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Morphological, cellular, and molecular basis of brain infection in COVID-19 patients

2022; National Academy of Sciences; Volume: 119; Issue: 35 Linguagem: Inglês

10.1073/pnas.2200960119

1091-6490

Fernanda Crunfli, Victor Corasolla Carregari, Flávio P. Veras, Lucas Scárdua Silva, Mateus Henrique Nogueira, André Saraiva Leão Marcelo Antunes, Pedro Henrique Vendramini, Aline Gazzola Fragnani Valença, Caroline Brandão‐Teles, Giuliana S. Zuccoli, Guilherme Reis‐de‐Oliveira, Lícia C. Silva-Costa, Verônica M. Saia‐Cereda, Bradley J. Smith, Ana Campos Codo, Gabriela Fabiano de Souza, Stéfanie Primon Muraro, Pierina Lorencini Parise, Daniel A. Toledo-Teixeira, Ícaro Maia Santos de Castro, Bruno Marcel Silva de Melo, Glaucia M. Almeida, Egidi Mayara Silva Firmino, Isadora Marques Paiva, Bruna Manuella Souza Silva, Rafaela Mano Guimarães, Niele Dias Mendes, Raíssa L. Ludwig, Gabriel Palermo Ruiz, Thiago L. Knittel, Gustavo Gastão Davanzo, Jaqueline Aline Gerhardt, Patrícia Brito Rodrigues, Julia Forato, Mariene R. Amorim, Natália S. Brunetti, Matheus Cavalheiro Martini, Maíra Nilson Benatti, Sabrina Setembre Batah, Li Siyuan, Rafael Batista João, Ítalo Karmann Aventurato, Mariana Rabelo de Brito, Maria Julia Mendes, Beatriz Amorim Da Costa, Marina K. M. Alvim, José Roberto da Silva, Lívia Liviane Damião, Iêda Maria Pereira de Sousa, Elessandra Dias da Rocha, Solange Maria Gonçalves, Luiz H. Lopes da Silva, Vanessa Bettini, Brunno Machado de Campos, Guilherme Ludwig, Lucas Tavares, Marjorie Cornejo Pontelli, Rosa Maria Mendes Viana, Ronaldo B. Martins, André Schwambach Vieira, José C. Alves‐Filho, Eurico Arruda, Guilherme Gozzoli Podolsky Gondim, Marcelo Volpon Santos, Luciano Neder, André Damásio, Stevens K. Rehen, Marco Aurélio Ramirez Vinolo, Carolina Demarchi Munhoz, Paulo Louzada‐Júnior, Renê Donizeti Ribeiro de Oliveira, Fernando Q. Cunha, Helder I. Nakaya, Thaís Mauad, Amaro Nunes Duarte‐Neto, Luiz Fernando Ferraz da Silva, Marisa Dolhnikoff, Paulo Hilário Nascimento Saldiva, Alessandro S. Farias, Fernando Cendes, Pedro M. Moraes‐Vieira, Alexandre Todorovic Fabro, Adriano Sebollela, José Luiz Proença-Módena, Clarissa Lin Yasuda, Marcelo A. Mori, Thiago M. Cunha, Daniel Martins‐de‐Souza,

COVID-19 and Mental Health

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.