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Colinet M, Chiver I, Bonafina A, Masset G, Almansa D, Di Valentin E, Twizere JC, Nguyen L, Espuny-Camacho I. SARS-CoV2 infection triggers inflammatory conditions and astrogliosis-related gene expression in long-term human cortical organoids. Stem Cells 2025; 43:sxaf010. [PMID: 40103011 PMCID: PMC12121356 DOI: 10.1093/stmcls/sxaf010] [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: 02/03/2024] [Accepted: 02/18/2025] [Indexed: 03/20/2025]
Abstract
SARS-CoV2, severe acute respiratory syndrome coronavirus 2, is frequently associated with neurological manifestations. Despite the presence of mild to severe CNS-related symptoms in a cohort of patients, there is no consensus whether the virus can infect directly brain tissue or if the symptoms in patients are a consequence of peripheral infectivity of the virus. Here, we use long-term human stem cell-derived cortical organoids to assess SARS-CoV2 infectivity of brain cells and unravel the cell-type tropism and its downstream pathological effects. Our results show consistent and reproducible low levels of SARS-CoV2 infection of astrocytes, deep projection neurons, upper callosal neurons, and inhibitory neurons in 6 months of human cortical organoids. Interestingly, astrocytes showed the highest infection rate among all infected cell populations which led to changes in their morphology and upregulation of SERPINA3, CD44, and S100A10 astrogliosis markers. Further, transcriptomic analysis revealed overall changes in expression of genes related to cell metabolism, astrogliosis and, inflammation and further, upregulation of cell survival pathways. Thus, local and minor infectivity of SARS-CoV2 in the brain may induce widespread adverse effects and lead to the resilience of dysregulated neurons and astrocytes within an inflammatory environment.
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Affiliation(s)
- Mathilde Colinet
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Ioana Chiver
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Antonela Bonafina
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Gérald Masset
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Daniel Almansa
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Emmanuel Di Valentin
- GIGA Viral Vector Platform, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Jean-Claude Twizere
- Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute, University of Liège, Liège 4000, Belgium
| | - Laurent Nguyen
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
- WELBIO Department, WEL Research Institute, Wavre 1300, Belgium
| | - Ira Espuny-Camacho
- Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, Liège 4000, Belgium
- GIGA HIPS, GIGA Institute, University of Liège, Liège 4000, Belgium
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2
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Cappelletti G, Brambilla L, Strizzi S, Limanaqi F, Melzi V, Rizzuti M, Nizzardo M, Saulle I, Trabattoni D, Corti S, Clerici M, Biasin M. iPSC-derived human cortical organoids display profound alterations of cellular homeostasis following SARS-CoV-2 infection and Spike protein exposure. FASEB J 2025; 39:e70396. [PMID: 39950320 PMCID: PMC11826378 DOI: 10.1096/fj.202401604rrr] [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: 07/16/2024] [Revised: 01/31/2025] [Accepted: 02/05/2025] [Indexed: 02/16/2025]
Abstract
COVID-19 commonly leads to respiratory issues, yet numerous patients also exhibit a diverse range of neurological conditions, suggesting a detrimental impact of SARS-CoV-2 or the viral Spike protein on the central nervous system. Nonetheless, the molecular pathway behind neurological pathology and the presumed neurotropism of SARS-CoV-2 remains largely unexplored. We generated human cortical organoids (HCOs) derived from human induced pluripotent stem cells (hiPSC) to assess: (1) the expression of SARS-CoV-2 main entry factors; (2) their vulnerability to SARS-CoV-2 infection; and (3) the impact of SARS-CoV-2 infection and exposure to the Spike protein on their transcriptome. Results proved that (1) HCOs express the main SARS-CoV-2 receptors and co-receptors; (2) HCOs may be productively infected by SARS-CoV-2; (3) the viral particles released by SARS-CoV-2-infected HCOs are able to re-infect another cellular line; and (4) the infection resulted in the activation of apoptotic and stress pathways, along with inflammatory processes. Notably, these effects were recapitulated when HCOs were exposed to the Spike protein alone. The data obtained demonstrate that SARS-CoV-2 likely infects HCOs probably through the binding of ACE2, CD147, and NRP1 entry factors. Furthermore, exposure to the Spike protein alone proved sufficient to disrupt their homeostasis and induce neurotoxic effects, potentially contributing to the onset of long-COVID symptoms.
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Affiliation(s)
- Gioia Cappelletti
- Department of Biomedical and Clinical SciencesUniversity of MilanMilanItaly
| | - Lorenzo Brambilla
- Neurology UnitFoundation IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Sergio Strizzi
- Department of Biomedical and Clinical SciencesUniversity of MilanMilanItaly
| | - Fiona Limanaqi
- Department of Biomedical and Clinical SciencesUniversity of MilanMilanItaly
- Department of Pathophysiology and TransplantationUniversity of MilanMilanItaly
| | - Valentina Melzi
- Neurology UnitFoundation IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Mafalda Rizzuti
- Neurology UnitFoundation IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Monica Nizzardo
- Neurology UnitFoundation IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Irma Saulle
- Department of Biomedical and Clinical SciencesUniversity of MilanMilanItaly
- Department of Pathophysiology and TransplantationUniversity of MilanMilanItaly
| | - Daria Trabattoni
- Department of Biomedical and Clinical SciencesUniversity of MilanMilanItaly
| | - Stefania Corti
- Neurology UnitFoundation IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
- Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, Neuroscience SectionUniversity of MilanMilanItaly
- Neuromuscular and Rare Diseases Unit, Department of NeuroscienceFondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Mario Clerici
- Department of Pathophysiology and TransplantationUniversity of MilanMilanItaly
- Don C. Gnocchi FoundationIstituto di Ricovero e Cura a Carattere Scientifico (IRCCS) FoundationMilanItaly
| | - Mara Biasin
- Department of Biomedical and Clinical SciencesUniversity of MilanMilanItaly
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3
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Kulczyńska-Przybik A, Czupryna P, Adamczuk J, Kruszewska E, Mroczko B, Moniuszko-Malinowska A. Clinical usefulness of the serum levels of neuroinflammatory and lung fibrosis biomarkers in the assessment of cognitive dysfunction in post-COVID19 patients. Sci Rep 2024; 14:25798. [PMID: 39468309 PMCID: PMC11519350 DOI: 10.1038/s41598-024-76630-4] [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: 02/22/2024] [Accepted: 10/15/2024] [Indexed: 10/30/2024] Open
Abstract
A growing body of evidence indicates there is an increasing incidence of cognitive dysfunction in patients after coronavirus disease 2019 (COVID-19) infection. However, still lack diagnostic tools, which allow us to predict prognosis in such cases and improve the stratification of the disease. This study aims to evaluate the usefulness of the biomarkers that could allow to predict the severity and progression of COVID-19 in patients with post-COVID syndrome and cognitive problems. Data regarding clinical history, pre-existing conditions, chest CT scan, and therapy (remdesivir, steroids) were acquired. A total of 44 patients with hospitalized COVID-19, and healthy controls were enrolled in the investigation, and serum blood was obtained. After 6 months of observations, patients with COVID-19 were divided into two groups: first - without post-COVID syndrome and memory complaints, and second - with post-COVID and cognitive problems. Measurements of YKL-40 and MR-pro-ADM were taken in the serum with enzyme immunoassay kits at the time of admission (visit 1) and 6 months after discharge from the hospital (visit 2). Significantly higher concentrations of YKL-40 were found in patients with COVID-19 as compared to healthy individuals (p = 0.016). Moreover, YKL-40 ratio allowed to differentiate patients with and without post-COVID syndrome (median: 0.94 vs. 1.55, p = 0.004). Additionally, COVID-19 patients with dyspnea presented significantly elevated levels of MR-pro-ADM as compared to the group of COVID-19 survivors without dyspnea (p = 0.015). In the group of patients without post-COVID syndrome, the concentrations of YKL-40 and MR-pro-ADM decreased after treatment as compared to levels before therapy (77 vs. 36 ng/ml and 607 vs. 456 pmol/L). However, in patients with post-COVID syndrome and cognitive problems, the levels of both markers did not alter 6 months after hospital discharge in comparison to basal levels. Furthermore, after dexamethasone treatment the YKL-40 concentrations declined significantly (p = 0.003) in patients with COVID-19. This study demonstrated the predictive usefulness of YKL-40 as an indicator of successful treatment in patients with COVID-19 infection allowing risk stratification of hospitalized patients. It seems that indicators of neuroinflammation might have the potential to track development of cognitive complaints, however, it requires further investigations.
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Affiliation(s)
| | - Piotr Czupryna
- Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, 15-540, Białystok, Poland
| | - Justyna Adamczuk
- Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, 15-540, Białystok, Poland
| | - Ewelina Kruszewska
- Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, 15-540, Białystok, Poland
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Białystok, 15-269, Białystok, Poland
- Department of Biochemical Diagnostics, Medical University of Białystok, 15-269, Białystok, Poland
| | - Anna Moniuszko-Malinowska
- Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, 15-540, Białystok, Poland
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Orsini F, Bosica M, Martucci A, De Paola M, Comolli D, Pascente R, Forloni G, Fraser PE, Arancio O, Fioriti L. SARS-CoV-2 Nucleocapsid Protein Induces Tau Pathological Changes That Can Be Counteracted by SUMO2. Int J Mol Sci 2024; 25:7169. [PMID: 39000276 PMCID: PMC11241313 DOI: 10.3390/ijms25137169] [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: 05/31/2024] [Revised: 06/25/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Neurologic manifestations are an immediate consequence of SARS-CoV-2 infection, the etiologic agent of COVID-19, which, however, may also trigger long-term neurological effects. Notably, COVID-19 patients with neurological symptoms show elevated levels of biomarkers associated with brain injury, including Tau proteins linked to Alzheimer's pathology. Studies in brain organoids revealed that SARS-CoV-2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to the recruitment of Tau into stress granules (SGs) operated by the nucleocapsid protein (NCAP) of SARS-CoV-2. To test this hypothesis, we investigated whether NCAP interacts with Tau and localizes to SGs in hippocampal neurons in vitro and in vivo. Mechanistically, we tested whether SUMOylation, a posttranslational modification of NCAP and Tau, modulates their distribution in SGs and their pathological interaction. We found that NCAP and Tau colocalize and physically interact. We also found that NCAP induces hyperphosphorylation of Tau and causes cognitive impairment in mice infected with NCAP in their hippocampus. Finally, we found that SUMOylation modulates NCAP SG formation in vitro and cognitive performance in infected mice. Our data demonstrate that NCAP induces Tau pathological changes both in vitro and in vivo. Moreover, we demonstrate that SUMO2 ameliorates NCAP-induced Tau pathology, highlighting the importance of the SUMOylation pathway as a target of intervention against neurotoxic insults, such as Tau oligomers and viral infection.
