Morphological, cellular, and molecular basis of brain infection in COVID-19 patients
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Published:2022-08-11
Issue:35
Volume:119
Page:
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ISSN:0027-8424
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Container-title:Proceedings of the National Academy of Sciences
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language:en
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Short-container-title:Proc. Natl. Acad. Sci. U.S.A.
Author:
Crunfli Fernanda1ORCID, Carregari Victor C.1ORCID, Veras Flavio P.2, Silva Lucas S.1, Nogueira Mateus Henrique1ORCID, Antunes André Saraiva Leão Marcelo1ORCID, Vendramini Pedro Henrique1, Valença Aline Gazzola Fragnani1, Brandão-Teles Caroline1, Zuccoli Giuliana da Silva1, Reis-de-Oliveira Guilherme1, Silva-Costa Lícia C.1, Saia-Cereda Verônica Monteiro1, Smith Bradley J.1ORCID, Codo Ana Campos1ORCID, de Souza Gabriela F1ORCID, Muraro Stéfanie P.1, Parise Pierina Lorencini1ORCID, Toledo-Teixeira Daniel A.1, Santos de Castro Ícaro Maia3ORCID, Melo Bruno Marcel2, Almeida Glaucia M.2ORCID, Firmino Egidi Mayara Silva2, Paiva Isadora Marques2ORCID, Silva Bruna Manuella Souza2, Guimarães Rafaela Mano2ORCID, Mendes Niele D.2ORCID, Ludwig Raíssa L.1, Ruiz Gabriel P.1, Knittel Thiago L.1ORCID, Davanzo Gustavo G.1ORCID, Gerhardt Jaqueline Aline1, Rodrigues Patrícia Brito1, Forato Julia1, Amorim Mariene Ribeiro1ORCID, Brunetti Natália S.1, Martini Matheus Cavalheiro1, Benatti Maíra Nilson2, Batah Sabrina S.2, Siyuan Li2ORCID, João Rafael B.1, Aventurato Ítalo K.1ORCID, Rabelo de Brito Mariana1, Mendes Maria J.1, da Costa Beatriz A.1ORCID, Alvim Marina K. M.1, da Silva Júnior José Roberto1, Damião Lívia L.1, de Sousa Iêda Maria P.1, da Rocha Elessandra D.1, Gonçalves Solange M.1, Lopes da Silva Luiz H.1, Bettini Vanessa1, Campos Brunno M.1ORCID, Ludwig Guilherme1ORCID, Tavares Lucas Alves2ORCID, Pontelli Marjorie Cornejo2ORCID, Viana Rosa Maria Mendes2, Martins Ronaldo B.2ORCID, Vieira Andre Schwambach1, Alves-Filho José Carlos2ORCID, Arruda Eurico2ORCID, Podolsky-Gondim Guilherme Gozzoli2ORCID, Santos Marcelo Volpon2, Neder Luciano2, Damasio André1ORCID, Rehen Stevens45ORCID, Vinolo Marco Aurélio Ramirez1, Munhoz Carolina Demarchi3, Louzada-Junior Paulo2ORCID, Oliveira Renê Donizeti2, Cunha Fernando Q.2, Nakaya Helder I.3ORCID, Mauad Thais3, Duarte-Neto Amaro Nunes3, Ferraz da Silva Luiz Fernando3ORCID, Dolhnikoff Marisa3, Saldiva Paulo Hilario Nascimento3, Farias Alessandro S.1, Cendes Fernando1ORCID, Moraes-Vieira Pedro Manoel M.1ORCID, Fabro Alexandre T.2, Sebollela Adriano2ORCID, Proença-Modena José L.1ORCID, Yasuda Clarissa L.1ORCID, Mori Marcelo A.1ORCID, Cunha Thiago M.2, Martins-de-Souza Daniel14
Affiliation:
1. Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil 2. Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil 3. University of São Paulo, São Paulo, 05508-220, Brazil 4. D'Or Institute for Research and Education, 04502001, Brazil 5. Institute of Biomedical Science, Federal University of Rio de Janeiro, Rio de Janeiro, 21941590, Brazil
Abstract
Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of “long COVID-19” syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell–derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction. SARS-CoV-2–infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.
Publisher
Proceedings of the National Academy of Sciences
Subject
Multidisciplinary
Cited by
102 articles.
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