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      Neuroinvasion of SARS-CoV-2 in human and mouse brain

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      1 , 2 , 3 , 1 , 4 , 1 , 5 , 5 , 1 , 1 , 1 , 6 , 1 , 7 , 7 , 8 , 8 , 8 , 8 , 8 , 1 , 9 , 5 , 10 , 11 , 12 , 11 , 12 , 2 , 8 , 2 , 3 , 13 , 1 , 14 , 14 , 1 , 9 , 7 , 5 , 16 , 5 , 10 , 16 , 17 , 5 , 18 , 3 , 13 , 4 , 18 , 19 , 5 , 16 , 5 , 2 , 8 , , 1 , 15 , 20 ,
      The Journal of Experimental Medicine
      Rockefeller University Press

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          Abstract

          Neurological symptoms are frequently observed in COVID-19. Here, we examine the neuroinvasive potential of SARS-CoV-2 and demonstrate infection of neurons in three separate approaches: mouse model, human brain organoid, and autopsy of COVID-19 patients.

          Abstract

          Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

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          Most cited references43

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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            Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China

            The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations.
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              Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

              Summary Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: InvestigationRole: MethodologyRole: Resources
                Role: InvestigationRole: Methodology
                Role: Investigation
                Role: Formal analysis
                Role: Investigation
                Role: Investigation
                Role: Data curationRole: Investigation
                Role: Investigation
                Role: Investigation
                Role: Data curationRole: Visualization
                Role: Formal analysisRole: MethodologyRole: Resources
                Role: Data curation
                Role: InvestigationRole: Resources
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Resources
                Role: Project administrationRole: Resources
                Role: Formal analysisRole: MethodologyRole: SoftwareRole: Visualization
                Role: Supervision
                Role: MethodologyRole: Resources
                Role: Resources
                Role: Funding acquisitionRole: Project administrationRole: Supervision
                Role: ResourcesRole: Validation
                Role: ResourcesRole: Validation
                Role: Funding acquisitionRole: ResourcesRole: Writing - review & editing
                Role: InvestigationRole: SupervisionRole: Validation
                Role: InvestigationRole: Resources
                Role: InvestigationRole: ResourcesRole: Writing - review & editing
                Role: ResourcesRole: Writing - review & editing
                Role: SupervisionRole: Writing - review & editing
                Role: Funding acquisitionRole: ResourcesRole: Writing - review & editing
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Writing - review & editing
                Role: InvestigationRole: Resources
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: Visualization
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing
                Journal
                J Exp Med
                J Exp Med
                jem
                The Journal of Experimental Medicine
                Rockefeller University Press
                0022-1007
                1540-9538
                01 March 2021
                12 January 2021
                12 January 2021
                : 218
                : 3
                : e20202135
                Affiliations
                [1 ]Department of Immunobiology, Yale School of Medicine, New Haven, CT
                [2 ]Department of Genetics, Yale School of Medicine, New Haven, CT
                [3 ]Department of Neuroscience, Yale School of Medicine, New Haven, CT
                [4 ]Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT
                [5 ]Sorbonne Université, INSERM U1127, French National Centre for Scientific Research, Joint Research Unit 7225, Paris Brain Institute, Institut du Cerveau et de la Moelle Épinière, Paris, France
                [6 ]Department of Biomedical Engineering, Yale University, New Haven, CT
                [7 ]Department of Comparative Medicine, Yale School of Medicine, New Haven, CT
                [8 ]Yale Center for Genome Analysis, West Haven, CT
                [9 ]Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT
                [10 ]Yale Environmental Health and Safety, Yale University, New Haven, CT
                [11 ]Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT
                [12 ]Department of Computer Science, Yale University, New Haven, CT
                [13 ]Department of Neurosurgery, Yale School of Medicine, New Haven, CT
                [14 ]Department of Laboratory Medicine, Geisinger Medical Center, Danville, PA
                [15 ]Department of Molecular, Cellular, and Developmental Biology, Yale School of Medicine, New Haven, CT
                [16 ]Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neuropathologie, Paris, France
                [17 ]Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Cellule nationale de référence des maladies de Creutzfeldt-Jakob, Paris, France
                [18 ]Department of Neurology, Yale School of Medicine, New Haven, CT
                [19 ]Department of Pathology, Yale School of Medicine, New Haven, CT
                [20 ]Howard Hughes Medical Institute, Chevy Chase, MD
                Author notes
                Correspondence to Akiko Iwasaki: akiko.iwasaki@ 123456yale.edu