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Affiliation(s)
- Franca Orsini
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, MI, Italy; (F.O.); (M.B.); (A.M.); (M.D.P.); (D.C.); (R.P.); (G.F.)
| | - Marco Bosica
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, MI, Italy; (F.O.); (M.B.); (A.M.); (M.D.P.); (D.C.); (R.P.); (G.F.)
| | - Annacarla Martucci
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, MI, Italy; (F.O.); (M.B.); (A.M.); (M.D.P.); (D.C.); (R.P.); (G.F.)
| | - Massimiliano De Paola
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, MI, Italy; (F.O.); (M.B.); (A.M.); (M.D.P.); (D.C.); (R.P.); (G.F.)
| | - Davide Comolli
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, MI, Italy; (F.O.); (M.B.); (A.M.); (M.D.P.); (D.C.); (R.P.); (G.F.)
| | - Rosaria Pascente
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, MI, Italy; (F.O.); (M.B.); (A.M.); (M.D.P.); (D.C.); (R.P.); (G.F.)
| | - Gianluigi Forloni
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, MI, Italy; (F.O.); (M.B.); (A.M.); (M.D.P.); (D.C.); (R.P.); (G.F.)
| | - Paul E. Fraser
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5T 2S8, Canada;
| | - Ottavio Arancio
- Department of Pathology and Cell Biology, Taub Institute for Research of Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY 10032, USA;
| | - Luana Fioriti
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, MI, Italy; (F.O.); (M.B.); (A.M.); (M.D.P.); (D.C.); (R.P.); (G.F.)
- Department of Pathology and Cell Biology, Taub Institute for Research of Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY 10032, USA;
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5
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Partiot E, Hirschler A, Colomb S, Lutz W, Claeys T, Delalande F, Deffieu MS, Bare Y, Roels JRE, Gorda B, Bons J, Callon D, Andreoletti L, Labrousse M, Jacobs FMJ, Rigau V, Charlot B, Martens L, Carapito C, Ganesh G, Gaudin R. Brain exposure to SARS-CoV-2 virions perturbs synaptic homeostasis. Nat Microbiol 2024; 9:1189-1206. [PMID: 38548923 DOI: 10.1038/s41564-024-01657-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 03/04/2024] [Indexed: 04/21/2024]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with short- and long-term neurological complications. The variety of symptoms makes it difficult to unravel molecular mechanisms underlying neurological sequalae after coronavirus disease 2019 (COVID-19). Here we show that SARS-CoV-2 triggers the up-regulation of synaptic components and perturbs local electrical field potential. Using cerebral organoids, organotypic culture of human brain explants from individuals without COVID-19 and post-mortem brain samples from individuals with COVID-19, we find that neural cells are permissive to SARS-CoV-2 to a low extent. SARS-CoV-2 induces aberrant presynaptic morphology and increases expression of the synaptic components Bassoon, latrophilin-3 (LPHN3) and fibronectin leucine-rich transmembrane protein-3 (FLRT3). Furthermore, we find that LPHN3-agonist treatment with Stachel partially restored organoid electrical activity and reverted SARS-CoV-2-induced aberrant presynaptic morphology. Finally, we observe accumulation of relatively static virions at LPHN3-FLRT3 synapses, suggesting that local hindrance can contribute to synaptic perturbations. Together, our study provides molecular insights into SARS-CoV-2-brain interactions, which may contribute to COVID-19-related neurological disorders.
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Affiliation(s)
- Emma Partiot
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France
- Univ Montpellier, Montpellier, France
| | - Aurélie Hirschler
- Laboratoire de Spectrométrie de Masse Bio-Organique, IPHC, UMR 7178, CNRS-Université de Strasbourg, Strasbourg, France
- Infrastructure Nationale de Protéomique ProFI─FR2048, Strasbourg, France
| | - Sophie Colomb
- EDPFM (Equipe de Droit Pénal et de Sciences Forensiques de Montpellier), Univ Montpellier, Montpellier, France
- Emergency Pole, Forensic Medicine Department, Montpellier University Hospital, Montpellier, France
| | - Willy Lutz
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France
- Univ Montpellier, Montpellier, France
- UM-CNRS Laboratoire d'Informatique de Robotique et de Microelectronique de Montpellier (LIRMM), Montpellier, France
| | - Tine Claeys
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - François Delalande
- Laboratoire de Spectrométrie de Masse Bio-Organique, IPHC, UMR 7178, CNRS-Université de Strasbourg, Strasbourg, France
- Infrastructure Nationale de Protéomique ProFI─FR2048, Strasbourg, France
| | - Maika S Deffieu
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France
- Univ Montpellier, Montpellier, France
| | - Yonis Bare
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France
- Univ Montpellier, Montpellier, France
| | - Judith R E Roels
- Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands
| | - Barbara Gorda
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France
- Univ Montpellier, Montpellier, France
| | - Joanna Bons
- Laboratoire de Spectrométrie de Masse Bio-Organique, IPHC, UMR 7178, CNRS-Université de Strasbourg, Strasbourg, France
- Infrastructure Nationale de Protéomique ProFI─FR2048, Strasbourg, France
| | - Domitille Callon
- University of Reims Champagne-Ardenne, Medicine Faculty, Laboratory of Virology, CardioVir UMR-S 1320, Reims, France
- Forensic, Virology and ENT Departments, University Hospital Centre (CHU), Reims, France
| | - Laurent Andreoletti
- University of Reims Champagne-Ardenne, Medicine Faculty, Laboratory of Virology, CardioVir UMR-S 1320, Reims, France
- Forensic, Virology and ENT Departments, University Hospital Centre (CHU), Reims, France
| | - Marc Labrousse
- Forensic, Virology and ENT Departments, University Hospital Centre (CHU), Reims, France
- Anatomy laboratory, UFR Médecine, Université de Reims Champagne-Ardenne, Reims, France
| | - Frank M J Jacobs
- Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands
| | - Valérie Rigau
- Univ Montpellier, Montpellier, France
- Pathological Department and Biological Resources Center BRC, Montpellier University Hospital, 'Cerebral plasticity, Stem cells and Glial tumors' team. IGF- Institut de génomique fonctionnelle INSERM U 1191 - CNRS UMR 5203, Univ Montpellier, Montpellier, France
| | - Benoit Charlot
- Univ Montpellier, Montpellier, France
- Institut d'Electronique et des Systèmes (IES), CNRS, Montpellier, France
| | - Lennart Martens
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Christine Carapito
- Laboratoire de Spectrométrie de Masse Bio-Organique, IPHC, UMR 7178, CNRS-Université de Strasbourg, Strasbourg, France
- Infrastructure Nationale de Protéomique ProFI─FR2048, Strasbourg, France
| | - Gowrishankar Ganesh
- Univ Montpellier, Montpellier, France
- UM-CNRS Laboratoire d'Informatique de Robotique et de Microelectronique de Montpellier (LIRMM), Montpellier, France
| | - Raphael Gaudin
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France.
- Univ Montpellier, Montpellier, France.
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Dell’Aquila M, Cafiero C, Micera A, Stigliano E, Ottaiano MP, Benincasa G, Schiavone B, Guidobaldi L, Santacroce L, Pisconti S, Arena V, Palmirotta R. SARS-CoV-2-Related Olfactory Dysfunction: Autopsy Findings, Histopathology, and Evaluation of Viral RNA and ACE2 Expression in Olfactory Bulbs. Biomedicines 2024; 12:830. [PMID: 38672185 PMCID: PMC11048640 DOI: 10.3390/biomedicines12040830] [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: 03/07/2024] [Revised: 03/29/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND The COVID-19 pandemic has been a health emergency with a significant impact on the world due to its high infectiousness. The disease, primarily identified in the lower respiratory tract, develops with numerous clinical symptoms affecting multiple organs and displays a clinical finding of anosmia. Several authors have investigated the pathogenetic mechanisms of the olfactory disturbances caused by SARS-CoV-2 infection, proposing different hypotheses and showing contradictory results. Since uncertainties remain about possible virus neurotropism and direct damage to the olfactory bulb, we investigated the expression of SARS-CoV-2 as well as ACE2 receptor transcripts in autoptic lung and olfactory bulb tissues, with respect to the histopathological features. METHODS Twenty-five COVID-19 olfactory bulbs and lung tissues were randomly collected from 200 initial autopsies performed during the COVID-19 pandemic. Routine diagnosis was based on clinical and radiological findings and were confirmed with post-mortem swabs. Real-time RT-PCR for SARS-CoV-2 and ACE2 receptor RNA was carried out on autoptic FFPE lung and olfactory bulb tissues. Histological staining was performed on tissue specimens and compared with the molecular data. RESULTS While real-time RT-PCR for SARS-CoV-2 was positive in 23 out of 25 lung samples, the viral RNA expression was absent in olfactory bulbs. ACE2-receptor RNA was present in all tissues examined, being highly expressed in lung samples than olfactory bulbs. CONCLUSIONS Our finding suggests that COVID-19 anosmia is not only due to neurotropism and the direct action of SARS-CoV-2 entering the olfactory bulb. The mechanism of SARS-CoV-2 neuropathogenesis in the olfactory bulb requires a better elucidation and further research studies to mitigate the olfactory bulb damage associated with virus action.
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Affiliation(s)
- Marco Dell’Aquila
- Anatomic Pathology Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (M.D.); (E.S.); (V.A.)
