ottmann
- Centre international de recherche en infectiologie (CIRI), université Claude Bernard-Lyon 1, université de Lyon, Inserm U1111 - CNRS UMR 5308 - ENS, Laboratoire de virologie et pathologies humaines, Faculté de médecine RTH Laennec, 7 rue Guillaume Paradin, 69372 Lyon cedex 08, France
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17
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Jamal QMS. Antiviral Potential of Plants against COVID-19 during Outbreaks-An Update. Int J Mol Sci 2022; 23:13564. [PMID: 36362351 PMCID: PMC9655040 DOI: 10.3390/ijms232113564] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 10/06/2022] [Accepted: 11/02/2022] [Indexed: 12/01/2023] Open
Abstract
Several human diseases are caused by viruses, including cancer, Type I diabetes, Alzheimer's disease, and hepatocellular carcinoma. In the past, people have suffered greatly from viral diseases such as polio, mumps, measles, dengue fever, SARS, MERS, AIDS, chikungunya fever, encephalitis, and influenza. Recently, COVID-19 has become a pandemic in most parts of the world. Although vaccines are available to fight the infection, their safety and clinical trial data are still questionable. Social distancing, isolation, the use of sanitizer, and personal productive strategies have been implemented to prevent the spread of the virus. Moreover, the search for a potential therapeutic molecule is ongoing. Based on experiences with outbreaks of SARS and MERS, many research studies reveal the potential of medicinal herbs/plants or chemical compounds extracted from them to counteract the effects of these viral diseases. COVID-19's current status includes a decrease in infection rates as a result of large-scale vaccination program implementation by several countries. But it is still very close and needs to boost people's natural immunity in a cost-effective way through phytomedicines because many underdeveloped countries do not have their own vaccination facilities. In this article, phytomedicines as plant parts or plant-derived metabolites that can affect the entry of a virus or its infectiousness inside hosts are described. Finally, it is concluded that the therapeutic potential of medicinal plants must be analyzed and evaluated entirely in the control of COVID-19 in cases of uncontrollable SARS infection.
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Affiliation(s)
- Qazi Mohammad Sajid Jamal
- Department of Health Informatics, College of Public Health and Health Informatics, Qassim University, Al Bukayriyah 52741, Saudi Arabia
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18
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Association between Pediatric Adenovirus Infection and Type 1 Diabetes. CHILDREN 2022; 9:children9101494. [PMID: 36291430 PMCID: PMC9600003 DOI: 10.3390/children9101494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/16/2022] [Accepted: 09/23/2022] [Indexed: 12/05/2022]
Abstract
Background: Viruses are among the inducers of type 1 diabetes (T1D) as they are implicated in the initiation of β-cell destruction. This study aimed to explore the link between adenoviruses’ infection, inflammatory biomarkers, and the development of T1D. Methods: The study population included 80 children with T1D and 40 healthy controls (2–16 years old). The T1D group was further clustered into two groups according to time of T1D diagnosis: a group of children who were diagnosed during the first year of life and a second group who were diagnosed after the first year of life. Adenovirus DNA, anti-adenovirus IgG, cytokines, and lipid profiles were screened in the different groups. The results were statistically assessed using one-way analysis of variance (ANOVA) and LSD t-test. Results: Positive adenovirus PCR was detected in 2.5% and 20% of normal and T1D children, respectively. Moreover, the positive PCR results for adenovirus were found significantly higher in the T1D group, who were diagnosed during the first year of life (33.4%), in comparison to those diagnosed after the first year of life (12%). Anti-adenoviruses IgG was found in 12.5% and 40% of healthy controls and diabetic children, respectively. Seropositive results were found to be higher in newly diagnosed children (46.7%) in comparison to those previously diagnosed with T1D (36%). Body mass index (BMI), IFN-γ, IL-15, adiponectin, lipid profile, and microalbuminuria were significantly increased in T1D adenoviruses-positive children compared to children who were negative for adenoviruses. Conclusions: Adenovirus infection could be among the contributing risk factors and may play a role in the induction of T1D in children.