                Disclosures: M. Gunel reported personal fees from AI Therapeutics outside the submitted work; and reported, "AI Therapeutics is currently sponsoring a clinical trial for a therapeutic, which has no relevance for this study, in COVID-19. I am the Chief Scientific Advisor to AI Therapeutics." C.B. Wilen reported personal fees from ZymoResearch outside the submitted work; in addition, C.B. Wilen had a patent for compounds and compositions for treating, ameliorating, and/or preventing SARS-CoV-2 infection and/or complications thereof pending. S. Haik reported a patent to Method for treating prion diseases (PCT/EP 2019/070457) pending. A. Iwasaki reported "other" from RIGImmune and grants from Spring Discovery during the conduct of the study; in addition, A. Iwasaki had a patent to 14/776,463 pending, a patent for a T cell-based immunotherapy for central nervous system viral infections and tumors pending, and a patent to manipulation of meningeal lymphatic vasculature for brain and CNS tumor therapy pending. No other disclosures were reported.

                [*]

                E. Song and C. Zhang contributed equally to this paper.

                Author information
                https://orcid.org/0000-0001-5448-5865
                https://orcid.org/0000-0002-2736-8791
                https://orcid.org/0000-0002-1308-8246
                https://orcid.org/0000-0003-0097-0923
                https://orcid.org/0000-0002-8807-3321
                https://orcid.org/0000-0003-1733-515X
                https://orcid.org/0000-0001-6118-872X
                https://orcid.org/0000-0002-1132-8170
                https://orcid.org/0000-0003-2663-6544
                https://orcid.org/0000-0002-7761-3361
                https://orcid.org/0000-0002-9428-8820
                https://orcid.org/0000-0001-9882-4478
                https://orcid.org/0000-0002-7835-3186
                https://orcid.org/0000-0003-4880-801X
                https://orcid.org/0000-0002-1605-6119
                https://orcid.org/0000-0002-3954-6292
                https://orcid.org/0000-0002-5786-3718
                https://orcid.org/0000-0002-6402-2730
                https://orcid.org/0000-0002-5827-2952
                https://orcid.org/0000-0001-6576-5432
                https://orcid.org/0000-0001-5558-3758
                https://orcid.org/0000-0003-3911-9925
                https://orcid.org/0000-0002-3267-5139
                https://orcid.org/0000-0002-2290-7055
                https://orcid.org/0000-0003-3699-2446
                https://orcid.org/0000-0002-1577-8419
                https://orcid.org/0000-0002-5274-3194
                https://orcid.org/0000-0003-2495-9403
                https://orcid.org/0000-0002-7522-4602
                https://orcid.org/0000-0002-1956-0150
                https://orcid.org/0000-0001-6022-1188
                https://orcid.org/0000-0003-3397-0292
                https://orcid.org/0000-0003-1737-8707
                https://orcid.org/0000-0001-7230-1409
                https://orcid.org/0000-0003-2143-4329
                https://orcid.org/0000-0003-3498-4602
                https://orcid.org/0000-0003-2642-4402
                https://orcid.org/0000-0002-7313-7652
                https://orcid.org/0000-0002-7824-9856
                Article
                jem.20202135
                10.1084/jem.20202135
                7808299
                33433624
                546edb94-b53b-4735-9185-cb3fd26fb8a7
                © 2021 Song et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 04 October 2020
                : 23 November 2020
                : 10 December 2020
                Page count
                Pages: 18
                Funding
                Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;
                Award ID: R01AI157488
                Award ID: R01NS111242
                Award ID: T32GM007205
                Award ID: F30CA239444
                Award ID: 2T32AI007517
                Award ID: K23MH118999
                Funded by: Yale University, DOI http://dx.doi.org/10.13039/100005326;
                Funded by: Emergent Ventures at the Mercatus Center;
                Funded by: Mathers Foundation, DOI http://dx.doi.org/10.13039/100011671;
                Funded by: Ludwig Family Foundation;
                Funded by: Howard Hughes Medical Institute, DOI http://dx.doi.org/10.13039/100000011;
                Categories
                Article
                Infectious Disease and Host Defense

                Medicine
                Medicine

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