- Pathology Unit, Belcolle Hospital, ASL Viterbo, 01100 Viterbo, Italy
| | - Concetta Cafiero
- Medical Oncology, SG Moscati Hospital, 74010 Statte, Italy;
- Anatomic Pathology Unit, Fabrizio Spaziani Hospital, 03100 Frosinone, Italy
| | - Alessandra Micera
- Research and Development Laboratory for Biochemical, Molecular and Cellular Applications in Ophthalmological Science, IRCCS–Fondazione Bietti, 00184 Rome, Italy
| | - Egidio Stigliano
- Anatomic Pathology Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (M.D.); (E.S.); (V.A.)
| | - Maria Pia Ottaiano
- Department of Clinical Pathology and Molecular Biology, Pineta Grande Hospital, 81030 Castel Volturno, Italy; (M.P.O.); (G.B.); (B.S.)
| | - Giulio Benincasa
- Department of Clinical Pathology and Molecular Biology, Pineta Grande Hospital, 81030 Castel Volturno, Italy; (M.P.O.); (G.B.); (B.S.)
| | - Beniamino Schiavone
- Department of Clinical Pathology and Molecular Biology, Pineta Grande Hospital, 81030 Castel Volturno, Italy; (M.P.O.); (G.B.); (B.S.)
| | - Leo Guidobaldi
- Cytodiagnostic Unit, Section of Pathology Sandro Pertini Hospital, ASL Rm2, 00157 Rome, Italy;
| | - Luigi Santacroce
- Section of Microbiology and Virology, Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | | | - Vincenzo Arena
- Anatomic Pathology Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (M.D.); (E.S.); (V.A.)
| | - Raffaele Palmirotta
- Section of Sciences and Technologies of Laboratory Medicine, Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy;
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7
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Tyagi K, Rai P, Gautam A, Kaur H, Kapoor S, Suttee A, Jaiswal PK, Sharma A, Singh G, Barnwal RP. Neurological manifestations of SARS-CoV-2: complexity, mechanism and associated disorders. Eur J Med Res 2023; 28:307. [PMID: 37649125 PMCID: PMC10469568 DOI: 10.1186/s40001-023-01293-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 08/16/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND Coronaviruses such as Severe Acute Respiratory Syndrome coronavirus (SARS), Middle Eastern Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are associated with critical illnesses, including severe respiratory disorders. SARS-CoV-2 is the causative agent of the deadly COVID-19 illness, which has spread globally as a pandemic. SARS-CoV-2 may enter the human body through olfactory lobes and interact with the angiotensin-converting enzyme2 (ACE2) receptor, further facilitating cell binding and entry into the cells. Reports have shown that the virus can pass through the blood-brain barrier (BBB) and enter the central nervous system (CNS), resulting in various disorders. Cell entry by SARS-CoV-2 largely relies on TMPRSS2 and cathepsin L, which activate S protein. TMPRSS2 is found on the cell surface of respiratory, gastrointestinal and urogenital epithelium, while cathepsin-L is a part of endosomes. AIM The current review aims to provide information on how SARS-CoV-2 infection affects brain function.. Furthermore, CNS disorders associated with SARS-CoV-2 infection, including ischemic stroke, cerebral venous thrombosis, Guillain-Barré syndrome, multiple sclerosis, meningitis, and encephalitis, are discussed. The many probable mechanisms and paths involved in developing cerebrovascular problems in COVID patients are thoroughly detailed. MAIN BODY There have been reports that the SARS-CoV-2 virus can cross the blood-brain barrier (BBB) and enter the central nervous system (CNS), where it could cause a various illnesses. Patients suffering from COVID-19 experience a range of neurological complications, including sleep disorders, viral encephalitis, headaches, dysgeusia, and cognitive impairment. The presence of SARS-CoV-2 in the cerebrospinal fluid (CSF) of COVID-19 patients has been reported. Health experts also reported its presence in cortical neurons and human brain organoids. The possible mechanism of virus infiltration into the brain can be neurotropic, direct infiltration and cytokine storm-based pathways. The olfactory lobes could also be the primary pathway for the entrance of SARS-CoV-2 into the brain. CONCLUSIONS SARS-CoV-2 can lead to neurological complications, such as cerebrovascular manifestations, motor movement complications, and cognitive decline. COVID-19 infection can result in cerebrovascular symptoms and diseases, such as strokes and thrombosis. The virus can affect the neural system, disrupt cognitive function and cause neurological disorders. To combat the epidemic, it is crucial to repurpose drugs currently in use quickly and develop novel therapeutics.
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Affiliation(s)
- Kritika Tyagi
- Department of Biophysics, Panjab University, Chandigarh, India
| | - Prachi Rai
- Department of Biophysics, Panjab University, Chandigarh, India
| | - Anuj Gautam
- Department of Biophysics, Panjab University, Chandigarh, India
| | - Harjeet Kaur
- Department of Biophysics, Panjab University, Chandigarh, India
| | - Sumeet Kapoor
- Centre for Biomedical Engineering, Indian Institute of Technology, New Delhi, India
| | - Ashish Suttee
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Pradeep Kumar Jaiswal
- Department of Biochemistry and Biophysics, Texas A & M University, College Station, TX, 77843, USA
| | - Akanksha Sharma
- Department of Biophysics, Panjab University, Chandigarh, India.
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
| | - Gurpal Singh
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
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8
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Recaioglu H, Kolk SM. Developing brain under renewed attack: viral infection during pregnancy. Front Neurosci 2023; 17:1119943. [PMID: 37700750 PMCID: PMC10493316 DOI: 10.3389/fnins.2023.1119943] [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: 12/09/2022] [Accepted: 04/26/2023] [Indexed: 09/14/2023] Open
Abstract
Living in a globalized world, viral infections such as CHIKV, SARS-COV-2, and ZIKV have become inevitable to also infect the most vulnerable groups in our society. That poses a danger to these populations including pregnant women since the developing brain is sensitive to maternal stressors including viral infections. Upon maternal infection, the viruses can gain access to the fetus via the maternofetal barrier and even to the fetal brain during which factors such as viral receptor expression, time of infection, and the balance between antiviral immune responses and pro-viral mechanisms contribute to mother-to-fetus transmission and fetal infection. Both the direct pro-viral mechanisms and the resulting dysregulated immune response can cause multi-level impairment in the maternofetal and brain barriers and the developing brain itself leading to dysfunction or even loss of several cell populations. Thus, maternal viral infections can disturb brain development and even predispose to neurodevelopmental disorders. In this review, we discuss the potential contribution of maternal viral infections of three relevant relative recent players in the field: Zika, Chikungunya, and Severe Acute Respiratory Syndrome Coronavirus-2, to the impairment of brain development throughout the entire route.
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Affiliation(s)
| | - Sharon M. Kolk
- Faculty of Science, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, Netherlands
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9
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Phouphetlinthong O, Partiot E, Bernou C, Sebban A, Gaudin R, Charlot B. Protruding cantilever microelectrode array to monitor the inner electrical activity of cerebral organoids. LAB ON A CHIP 2023; 23:3603-3614. [PMID: 37489118 DOI: 10.1039/d3lc00294b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
Stem cell-derived cerebral organoids are artificially grown miniature organ-like structures mimicking embryonic brain architecture. They are composed of multiple neural cell types with 3D cell layer organization exhibiting local field potential. Measuring the extracellular electrical activity by means of conventional planar microelectrode arrays is particularly challenging due to the 3D architecture of organoids. In order to monitor the intra-organoid electrical activity of thick spheroid-shaped samples, we developed long protruding microelectrode arrays able to penetrate the inner regions of cerebral organoids to measure the local potential of neurons within the organoids. A new microfabrication process has been developed which, thanks to the relaxation of internal stresses of a stack of materials deposited over a sacrificial layer, allows one to build a protruding cantilever microelectrode array placed at the apex of beams which rise vertically, over two hundred microns. These slender beams inserted deeply into the organoids give access to the recording of local field potential from neurons buried inside the organoid. This novel device shall provide valuable tools to study neural functions in greater detail.
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Affiliation(s)
- Oramany Phouphetlinthong
- IES, Institut d'Electronique et des Systèmes, UMR 5214 CNRS, Montpellier, France
- University of Montpellier, Montpellier, France.
| | - Emma Partiot
- IRIM, Institut de Recherche en Infectiologie de Montpellier, UMR 9004 CNRS, Montpellier, France
- University of Montpellier, Montpellier, France.
| | - Corentin Bernou
- IRIM, Institut de Recherche en Infectiologie de Montpellier, UMR 9004 CNRS, Montpellier, France
- University of Montpellier, Montpellier, France.
| | - Audrey Sebban
- IES, Institut d'Electronique et des Systèmes, UMR 5214 CNRS, Montpellier, France
- University of Montpellier, Montpellier, France.
| | - Raphael Gaudin
- IRIM, Institut de Recherche en Infectiologie de Montpellier, UMR 9004 CNRS, Montpellier, France
- University of Montpellier, Montpellier, France.
| | - Benoit Charlot
- IES, Institut d'Electronique et des Systèmes, UMR 5214 CNRS, Montpellier, France
- University of Montpellier, Montpellier, France.
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10
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Peron JPS. Direct and indirect impact of SARS-CoV-2 on the brain. Hum Genet 2023; 142:1317-1326. [PMID: 37004544 PMCID: PMC10066989 DOI: 10.1007/s00439-023-02549-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 03/22/2023] [Indexed: 04/04/2023]
Abstract
Although COVID-19 is mostly a pulmonary disease, it is now well accepted that it can cause a much broader spectrum of signs and symptoms and affect many other organs and tissue. From mild anosmia to severe ischemic stroke, the impact of SARS-CoV-2 on the central nervous system is still a great challenge to scientists and health care practitioners. Besides the acute and severe neurological problems described, as encephalopathies, leptomeningitis, and stroke, after 2 years of pandemic, the chronic impact observed during long-COVID or the post-acute sequelae of COVID-19 (PASC) greatly intrigues scientists worldwide. Strikingly, even asymptomatic, and mild diseased patients may evolve with important neurological and psychiatric symptoms, as confusion, memory loss, cognitive decline, chronic fatigue, associated or not with anxiety and depression. Thus, the knowledge on the correlation between COVID-19 and the central nervous system is of great relevance. In this sense, here we discuss some important mechanisms obtained from in vitro and in vivo investigation regarding how SARS-CoV-2 impacts the brain and its cells and function.
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Affiliation(s)
- J P S Peron
- Neuroimmune Interactions Laboratory, Department of Immunology, University of Sao Paulo, Av. Prof. Lineu Prestes, 1730 Lab 232. Cidade Universitária, São Paulo, SP, CEP 05508-000, Brazil.