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19
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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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20
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Zajec A, Trebušak Podkrajšek K, Tesovnik T, Šket R, Čugalj Kern B, Jenko Bizjan B, Šmigoc Schweiger D, Battelino T, Kovač J. Pathogenesis of Type 1 Diabetes: Established Facts and New Insights. Genes (Basel) 2022; 13:genes13040706. [PMID: 35456512 PMCID: PMC9032728 DOI: 10.3390/genes13040706] [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: 03/28/2022] [Revised: 04/13/2022] [Accepted: 04/13/2022] [Indexed: 01/08/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. In this review, we highlight the interplay between genetic predisposition and other non-genetic factors, such as viral infections, diet, and gut biome, which all potentially contribute to the aetiology of T1D. We also discuss a possible active role for β-cells in initiating the pathological processes. Another component in T1D predisposition is epigenetic influences, which represent a link between genetic susceptibility and environmental factors and may account for some of the disease heterogeneity. Accordingly, a shift towards personalized therapies may improve the treatment results and, therefore, result in better outcomes for individuals in the long-run. There is also a clear need for a better understanding of the preclinical phases of T1D and finding new predictive biomarkers for earlier diagnosis and therapy, with the final goal of reverting or even preventing the development of the disease.
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Affiliation(s)
- Ana Zajec
- Division of Paediatrics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.Z.); (K.T.P.); (T.T.); (R.Š.); (B.Č.K.); (B.J.B.); (D.Š.S.); (T.B.)
- Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Katarina Trebušak Podkrajšek
- Division of Paediatrics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.Z.); (K.T.P.); (T.T.); (R.Š.); (B.Č.K.); (B.J.B.); (D.Š.S.); (T.B.)
- Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Tine Tesovnik
- Division of Paediatrics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.Z.); (K.T.P.); (T.T.); (R.Š.); (B.Č.K.); (B.J.B.); (D.Š.S.); (T.B.)
| | - Robert Šket
- Division of Paediatrics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.Z.); (K.T.P.); (T.T.); (R.Š.); (B.Č.K.); (B.J.B.); (D.Š.S.); (T.B.)
| | - Barbara Čugalj Kern
- Division of Paediatrics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.Z.); (K.T.P.); (T.T.); (R.Š.); (B.Č.K.); (B.J.B.); (D.Š.S.); (T.B.)
- Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Barbara Jenko Bizjan
- Division of Paediatrics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.Z.); (K.T.P.); (T.T.); (R.Š.); (B.Č.K.); (B.J.B.); (D.Š.S.); (T.B.)
- Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Darja Šmigoc Schweiger
- Division of Paediatrics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.Z.); (K.T.P.); (T.T.); (R.Š.); (B.Č.K.); (B.J.B.); (D.Š.S.); (T.B.)
- Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Tadej Battelino
- Division of Paediatrics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.Z.); (K.T.P.); (T.T.); (R.Š.); (B.Č.K.); (B.J.B.); (D.Š.S.); (T.B.)
- Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Jernej Kovač
- Division of Paediatrics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.Z.); (K.T.P.); (T.T.); (R.Š.); (B.Č.K.); (B.J.B.); (D.Š.S.); (T.B.)
- Department of Paediatrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
- Correspondence:
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21
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Nekoua MP, Mercier A, Alhazmi A, Sane F, Alidjinou EK, Hober D. Fighting Enteroviral Infections to Prevent Type 1 Diabetes. Microorganisms 2022; 10:microorganisms10040768. [PMID: 35456818 PMCID: PMC9031364 DOI: 10.3390/microorganisms10040768] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 03/24/2022] [Accepted: 03/30/2022] [Indexed: 12/16/2022] Open
Abstract
Enteroviruses (EVs), especially coxsackieviruses B (CVB), are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals that results in type 1 diabetes (T1D). Therefore, strategies are needed to fight against EV infections. There are no approved antiviral drugs currently available, but various antiviral drugs targeting viral or host cell proteins and vaccines have recently shown potential to combat CVB infections and may be used as new therapeutic strategies to prevent or reduce the risk of T1D and/or preserve β-cell function among patients with islet autoantibodies or T1D.