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11
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Acharya A, Ambikan AT, Thurman M, Malik MR, Dyavar SR, Végvári Á, Neogi U, Byrareddy SN. Proteomic landscape of astrocytes and pericytes infected with HIV/SARS-CoV-2 mono/co-infection, impacting on neurological complications. RESEARCH SQUARE 2023:rs.3.rs-3031591. [PMID: 37398206 PMCID: PMC10312942 DOI: 10.21203/rs.3.rs-3031591/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Background Although most individuals recover from coronavirus disease 2019 (COVID-19) within a few weeks, some people continue to experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Majority of patients with PASC develop neurological disorders like brain fog, fatigue, mood swings, sleep disorders, loss of smell and test among others collectively called neuro-PASC. While the people living with HIV (PWH) do not have a higher risk of developing severe disease and mortality/morbidity due to COVID-19. As a large section of PWH suffered from HIV-associated neurocognitive disorders (HAND), it is essential to understand the impact of neuro-PASC on people with HAND. In pursuit of this, we infected HIV/SARS-CoV-2 alone or together in primary human astrocytes and pericytes and performed proteomics to understand the impact of co-infection in the central nervous system. Methods Primary human astrocytes and pericytes were infected with SARS-CoV-2 or HIV or HIV + SARS-CoV-2. The concentration of HIV and SARS-CoV-2 genomic RNA in the culture supernatant was quantified using reverse transcriptase quantitative real time polymerase chain reaction (RT-qPCR). This was followed by a quantitative proteomics analysis of mock, HIV, SARS-CoV-2, and HIV + SARS-CoV-2 infected astrocytes and pericytes to understand the impact of the virus in CNS cell types. Results Both healthy and HIV-infected astrocytes and pericytes support abortive/low level of SARS-CoV-2 replication. In both mono-infected and co-infected cells, we observe a modest increase in the expression of SARS-CoV-2 host cell entry factors (ACE2, TMPRSS2, NRP1, and TRIM28) and inflammatory mediators (IL-6, TNF-α, IL-1β and IL-18). Quantitative proteomic analysis has identified uniquely regulated pathways in mock vs SARS-CoV-2, mock vs HIV + SARS-CoV-2, and HIV vs HIV + SARS-CoV-2 infected astrocytes and pericytes. The gene set enrichment analysis revealed that the top ten enriched pathways are linked to several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Conclusions Our study emphasizes the significance of long-term monitoring of patients co-infected with HIV and SARS-CoV-2 to detect and understand the development of neurological abnormalities. By unraveling the molecular mechanisms involved, we can identify potential targets for future therapeutic interventions.
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12
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Afewerki S, Stocco TD, Rosa da Silva AD, Aguiar Furtado AS, Fernandes de Sousa G, Ruiz-Esparza GU, Webster TJ, Marciano FR, Strømme M, Zhang YS, Lobo AO. In vitro high-content tissue models to address precision medicine challenges. Mol Aspects Med 2023; 91:101108. [PMID: 35987701 PMCID: PMC9384546 DOI: 10.1016/j.mam.2022.101108] [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: 04/08/2022] [Revised: 06/29/2022] [Accepted: 07/20/2022] [Indexed: 01/18/2023]
Abstract
The field of precision medicine allows for tailor-made treatments specific to a patient and thereby improve the efficiency and accuracy of disease prevention, diagnosis, and treatment and at the same time would reduce the cost, redundant treatment, and side effects of current treatments. Here, the combination of organ-on-a-chip and bioprinting into engineering high-content in vitro tissue models is envisioned to address some precision medicine challenges. This strategy could be employed to tackle the current coronavirus disease 2019 (COVID-19), which has made a significant impact and paradigm shift in our society. Nevertheless, despite that vaccines against COVID-19 have been successfully developed and vaccination programs are already being deployed worldwide, it will likely require some time before it is available to everyone. Furthermore, there are still some uncertainties and lack of a full understanding of the virus as demonstrated in the high number new mutations arising worldwide and reinfections of already vaccinated individuals. To this end, efficient diagnostic tools and treatments are still urgently needed. In this context, the convergence of bioprinting and organ-on-a-chip technologies, either used alone or in combination, could possibly function as a prominent tool in addressing the current pandemic. This could enable facile advances of important tools, diagnostics, and better physiologically representative in vitro models specific to individuals allowing for faster and more accurate screening of therapeutics evaluating their efficacy and toxicity. This review will cover such technological advances and highlight what is needed for the field to mature for tackling the various needs for current and future pandemics as well as their relevancy towards precision medicine.
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Affiliation(s)
- Samson Afewerki
- Division of Nanotechnology and Functional Materials, Department of Materials Science and Engineering, Ångström Laboratory, Uppsala University, BOX 35, 751 03, Uppsala, Sweden
| | - Thiago Domingues Stocco
- Bioengineering Program, Technological and Scientific Institute, Brazil University, 08230-030, São Paulo, SP, Brazil; Faculty of Medical Sciences, Unicamp - State University of Campinas, 13083-877, Campinas, SP, Brazil
| | | | - André Sales Aguiar Furtado
- Interdisciplinary Laboratory for Advanced Materials, BioMatLab, Department of Materials Engineering, Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Gustavo Fernandes de Sousa
- Interdisciplinary Laboratory for Advanced Materials, BioMatLab, Department of Materials Engineering, Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Guillermo U Ruiz-Esparza
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA; Division of Health Sciences and Technology, Harvard University ‑ Massachusetts Institute of Technology, Boston, MA, 02115, USA
| | - Thomas J Webster
- Interdisciplinary Laboratory for Advanced Materials, BioMatLab, Department of Materials Engineering, Federal University of Piauí (UFPI), Teresina, PI, Brazil; Hebei University of Technology, Tianjin, China
| | - Fernanda R Marciano
- Department of Physics, Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Maria Strømme
- Division of Nanotechnology and Functional Materials, Department of Materials Science and Engineering, Ångström Laboratory, Uppsala University, BOX 35, 751 03, Uppsala, Sweden
| | - Yu Shrike Zhang
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA; Division of Health Sciences and Technology, Harvard University ‑ Massachusetts Institute of Technology, Boston, MA, 02115, USA.
| | - Anderson Oliveira Lobo
- Interdisciplinary Laboratory for Advanced Materials, BioMatLab, Department of Materials Engineering, Federal University of Piauí (UFPI), Teresina, PI, Brazil.
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Mulder LA, Depla JA, Sridhar A, Wolthers K, Pajkrt D, Vieira de Sá R. A beginner's guide on the use of brain organoids for neuroscientists: a systematic review. Stem Cell Res Ther 2023; 14:87. [PMID: 37061699 PMCID: PMC10105545 DOI: 10.1186/s13287-023-03302-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 03/27/2023] [Indexed: 04/17/2023] Open
Abstract
BACKGROUND The first human brain organoid protocol was presented in the beginning of the previous decade, and since then, the field witnessed the development of many new brain region-specific models, and subsequent protocol adaptations and modifications. The vast amount of data available on brain organoid technology may be overwhelming for scientists new to the field and consequently decrease its accessibility. Here, we aimed at providing a practical guide for new researchers in the field by systematically reviewing human brain organoid publications. METHODS Articles published between 2010 and 2020 were selected and categorised for brain organoid applications. Those describing neurodevelopmental studies or protocols for novel organoid models were further analysed for culture duration of the brain organoids, protocol comparisons of key aspects of organoid generation, and performed functional characterisation assays. We then summarised the approaches taken for different models and analysed the application of small molecules and growth factors used to achieve organoid regionalisation. Finally, we analysed articles for organoid cell type compositions, the reported time points per cell type, and for immunofluorescence markers used to characterise different cell types. RESULTS Calcium imaging and patch clamp analysis were the most frequently used neuronal activity assays in brain organoids. Neural activity was shown in all analysed models, yet network activity was age, model, and assay dependent. Induction of dorsal forebrain organoids was primarily achieved through combined (dual) SMAD and Wnt signalling inhibition. Ventral forebrain organoid induction was performed with dual SMAD and Wnt signalling inhibition, together with additional activation of the Shh pathway. Cerebral organoids and dorsal forebrain model presented the most cell types between days 35 and 60. At 84 days, dorsal forebrain organoids contain astrocytes and potentially oligodendrocytes. Immunofluorescence analysis showed cell type-specific application of non-exclusive markers for multiple cell types. CONCLUSIONS We provide an easily accessible overview of human brain organoid cultures, which may help those working with brain organoids to define their choice of model, culture time, functional assay, differentiation, and characterisation strategies.
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Affiliation(s)
- Lance A Mulder
- Department of Paediatric Infectious Diseases, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
- Department Medical Microbiology, OrganoVIR Labs, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands.
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, the Netherlands.
| | - Josse A Depla
- Department of Paediatric Infectious Diseases, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
- Department Medical Microbiology, OrganoVIR Labs, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, the Netherlands
- uniQure Biopharma B.V., Amsterdam, The Netherlands
| | - Adithya Sridhar
- Department of Paediatric Infectious Diseases, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
- Department Medical Microbiology, OrganoVIR Labs, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, the Netherlands
| | - Katja Wolthers
- Department Medical Microbiology, OrganoVIR Labs, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, the Netherlands
| | - Dasja Pajkrt
- Department of Paediatric Infectious Diseases, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
- Department Medical Microbiology, OrganoVIR Labs, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, the Netherlands
| | - Renata Vieira de Sá
- Department Medical Microbiology, OrganoVIR Labs, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, the Netherlands
- uniQure Biopharma B.V., Amsterdam, The Netherlands
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14
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Ostermann PN, Schaal H. Human brain organoids to explore SARS-CoV-2-induced effects on the central nervous system. Rev Med Virol 2023; 33:e2430. [PMID: 36790825 DOI: 10.1002/rmv.2430] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/26/2023] [Accepted: 01/31/2023] [Indexed: 02/16/2023]
Abstract
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). In less than three years, an estimated 600 million infections with SARS-CoV-2 occurred worldwide, resulting in a pandemic with tremendous impact especially on economic and health sectors. Initially considered a respiratory disease, COVID-19, along with its long-term sequelae (long-COVID) rather is a systemic disease. Neurological symptoms like dementia or encephalopathy were reported early during the pandemic as concomitants of the acute phase and as characteristics of long-COVID. An excessive inflammatory immune response is hypothesized to play a major role in this context. However, direct infection of neural cells may also contribute to the neurological aspects of (long)-COVID-19. To mainly explore such direct effects of SARS-CoV-2 on the central nervous system, human brain organoids provide a useful platform. Infecting these three-dimensional tissue cultures allows the study of viral neurotropism as well as of virus-induced effects on single cells or even the complex cellular network within the organoid. In this review, we summarize the experimental studies that used SARS-CoV-2-infected human brain organoids to unravel the complex nature of (long)-COVID-19-related neurological manifestations.
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Affiliation(s)
- Philipp Niklas Ostermann
- Institute of Virology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Heiner Schaal
- Institute of Virology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Do SARS-CoV-2 Variants Differ in Their Neuropathogenicity? mBio 2023; 14:e0292022. [PMID: 36651750 PMCID: PMC9973339 DOI: 10.1128/mbio.02920-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Neurological complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are a huge societal problem. Although the neuropathogenicity of SARS-CoV-2 is not yet fully understood, there is evidence that SARS-CoV-2 can invade and infect cells of the central nervous system. Kong et al. (https://doi.org/10.1128/mbio.02308-22) shows that the mechanism of virus entry into astrocytes in brain organoids and primary astrocytes differs from entry into respiratory epithelial cells. However, how SARS-CoV-2 enters susceptible CNS cells and whether there are differences among SARS-CoV-2 variants is still unclear. In vivo and in vitro models are useful to study these important questions and may reveal important differences among SARS-CoV-2 variants in their neuroinvasive, neurotropic, and neurovirulent potential. In this commentary we address how this study contributes to the understanding of the neuropathology of SARS-CoV-2 and its variants.
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16
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Ocular tropism of SARS-CoV-2 in animal models with retinal inflammation via neuronal invasion following intranasal inoculation. Nat Commun 2022; 13:7675. [PMID: 36509737 PMCID: PMC9743116 DOI: 10.1038/s41467-022-35225-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 11/22/2022] [Indexed: 12/14/2022] Open
Abstract
Although ocular manifestations are reported in patients with COVID-19, consensus on ocular tropism of SARS-CoV-2 is lacking. Here, we infect K18-hACE2 transgenic mice with SARS-CoV-2 using various routes. We observe ocular manifestation and retinal inflammation with production of pro-inflammatory cytokines in the eyes of intranasally (IN)-infected mice. Intratracheal (IT) infection results in dissemination of the virus from the lungs to the brain and eyes via trigeminal and optic nerves. Ocular and neuronal invasions are confirmed using intracerebral (IC) infection. Notably, the eye-dropped (ED) virus does not cause lung infection and becomes undetectable with time. Ocular and neurotropic distribution of the virus in vivo is evident in fluorescence imaging with an infectious clone of SARS-CoV-2-mCherry. The ocular tropic and neuroinvasive characteristics of SARS-CoV-2 are confirmed in wild-type Syrian hamsters. Our data can improve the understanding regarding viral transmission and clinical characteristics of SARS-CoV-2 and help in improving COVID-19 control procedures.
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Al-Beltagi M, Saeed NK, Bediwy AS, Alhawamdeh R, Qaraghuli S. Effects of COVID-19 on children with autism. World J Virol 2022; 11:411-425. [PMID: 36483100 PMCID: PMC9724198 DOI: 10.5501/wjv.v11.i6.411] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/12/2022] [Accepted: 10/04/2022] [Indexed: 11/23/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic affects all countries and populations worldwide, significantly impacting people with autism with a high risk of morbidity and mortality due to COVID-19. Approximately 25% of children with autism have an asymptomatic or symptomatic immune deficiency or dysfunction. In addition, they frequently have various comorbid conditions that increase the severity of COVID-19. In addition, severe COVID-19 during pregnancy may increase the risk of autism in the offspring. Furthermore, severe acute respiratory syndrome coronavirus 2 could target human nervous system tissues due to its neurotrophic effects. The COVID-19 pandemic intensely impacts many patients and families in the autism community, especially the complex management of autism-associated disorders during the complete lockdown. During the complete lockdown, children with autism had difficulties coping with the change in their routine, lack of access to special education services, limited physical space available, and problems related to food and sleep. Additionally, children with autism or intellectual disabilities are more liable to be abused by others during the pandemic when the standard community supports are no longer functioning to protect them. Early detection and vaccination of children with autism against COVID-19 are highly indicated. They should be prioritized for testing, vaccination, and proper management of COVID-19 and other infectious diseases. In this review, we discuss the various effects of COVID-19 on children with autism, the difficulties they face, the increased risk of infection during pregnancy, how to alleviate the impact of COVID-19, and how to correct the inequalities in children with autism.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta 31527, Alghrabia, Egypt
- Department of Pediatrics, University Medical Center, Arabian Gulf University, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Manama, Bahrain
- Department of Pediatrics, University Medical Center, Dr. Sulaiman Al-Habib Medical Group, Manama 26671, Manama, Bahrain
| | - Nermin Kamal Saeed
- Department of Medical Microbiology Section, Pathology Department, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Manama, Bahrain
- Department of Microbiology Section, Pathology Department, Irish Royal College of Surgeon, Busiateen 15503, Muharraq, Bahrain
| | - Adel Salah Bediwy
- Department of Chest Disease, Faculty of Medicine, Tanta University, Tanta 31527, Alghrabia, Egypt
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Manama, Bahrain
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Dr. Sulaiman Al-Habib Medical Group, Manama 26671, Manama, Bahrain
| | - Rawan Alhawamdeh
- Research and Development Department, Pediatric Occupational Therapist and Neuropsychologist, Genomics Development and Play Center (Genomisc WLL), 0000, Manama, Bahrain
- Research and Development Department, Pediatric Occupational Therapist and Neuropsychologist, Sensory Middle East (SENSORYME DWC-LLC), 282228 Dubai, United Arab Emirates
| | - Samara Qaraghuli
- Department of Pharmacognosy and Medicinal Plants, Faculty of Pharmacy, Al-Mustansiriya University, Baghdad 14022, Baghdad, Iraq
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Baig AM. Differential diagnosis and pathogenesis of the neurological signs and symptoms in COVID-19 and long-COVID syndrome. CNS Neurosci Ther 2022; 28:1905-1907. [PMID: 36117492 PMCID: PMC9539369 DOI: 10.1111/cns.13957] [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: 01/24/2022] [Revised: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 02/06/2023] Open
Abstract
Neurological features have now been reported very frequently in the ongoing COVID-19 pandemic caused by SARS-CoV-2. The neurological deficits associated features are observed in both acute and chronic stages of COVID-19 and they appear to overlap with wide-ranging symptoms that can be attributed to being of non-neural origins, thus obscuring the definitive diagnosis of neuro-COVID. The pathogenetic factors acting in concert to cause neuronal injury are now emerging, with SARS-CoV-2 directly affecting the brain coupled with the neuroinflammatory factors have been implicated in the causation of disabilities in acute COVID-19 and patients with Long-COVID syndrome. As the differentiation between a neural origin and other organ-based causation of a particular neurological feature is of prognostic significance, it implores a course of action to this covert, yet important neurological challenge.
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Affiliation(s)
- Abdul Mannan Baig
- Department of Biological and Biomedical SciencesAga Khan UniversityKarachiPakistan
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19
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Krishnan R, Rajendran R, Jang YS, Kim JO, Yoon SY, Oh MJ. NLRC3 attenuates antiviral immunity and activates inflammasome responses in primary grouper brain cells following nervous necrosis virus infection. FISH & SHELLFISH IMMUNOLOGY 2022; 127:219-227. [PMID: 35750116 DOI: 10.1016/j.fsi.2022.06.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/07/2022] [Accepted: 06/16/2022] [Indexed: 06/15/2023]
Abstract
NLRC3 is identified as a unique regulatory NLR involved in the modulation of cellular processes and inflammatory responses. In this study, a novel Nod like receptor C3 (NLRC3) was functionally characterized from seven band grouper in the context of nervous necrosis virus infection. The grouper NLRC3 is highly conserved and homologous with other vertebrate proteins with a NACHT domain and a C-terminal leucine-rich repeat (LRR) domain and an N-terminal CARD domain. Quantitative gene expression analysis revealed the highest mRNA levels of NLRC3 were in the brain and gill followed by the spleen and kidney following NNV infection. Overexpression of NLRC3 augmented the NNV replication kinetics in primary grouper brain cells. NLRC3 attenuated the interferon responses in the cells following NNV infection by impacting the TRAF6/NF-κB activity and exhibited reduced IFN sensitivity, ISRE promoter activity, and IFN pathway gene expression. In contrast, NLRC3 expression positively regulated the inflammasome response and pro-inflammatory gene expression during NNV infection. NLRC3 negatively regulates the PI3K-mTOR axis and activated the cellular autophagic response. Delineating the complexity of NLRC3 regulation of immune response in the primary grouper brain cells following NNV infection suggests that the protein acts as a virally manipulated host factor that negatively regulated the antiviral immune response to augment the NNV replication.
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Affiliation(s)
- Rahul Krishnan
- Department of Aqualife Medicine, Chonnam National University, Yeosu, 59629, Republic of Korea.
| | - Rahul Rajendran
- Department of Aqualife Medicine, Chonnam National University, Yeosu, 59629, Republic of Korea
| | - Yo-Seb Jang
- Department of Aqualife Medicine, Chonnam National University, Yeosu, 59629, Republic of Korea
| | - Jong-Oh Kim
- Department of Microbiology, Pukyong National University, Busan, Republic of Korea
| | - Su-Young Yoon
- Department of Aqualife Medicine, Chonnam National University, Yeosu, 59629, Republic of Korea
| | - Myung-Joo Oh
- Department of Aqualife Medicine, Chonnam National University, Yeosu, 59629, Republic of Korea.
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20
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Affiliation(s)
- Shuhan Huang
- Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142
- Program in Neuroscience, Harvard Medical School, Boston, MA 02115
| | - Gord Fishell
- Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142
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21
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Adams Y, Jensen AR. Cerebral malaria - modelling interactions at the blood-brain barrier in vitro. Dis Model Mech 2022; 15:275963. [PMID: 35815443 PMCID: PMC9302004 DOI: 10.1242/dmm.049410] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The blood–brain barrier (BBB) is a continuous endothelial barrier that is supported by pericytes and astrocytes and regulates the passage of solutes between the bloodstream and the brain. This structure is called the neurovascular unit and serves to protect the brain from blood-borne disease-causing agents and other risk factors. In the past decade, great strides have been made to investigate the neurovascular unit for delivery of chemotherapeutics and for understanding how pathogens can circumvent the barrier, leading to severe and, at times, fatal complications. One such complication is cerebral malaria, in which Plasmodium falciparum-infected red blood cells disrupt the barrier function of the BBB, causing severe brain swelling. Multiple in vitro models of the BBB are available to investigate the mechanisms underlying the pathogenesis of cerebral malaria and other diseases. These range from single-cell monolayer cultures to multicellular BBB organoids and highly complex cerebral organoids. Here, we review the technologies available in malaria research to investigate the interaction between P. falciparum-infected red blood cells and the BBB, and discuss the advantages and disadvantages of each model. Summary: This Review discusses the available in vitro models to investigate the impact of adhesion of Plasmodium falciparum-infected red blood cells on the blood–brain barrier, a process associated with cerebral malaria.