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Affiliation(s)
- Magloire Pandoua Nekoua
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, 59000 Lille, France; (M.P.N.); (A.M.); (A.A.); (F.S.); (E.K.A.)
| | - Ambroise Mercier
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, 59000 Lille, France; (M.P.N.); (A.M.); (A.A.); (F.S.); (E.K.A.)
| | - Abdulaziz Alhazmi
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, 59000 Lille, France; (M.P.N.); (A.M.); (A.A.); (F.S.); (E.K.A.)
- Microbiology and Parasitology Department, College of Medicine, Jazan University, Jazan 82911, Saudi Arabia
| | - Famara Sane
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, 59000 Lille, France; (M.P.N.); (A.M.); (A.A.); (F.S.); (E.K.A.)
| | - Enagnon Kazali Alidjinou
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, 59000 Lille, France; (M.P.N.); (A.M.); (A.A.); (F.S.); (E.K.A.)
| | - Didier Hober
- Laboratoire de Virologie ULR3610, Université de Lille, CHU Lille, 59000 Lille, France; (M.P.N.); (A.M.); (A.A.); (F.S.); (E.K.A.)
- Correspondence: ; Tel.: +33-(0)-3-2044-6688
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22
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Raicevic M, Samardzic M, Soldatovic I, Curovic Popovic N, Vukovic R. Trends in nationwide incidence of pediatric type 1 diabetes in Montenegro during the last 30 years. Front Endocrinol (Lausanne) 2022; 13:991533. [PMID: 36147568 PMCID: PMC9485557 DOI: 10.3389/fendo.2022.991533] [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: 07/11/2022] [Accepted: 08/18/2022] [Indexed: 12/01/2022] Open
Abstract
Significant and unexplained variations in type 1 diabetes (T1D) incidence through the years were observed all around the world. The update on this disorder's incidence is crucial for adequate healthcare resource planning and monitoring of the disease. The aim of this study was to give an update on the current incidence of pediatric T1D in Montenegro and to analyze incidence changes over time and how the exposure to different factors might have affected it. This retrospective cohort study included a total of 582 patients younger than 15 years who were newly diagnosed with T1D during the past 30 years. The average age at diagnosis was 8.4 ± 3.91 years. The mean annual incidence of T1D in the Montenegro population during the whole study period of 30 years was 15.2/100,000 person-years. Slightly higher incidence rates were observed in male compared to female individuals, and the incidence increased with age, with the highest incidence in the 10-14 age group. If the model is observed as one without jointpoints, the annual percentage change (APC) for the total population is 3.1 (1.8-4.4); for male individuals, 3.8 (2.1-5.5); and for female individuals, 2.1 (0.6-3.5). In 2020, the first year of the coronavirus disease of 2019 (COVID-19) pandemic, in comparison to 2019, the incidence rate increased from 19.7/100,000 to 21.5/100,000, with the highest increase in the age group of 5-9 years. This is the first nationwide report on a 30-year period of T1D incidence trend in Montenegro. It suggests that T1D incidence among Montenegrin children is rising again and that there is a short-term influence of COVID-19 on new-onset T1D.
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Affiliation(s)
- Maja Raicevic
- Department of Endocrinology, Institute for Children’s Diseases, Clinical Centre of Montenegro, Podgorica, Montenegro
- *Correspondence: Maja Raicevic,
| | - Mira Samardzic
- Department of Endocrinology, Institute for Children’s Diseases, Clinical Centre of Montenegro, Podgorica, Montenegro
- Faculty of Medicine, University of Montenegro, Podgorica, Montenegro
| | - Ivan Soldatovic
- Institute of Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Natasa Curovic Popovic
- Department of Endocrinology, Institute for Children’s Diseases, Clinical Centre of Montenegro, Podgorica, Montenegro
| | - Rade Vukovic
- Department of Endocrinology, Mother and Child Health Care Institute of Serbia “Dr Vukan Cupic”, Belgrade, Serbia
- School of Medicine, University of Belgrade, Belgrade, Serbia
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