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Affiliation(s)
- Yvonne Adams
- Centre for Medical Parasitology at the Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Anja Ramstedt Jensen
- Centre for Medical Parasitology at the Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
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22
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Chia SPS, Kong SLY, Pang JKS, Soh BS. 3D Human Organoids: The Next "Viral" Model for the Molecular Basis of Infectious Diseases. Biomedicines 2022; 10:1541. [PMID: 35884846 PMCID: PMC9312734 DOI: 10.3390/biomedicines10071541] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 06/25/2022] [Accepted: 06/27/2022] [Indexed: 02/07/2023] Open
Abstract
The COVID-19 pandemic has driven the scientific community to adopt an efficient and reliable model that could keep up with the infectious disease arms race. Coinciding with the pandemic, three dimensional (3D) human organoids technology has also gained traction in the field of infectious disease. An in vitro construct that can closely resemble the in vivo organ, organoid technology could bridge the gap between the traditional two-dimensional (2D) cell culture and animal models. By harnessing the multi-lineage characteristic of the organoid that allows for the recapitulation of the organotypic structure and functions, 3D human organoids have emerged as an essential tool in the field of infectious disease research. In this review, we will be providing a comparison between conventional systems and organoid models. We will also be highlighting how organoids played a role in modelling common infectious diseases and molecular mechanisms behind the pathogenesis of causative agents. Additionally, we present the limitations associated with the current organoid models and innovative strategies that could resolve these shortcomings.
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Affiliation(s)
- Shirley Pei Shan Chia
- Disease Modeling and Therapeutics Laboratory, ASTAR Institute of Molecular and Cell Biology, Singapore 138673, Singapore; (S.P.S.C.); (S.L.Y.K.); (J.K.S.P.)
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore
| | - Sharleen Li Ying Kong
- Disease Modeling and Therapeutics Laboratory, ASTAR Institute of Molecular and Cell Biology, Singapore 138673, Singapore; (S.P.S.C.); (S.L.Y.K.); (J.K.S.P.)
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore
| | - Jeremy Kah Sheng Pang
- Disease Modeling and Therapeutics Laboratory, ASTAR Institute of Molecular and Cell Biology, Singapore 138673, Singapore; (S.P.S.C.); (S.L.Y.K.); (J.K.S.P.)
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore
| | - Boon-Seng Soh
- Disease Modeling and Therapeutics Laboratory, ASTAR Institute of Molecular and Cell Biology, Singapore 138673, Singapore; (S.P.S.C.); (S.L.Y.K.); (J.K.S.P.)
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore
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23
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Bauer L, Laksono BM, de Vrij FMS, Kushner SA, Harschnitz O, van Riel D. The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2. Trends Neurosci 2022; 45:358-368. [PMID: 35279295 PMCID: PMC8890977 DOI: 10.1016/j.tins.2022.02.006] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 02/14/2022] [Accepted: 02/28/2022] [Indexed: 11/26/2022]
Abstract
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection is associated with a diverse spectrum of neurological complications during the acute and postacute stages. The pathogenesis of these complications is complex and dependent on many factors. For accurate and consistent interpretation of experimental data in this fast-growing field of research, it is essential to use terminology consistently. In this article, we outline the distinctions between neuroinvasiveness, neurotropism, and neurovirulence. Additionally, we discuss current knowledge of these distinct features underlying the pathogenesis of SARS-CoV-2-associated neurological complications. Lastly, we briefly discuss the advantages and limitations of different experimental models, and how these approaches can further be leveraged to advance the field.
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Affiliation(s)
- Lisa Bauer
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
| | | | | | - Steven A Kushner
- Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands
| | | | - Debby van Riel
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
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24
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Lyra E Silva NM, Barros-Aragão FGQ, De Felice FG, Ferreira ST. Inflammation at the crossroads of COVID-19, cognitive deficits and depression. Neuropharmacology 2022; 209:109023. [PMID: 35257690 PMCID: PMC8894741 DOI: 10.1016/j.neuropharm.2022.109023] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/27/2022] [Accepted: 03/02/2022] [Indexed: 12/17/2022]
Affiliation(s)
- Natalia M Lyra E Silva
- Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada; Department of Psychiatry, Queen's University, Kingston, ON, Canada.
| | - Fernanda G Q Barros-Aragão
- D'OR Institute for Research & Education, RJ, Brazil; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, RJ, Brazil.
| | - Fernanda G De Felice
- Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada; Department of Psychiatry, Queen's University, Kingston, ON, Canada; D'OR Institute for Research & Education, RJ, Brazil; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, RJ, Brazil
| | - Sergio T Ferreira
- D'OR Institute for Research & Education, RJ, Brazil; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, RJ, Brazil; Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, RJ, Brazil
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25
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Depla JA, Mulder LA, de Sá RV, Wartel M, Sridhar A, Evers MM, Wolthers KC, Pajkrt D. Human Brain Organoids as Models for Central Nervous System Viral Infection. Viruses 2022; 14:v14030634. [PMID: 35337041 PMCID: PMC8948955 DOI: 10.3390/v14030634] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/12/2022] [Accepted: 03/15/2022] [Indexed: 02/06/2023] Open
Abstract
Pathogenesis of viral infections of the central nervous system (CNS) is poorly understood, and this is partly due to the limitations of currently used preclinical models. Brain organoid models can overcome some of these limitations, as they are generated from human derived stem cells, differentiated in three dimensions (3D), and can mimic human neurodevelopmental characteristics. Therefore, brain organoids have been increasingly used as brain models in research on various viruses, such as Zika virus, severe acute respiratory syndrome coronavirus 2, human cytomegalovirus, and herpes simplex virus. Brain organoids allow for the study of viral tropism, the effect of infection on organoid function, size, and cytoarchitecture, as well as innate immune response; therefore, they provide valuable insight into the pathogenesis of neurotropic viral infections and testing of antivirals in a physiological model. In this review, we summarize the results of studies on viral CNS infection in brain organoids, and we demonstrate the broad application and benefits of using a human 3D model in virology research. At the same time, we describe the limitations of the studies in brain organoids, such as the heterogeneity in organoid generation protocols and age at infection, which result in differences in results between studies, as well as the lack of microglia and a blood brain barrier.
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Affiliation(s)
- Josse A. Depla
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC Location Academic Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.A.M.); (A.S.); (K.C.W.); (D.P.)
- Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC Location Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- UniQure Biopharma B.V., Department of Research & Development, Paasheuvelweg 25A, 1105 BE Amsterdam, The Netherlands; (R.V.d.S.); (M.W.); (M.M.E.)
- Correspondence:
| | - Lance A. Mulder
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC Location Academic Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.A.M.); (A.S.); (K.C.W.); (D.P.)
- Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC Location Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Renata Vieira de Sá
- UniQure Biopharma B.V., Department of Research & Development, Paasheuvelweg 25A, 1105 BE Amsterdam, The Netherlands; (R.V.d.S.); (M.W.); (M.M.E.)
| | - Morgane Wartel
- UniQure Biopharma B.V., Department of Research & Development, Paasheuvelweg 25A, 1105 BE Amsterdam, The Netherlands; (R.V.d.S.); (M.W.); (M.M.E.)
| | - Adithya Sridhar
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC Location Academic Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.A.M.); (A.S.); (K.C.W.); (D.P.)
| | - Melvin M. Evers
- UniQure Biopharma B.V., Department of Research & Development, Paasheuvelweg 25A, 1105 BE Amsterdam, The Netherlands; (R.V.d.S.); (M.W.); (M.M.E.)
| | - Katja C. Wolthers
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC Location Academic Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.A.M.); (A.S.); (K.C.W.); (D.P.)
| | - Dasja Pajkrt
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC Location Academic Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.A.M.); (A.S.); (K.C.W.); (D.P.)
- Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC Location Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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26
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Martínez-Salazar B, Holwerda M, Stüdle C, Piragyte I, Mercader N, Engelhardt B, Rieben R, Döring Y. COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences. Front Cell Dev Biol 2022; 10:824851. [PMID: 35242762 PMCID: PMC8887620 DOI: 10.3389/fcell.2022.824851] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/20/2022] [Indexed: 12/11/2022] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first identified in December 2019 as a novel respiratory pathogen and is the causative agent of Corona Virus disease 2019 (COVID-19). Early on during this pandemic, it became apparent that SARS-CoV-2 was not only restricted to infecting the respiratory tract, but the virus was also found in other tissues, including the vasculature. Individuals with underlying pre-existing co-morbidities like diabetes and hypertension have been more prone to develop severe illness and fatal outcomes during COVID-19. In addition, critical clinical observations made in COVID-19 patients include hypercoagulation, cardiomyopathy, heart arrythmia, and endothelial dysfunction, which are indicative for an involvement of the vasculature in COVID-19 pathology. Hence, this review summarizes the impact of SARS-CoV-2 infection on the vasculature and details how the virus promotes (chronic) vascular inflammation. We provide a general overview of SARS-CoV-2, its entry determinant Angiotensin-Converting Enzyme II (ACE2) and the detection of the SARS-CoV-2 in extrapulmonary tissue. Further, we describe the relation between COVID-19 and cardiovascular diseases (CVD) and their impact on the heart and vasculature. Clinical findings on endothelial changes during COVID-19 are reviewed in detail and recent evidence from in vitro studies on the susceptibility of endothelial cells to SARS-CoV-2 infection is discussed. We conclude with current notions on the contribution of cardiovascular events to long term consequences of COVID-19, also known as “Long-COVID-syndrome”. Altogether, our review provides a detailed overview of the current perspectives of COVID-19 and its influence on the vasculature.
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Affiliation(s)
- Berenice Martínez-Salazar
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Melle Holwerda
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Chiara Stüdle
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | - Indre Piragyte
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.,Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Nadia Mercader
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.,Institute of Anatomy, University of Bern, Bern, Switzerland.,Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.,Bern Center of Precision Medicine BCPM, University of Bern, Bern, Switzerland
| | | | - Robert Rieben
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Yvonne Döring
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.,Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), Munich, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
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27
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Rothan HA, Kumari P, Stone S, Natekar JP, Arora K, Auroni TT, Kumar M. SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways. Pathogens 2022; 11:pathogens11020257. [PMID: 35215199 PMCID: PMC8876293 DOI: 10.3390/pathogens11020257] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/05/2022] [Accepted: 02/15/2022] [Indexed: 02/01/2023] Open
Abstract
Transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) have been extensively used to investigate the pathogenesis and tissue tropism of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Neuroinvasion and the replication of SARS-CoV-2 within the central nervous system (CNS) of K18-hACE2 mice is associated with increased mortality; although, the mechanisms by which this occurs remain unclear. In this study, we generated primary neuronal cultures from K18-hACE2 mice to investigate the effects of a SARS-CoV-2 infection. We also evaluated the immunological response to SARS-CoV-2 infection in the CNS of K18-hACE2 mice and mouse neuronal cultures. Our data show that neuronal cultures obtained from K18-hACE2 mice are permissive to SARS-CoV-2 infection and support productive virus replication. Furthermore, SARS-CoV-2 infection upregulated the expression of genes involved in innate immunity and inflammation, including IFN-α, ISG-15, CXCL10, CCL2, IL-6 and TNF-α, in the neurons and mouse brains. In addition, we found that SARS-CoV-2 infection of neurons and mouse brains activates the ZBP1/pMLKL-regulated necroptosis pathway. Together, our data provide insights into the neuropathogenesis of SARS-CoV-2 infection in K18-hACE2 mice.
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28
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Cavallieri F, Sellner J, Zedde M, Moro E. Neurologic complications of coronavirus and other respiratory viral infections. HANDBOOK OF CLINICAL NEUROLOGY 2022; 189:331-358. [PMID: 36031313 PMCID: PMC9418023 DOI: 10.1016/b978-0-323-91532-8.00004-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In humans, several respiratory viruses can have neurologic implications affecting both central and peripheral nervous system. Neurologic manifestations can be linked to viral neurotropism and/or indirect effects of the infection due to endothelitis with vascular damage and ischemia, hypercoagulation state with thrombosis and hemorrhages, systemic inflammatory response, autoimmune reactions, and other damages. Among these respiratory viruses, recent and huge attention has been given to the coronaviruses, especially the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic started in 2020. Besides the common respiratory symptoms and the lung tropism of SARS-CoV-2 (COVID-19), neurologic manifestations are not rare and often present in the severe forms of the infection. The most common acute and subacute symptoms and signs include headache, fatigue, myalgia, anosmia, ageusia, sleep disturbances, whereas clinical syndromes include mainly encephalopathy, ischemic stroke, seizures, and autoimmune peripheral neuropathies. Although the pathogenetic mechanisms of COVID-19 in the various acute neurologic manifestations are partially understood, little is known about long-term consequences of the infection. These consequences concern both the so-called long-COVID (characterized by the persistence of neurological manifestations after the resolution of the acute viral phase), and the onset of new neurological symptoms that may be linked to the previous infection.
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Affiliation(s)
- Francesco Cavallieri
- Neurology Unit, Neuromotor and Rehabilitation Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy,Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
| | - Johann Sellner
- Department of Neurology, Landesklinikum Mistelbach-Gänserndorf, Mistelbach, Austria,Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, Salzburg, Austria
| | - Marialuisa Zedde
- Neurology Unit, Neuromotor and Rehabilitation Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Elena Moro
- Division of Neurology, CHU of Grenoble, Grenoble Alpes University, Grenoble Institute of Neurosciences, Grenoble, France,Correspondence to: Elena Moro, Service de neurologie, CHU de Grenoble (Hôpital Nord), Boulevard de la Chantourne, 38043 La Tronche, France. Tel: + 33-4-76-76-94-52, Fax: +33-4-76-76-56-31
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29
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Chapoval SP, Keegan AD. Perspectives and potential approaches for targeting neuropilin 1 in SARS-CoV-2 infection. Mol Med 2021; 27:162. [PMID: 34961486 PMCID: PMC8711287 DOI: 10.1186/s10020-021-00423-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 12/13/2021] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel type b coronavirus responsible for the COVID-19 pandemic. With over 224 million confirmed infections with this virus and more than 4.6 million people dead because of it, it is critically important to define the immunological processes occurring in the human response to this virus and pathogenetic mechanisms of its deadly manifestation. This perspective focuses on the contribution of the recently discovered interaction of SARS-CoV-2 Spike protein with neuropilin 1 (NRP1) receptor, NRP1 as a virus entry receptor for SARS-CoV-2, its role in different physiologic and pathologic conditions, and the potential to target the Spike-NRP1 interaction to combat virus infectivity and severe disease manifestations.
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Affiliation(s)
- Svetlana P Chapoval
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 West Baltimore Street, Baltimore, MD, 21201, USA.
- Program in Oncology at the Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
- SemaPlex LLC, Ellicott City, MD, USA.
| | - Achsah D Keegan
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 West Baltimore Street, Baltimore, MD, 21201, USA
- Program in Oncology at the Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
- VA Maryland Health Care System, Baltimore VA Medical Center, Baltimore, MD, USA
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30
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Potjewyd G, Kellett K, Hooper N. 3D hydrogel models of the neurovascular unit to investigate blood-brain barrier dysfunction. Neuronal Signal 2021; 5:NS20210027. [PMID: 34804595 PMCID: PMC8579151 DOI: 10.1042/ns20210027] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/16/2022] Open
Abstract
The neurovascular unit (NVU), consisting of neurons, glial cells, vascular cells (endothelial cells, pericytes and vascular smooth muscle cells (VSMCs)) together with the surrounding extracellular matrix (ECM), is an important interface between the peripheral blood and the brain parenchyma. Disruption of the NVU impacts on blood-brain barrier (BBB) regulation and underlies the development and pathology of multiple neurological disorders, including stroke and Alzheimer's disease (AD). The ability to differentiate induced pluripotent stem cells (iPSCs) into the different cell types of the NVU and incorporate them into physical models provides a reverse engineering approach to generate human NVU models to study BBB function. To recapitulate the in vivo situation such NVU models must also incorporate the ECM to provide a 3D environment with appropriate mechanical and biochemical cues for the cells of the NVU. In this review, we provide an overview of the cells of the NVU and the surrounding ECM, before discussing the characteristics (stiffness, functionality and porosity) required of hydrogels to mimic the ECM when incorporated into in vitro NVU models. We summarise the approaches available to measure BBB functionality and present the techniques in use to develop robust and translatable models of the NVU, including transwell models, hydrogel models, 3D-bioprinting, microfluidic models and organoids. The incorporation of iPSCs either without or with disease-specific genetic mutations into these NVU models provides a platform in which to study normal and disease mechanisms, test BBB permeability to drugs, screen for new therapeutic targets and drugs or to design cell-based therapies.
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Affiliation(s)
- Geoffrey Potjewyd
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, U.K
| | - Katherine A.B. Kellett
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, U.K
| | - Nigel M. Hooper
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, U.K
- Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and University of Manchester, Manchester, U.K
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Abstract
Incidence and Case Fatality Rate of COVID-19 in Patients With Active
Epilepsy Cabezudo-Garcia P, Ciano-Petersen NL, Mena-Vazquez N, et al.
Neurology. 2020;95(10):e1417-e1425.
doi:10.1212/WNL.0000000000010033 Objective: This article estimates the incidence and fatality of coronavirus disease 2019
(COVID-19) and identifies potential risk factors for fatality in patients with
active epilepsy. Methods: This is a cross-sectional observational study of patients with active epilepsy and
COVID-19. A control group was used to compare the cumulative incidence and case
fatality rate (CFR). The main outcomes of the study were cumulative incidence,
defined as number of patients with active epilepsy and COVID-19 admitted to an
emergency department divided by the total number of patients with epilepsy at risk,
and CFR based on the number of deaths during the enrollment period. Multiple
logistic regression analysis was performed to investigate risk factors for fatality
in patients with active epilepsy. Results: Of the 1537 patients who fulfilled the inclusion criteria, 21 (1.3%) had active
epilepsy. The cumulative incidence (95% CI) of COVID-19 in patients with epilepsy
was higher (1.2% [0.6-2.4]) compared to the population without epilepsy (0.5%
[0.5-0.5]). In reverse transcription polymerase chain reaction–positive patients,
there were no significant differences in CFR in patients with active epilepsy
compared to patients without epilepsy (33.3% vs 8.3%; P = .266). Of
the 21 patients with active epilepsy, 5 (23%) died. In multivariate analysis, the
factor associated with fatality in patients with active epilepsy was hypertension
(odds ratio [OR] 2.8 [95% CI: 1.3-21.6]). In another model, age (OR: 1.0 [95% CI:
1.0-1.1]) and epilepsy (OR: 5.1 [95% CI: 1.3-24.0]) were associated with fatality
during hospitalization. Conclusion: COVID-19 cumulative incidence was higher in patients with active epilepsy. Epilepsy
was associated with fatality during hospitalization. Hypertension was associated
with fatality in patients with epilepsy.
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Larijani B, Foroughi-Heravani N, Abedi M, Tayanloo-Beik A, Rezaei-Tavirani M, Adibi H, Arjmand B. Recent Advances of COVID-19 Modeling Based on Regenerative Medicine. Front Cell Dev Biol 2021; 9:683619. [PMID: 34760882 PMCID: PMC8573217 DOI: 10.3389/fcell.2021.683619] [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: 03/21/2021] [Accepted: 09/22/2021] [Indexed: 11/13/2022] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has caused a pandemic since December 2019 that originated in Wuhan, China. Soon after that, the world health organization declared Coronavirus disease-2019 a global health concern. SARS-CoV-2 is responsible for a lethal respiratory infection as well as the involvement of other organs due to its large tropism spectrum such as neurologic, cardiovascular, endocrine, gastrointestinal, and renal systems. Since the behavior of the virus is not fully understood, a new manifestation of the infection is revealed every day. In order to be able to design more efficient drugs and vaccines to treat the infection, finding out the exact mechanism of pathogenicity would be necessary. Although there have been some big steps toward understanding the relevant process, there are still some deficiencies in this field. Accordingly, regenerative medicine (RM), can offer promising opportunities in discovering the exact mechanisms and specific treatments. For instance, since it is not always possible to catch the pathophysiology mechanisms in human beings, several modeling methods have been introduced in this field that can be studied in three main groups: stem cell-based models, organoids, and animal models. Regarding stem cell-based models, induced pluripotent stem cells are the major study subjects, which are generated by reprogramming the somatic stem cells and then directing them into different adult cell populations to study their behavior toward the infection. In organoid models, different cell lines can be guided to produce a 3D structure including liver, heart, and brain-like platforms. Among animal models, mice are the most common species in this field. However, in order for mice models to be permissive to the virus, angiotensin-converting enzyme 2 receptors, the main receptor involved in the pathogenicity of the virus, should be introduced to the host cells through different methods. Here, the current known mechanism of SARS-CoV-2 infection, different suggested models, the specific response toward different manipulation as well as challenges and shortcomings in each case have been reviewed. Finally, we have tried to provide a quick summary of the present available RM-based models for SARS-CoV-2 infection, as an essential part of developing drugs, for future therapeutic goals.
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Affiliation(s)
- Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical sciences, Tehran, Iran
| | - Najmeh Foroughi-Heravani
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Abedi
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hossein Adibi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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The K18-hACE2 Transgenic Mouse Model Recapitulates Non-Severe and Severe COVID-19 in Response to Infectious Dose of SARS-CoV-2 Virus. J Virol 2021; 96:e0096421. [PMID: 34668775 PMCID: PMC8754221 DOI: 10.1128/jvi.00964-21] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
A comprehensive analysis and characterization of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection model that mimics non-severe and severe coronavirus disease 2019 (COVID-19) in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18-hACE2 mouse model expressing human (h)ACE2 in mice, controlled by the human keratin 18 (K18) promoter, in the epithelia, including airway epithelial cells where SARS-CoV-2 infections typically start. We found that intranasal inoculation with higher viral doses (2 × 103 and 2 × 104 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lung, liver, and kidney, while lower doses (2 × 101 and 2 × 102 PFU) led to less severe tissue damage and some mice recovered from the infection. In this hACE2 mouse model, SARS-CoV-2 infection damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in postmortem samples from COVID-19 patients. Finally, the mice that recovered from infection with a low dose of virus survived rechallenge with a high dose of virus. Compared to other existing models, the K18-hACE2 model seems to be the most sensitive COVID-19 model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human postmortem samples from COVID-19 patients. In conclusion, the K18-hACE2 mouse model recapitulates both severe and non-severe COVID-19 in humans being dose-dependent and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19. IMPORTANCE The pandemic of coronavirus disease 2019 (COVID-19) has reached nearly 240 million cases, caused nearly 5 million deaths worldwide as of October 2021, and has raised an urgent need for the development of novel drugs and therapeutics to prevent the spread and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To achieve this goal, an animal model that recapitulates the features of human COVID-19 disease progress and pathogenesis is greatly needed. In this study, we have comprehensively characterized a mouse model of SARS-CoV-2 infection using K18-hACE2 transgenic mice. We infected the mice with low and high doses of SARS-CoV-2 to study the pathogenesis and survival in response to different infection patterns. Moreover, we compared the pathogenesis of the K18-hACE2 transgenic mice with that of the COVID-19 patients to show that this model could be a useful tool for the development of antiviral drugs and therapeutics.
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Han Y, Yuan K, Wang Z, Liu WJ, Lu ZA, Liu L, Shi L, Yan W, Yuan JL, Li JL, Shi J, Liu ZC, Wang GH, Kosten T, Bao YP, Lu L. Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions. Transl Psychiatry 2021; 11:499. [PMID: 34593760 PMCID: PMC8482959 DOI: 10.1038/s41398-021-01629-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/03/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has caused large-scale economic and social losses and worldwide deaths. Although most COVID-19 patients have initially complained of respiratory insufficiency, the presence of neuropsychiatric manifestations is also reported frequently, ranging from headache, hyposmia/anosmia, and neuromuscular dysfunction to stroke, seizure, encephalopathy, altered mental status, and psychiatric disorders, both in the acute phase and in the long term. These neuropsychiatric complications have emerged as a potential indicator of worsened clinical outcomes and poor prognosis, thus contributing to mortality in COVID-19 patients. Their etiology remains largely unclear and probably involves multiple neuroinvasive pathways. Here, we summarize recent animal and human studies for neurotrophic properties of severe acute respiratory syndrome coronavirus (SARS-CoV-2) and elucidate potential neuropathogenic mechanisms involved in the viral invasion of the central nervous system as a cause for brain damage and neurological impairments. We then discuss the potential therapeutic strategy for intervening and preventing neuropsychiatric complications associated with SARS-CoV-2 infection. Time-series monitoring of clinical-neurochemical-radiological progress of neuropsychiatric and neuroimmune complications need implementation in individuals exposed to SARS-CoV-2. The development of a screening, intervention, and therapeutic framework to prevent and reduce neuropsychiatric sequela is urgently needed and crucial for the short- and long-term recovery of COVID-19 patients.
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Affiliation(s)
- Ying Han
- grid.11135.370000 0001 2256 9319National Institute on Drug Dependence and Beijing Key Laboratory on Drug Dependence, Peking University, Beijing, China
| | - Kai Yuan
- grid.11135.370000 0001 2256 9319Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Zhe Wang
- grid.11135.370000 0001 2256 9319Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Wei-Jian Liu
- grid.11135.370000 0001 2256 9319Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Zheng-An Lu
- grid.11135.370000 0001 2256 9319Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Lin Liu
- grid.11135.370000 0001 2256 9319National Institute on Drug Dependence and Beijing Key Laboratory on Drug Dependence, Peking University, Beijing, China ,grid.11135.370000 0001 2256 9319School of Public Health, Peking University, Beijing, China
| | - Le Shi
- grid.11135.370000 0001 2256 9319Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Wei Yan
- grid.11135.370000 0001 2256 9319Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Jun-Liang Yuan
- grid.11135.370000 0001 2256 9319Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China
| | - Jia-Li Li
- grid.11135.370000 0001 2256 9319National Institute on Drug Dependence and Beijing Key Laboratory on Drug Dependence, Peking University, Beijing, China
| | - Jie Shi
- grid.11135.370000 0001 2256 9319National Institute on Drug Dependence and Beijing Key Laboratory on Drug Dependence, Peking University, Beijing, China
| | - Zhong-Chun Liu
- grid.412632.00000 0004 1758 2270Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, China
| | - Gao-Hua Wang
- grid.412632.00000 0004 1758 2270Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, China
| | - Thomas Kosten
- grid.39382.330000 0001 2160 926XDivision of Alcohol and Addiction Psychiatry, Baylor College of Medicine, Houston, TX USA
| | - Yan-Ping Bao
- National Institute on Drug Dependence and Beijing Key Laboratory on Drug Dependence, Peking University, Beijing, China. .,School of Public Health, Peking University, Beijing, China.
| | - Lin Lu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing, China. .,Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
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35
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Are the Organoid Models an Invaluable Contribution to ZIKA Virus Research? Pathogens 2021; 10:pathogens10101233. [PMID: 34684182 PMCID: PMC8537471 DOI: 10.3390/pathogens10101233] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/15/2021] [Accepted: 09/20/2021] [Indexed: 12/16/2022] Open
Abstract
In order to prevent new pathogen outbreaks and avoid possible new global health threats, it is important to study the mechanisms of microbial pathogenesis, screen new antiviral agents and test new vaccines using the best methods. In the last decade, organoids have provided a groundbreaking opportunity for modeling pathogen infections in human brains, including Zika virus (ZIKV) infection. ZIKV is a member of the Flavivirus genus, and it is recognized as an emerging infectious agent and a serious threat to global health. Organoids are 3D complex cellular models that offer an in-scale organ that is physiologically alike to the original one, useful for exploring the mechanisms behind pathogens infection; additionally, organoids integrate data generated in vitro with traditional tools and often support those obtained in vivo with animal model. In this mini-review the value of organoids for ZIKV research is examined and sustained by the most recent literature. Within a 3D viewpoint, tissue engineered models are proposed as future biological systems to help in deciphering pathogenic processes and evaluate preventive and therapeutic strategies against ZIKV. The next steps in this field constitute a challenge that may protect people and future generations from severe brain defects.
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36
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Abstract
The appreciation of human microbiome is gaining strong grounds in biomedical research. In addition to gut-brain axis, is the lung-brain axis, which is hypothesised to link pulmonary microbes to neurodegenerative disorders and behavioural changes. There is a need for analysis based on emerging studies to map out the prospects for lung-brain axis. In this review, relevant English literature and researches in the field of 'lung-brain axis' is reported. We recommend all the highlighted prospective studies to be integrated with an interdisciplinary approach. This might require conceptual research approaches based on physiology and pathophysiology. Multimodal aspects should include experimental animal units, while exploring the research gaps and making reference to the already existing human data. The overall microbiome medicine is gaining more ground. Aetiological paths and experimental recommendations as per prospective studies in this review will be an important guideline to develop effective treatments for any lung induced neurodegenerative diseases. An in-depth knowledge of the bi-directional communication between host and microbiome in the lung could help treatment to respiratory infections, alleviate stress, anxiety and enhanced neurological effects. The timely prevention and treatment of neurodegenerative diseases requires paradigm shift of the aetiology and more innovative experimentation.Impact statementThe overall microbiome medicine is gaining more ground. An in-depth knowledge of the bi-directional communication between host and microbiome in the lung could confer treatment to respiratory infections, alleviate stress, anxiety and enhanced neurological effects. Based on this review, we recommend all the highlighted prospective studies to be integrated and be given an interdisciplinary approach. This might require conceptual research approaches based on physiology and pathophysiology. Multimodal aspects should include experimental animal units; while exploring the research gaps and making reference to the already existing human data.
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Affiliation(s)
- Ousman Bajinka
- Department of Medical Microbiology, Central South University, Changsha, Hunan Provinces, China.,China-Africa Research Center of Infectious Diseases, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.,School of Medicine and Allied Health Sciences, University of The Gambia, Banjul, Gambia
| | - Lucette Simbilyabo
- Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, Hunan Provinces, China
| | - Yurong Tan
- Department of Medical Microbiology, Central South University, Changsha, Hunan Provinces, China.,China-Africa Research Center of Infectious Diseases, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - John Jabang
- School of Medicine and Allied Health Sciences, University of The Gambia, Banjul, Gambia
| | - Shakeel Ahmed Saleem
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan Provinces, China
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Krishnan R, Kim JO, Jang YS, Oh MJ. Proteasome subunit beta type-8 from sevenband grouper negatively regulates cytokine responses by interfering NF-κB signaling upon nervous necrosis viral infection. FISH & SHELLFISH IMMUNOLOGY 2021; 113:118-124. [PMID: 33848637 DOI: 10.1016/j.fsi.2021.04.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/23/2021] [Accepted: 04/06/2021] [Indexed: 06/12/2023]
Abstract
During viral infection, proper regulation of immune signaling is essential to ensure successful clearance of virus. Immunoproteasome is constitutively expressed and gets induced during viral infection by interferon signaling and contributes to regulate proinflammatory cytokine production and activation of the NF-κB pathway. In this study, we identified Hs-PSMB8, a member of the proteasome β-subunits (PSMB) family, as a negative regulator of NF-κB responses during NNV infection. The transient expression of Hs-PSMB8 delayed the appearance of cytopathic effect (CPE) and showed a higher viral load. The Hs-PSMB8 interacted with NNV which was confirmed using immunocolocalization and co-IP. Overexpression of Hs-PSMB8 diminished virus induced activation of the NF-κB promoters and downregulated the activation of IL-1β, TNFα, IL6, IL8, IFNγ expression upon NNV infection. Collectively, our results demonstrate that PSMB8 is an important regulator of NF-κB signaling during NNV infection in sevenband grouper.
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Affiliation(s)
- Rahul Krishnan
- Department of Aqualife Medicine, Chonnam National University, Yeosu, Republic of Korea
| | - Jong-Oh Kim
- Institute of Marine Biotechnology, Pukyong National University, Busan, Republic of Korea.
| | - Yo-Seb Jang
- Department of Aqualife Medicine, Chonnam National University, Yeosu, Republic of Korea
| | - Myung-Joo Oh
- Department of Aqualife Medicine, Chonnam National University, Yeosu, Republic of Korea.
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