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

by Fernanda Crunfli, Victor Corasolla Carregari, Flavio Protasio Veras, Pedro Henrique Vendramini, Aline Gazzola Fragnani Valença, André Saraiva Leão Marcelo Antunes, Caroline Brandão-Teles, Giuliana da Silva Zuccoli, Guilherme Reis-de-Oliveira, Lícia C. Silva-Costa, Verônica Monteiro Saia-Cereda, Bradley Joseph 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 Melo, Glaucia M. Almeida, Egidi Mayara Silva Firmino, Isadora Marques Paiva, Bruna Manuella Souza Silva, Rafaela Mano Guimarães, Niele D. Mendes, Raíssa Guimarães Ludwig, Gabriel Palermo Ruiz, Thiago Leite Knittel, Gustavo Gastão Davanzo, Jaqueline Aline Gerhardt, Patrícia Brito Rodrigues, Julia Forato, Mariene Ribeiro Amorim, Natália Brunetti Silva, Matheus Cavalheiro Martini, Maíra Nilson Benatti, Sabrina Batah, Li Siyuan, Rafael Batista João, Lucas Scardua Silva, Mateus Henrique Nogueira, Ítalo Karmann Aventurato, Mariana Rabelo de Brito, Marina Koutsodontis Machado Alvim, José Roberto da Silva Júnior, Lívia Liviane Damião, Iêda Maria Pereira de Sousa, Elessandra Dias da Rocha, Solange Maria Gonçalves, Luiz Henrique Lopes da Silva, Vanessa Bettini, Brunno Machado de Campos, Guilherme Ludwig, Lucas Alves Tavares, Marjorie Cornejo Pontelli, Rosa Maria Mendes Viana, Ronaldo Martins, Andre S. Vieira, José Carlos Alves-Filho, Eurico Arruda, Guilherme Podolski-Gondim, Marcelo Volpon Santos, Luciano Neder, Fernando Cendes, Paulo Louzada-Junior, Renê Donizeti Oliveira, Fernando Queiroz Cunha, André Damásio, Marco Aurélio Ramirez Vinolo, Carolina Demarchi Munhoz, Stevens K. Rehen, Helder I Nakaya, Thais Mauad, Amaro Nunes Duarte-Neto, Luiz Fernando Ferraz da Silva, Marisa Dolhnikoff, Paulo Saldiva, Alessandro S. Farias, Pedro Manoel M. Moraes-Vieira, Alexandre Todorovic Fabro, Adriano S. Sebollela, José Luiz Proença Módena, Clarissa Lin Yasuda, Marcelo A. Mori, Thiago Mattar Cunha, and Daniel Martins-de-Souza

Posted: October 13, 2020
Server: medRxiv
DOI: 10.1101/2020.10.09.20207464

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, the long-term neuropsychiatric dysfunction has been frequently observed after mild infection. Here we show the spectrum of the cerebral impact of 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 trans-ethmoidal approach) from individuals who died of COVID-19. We used surface-based analyses of 3T MRI and identified orbitofrontal cortical atrophy in a group of 81 mildly infected patients (77% referred anosmia or dysgeusia during acute stage) compared to 145 healthy volunteers; this atrophy correlated with symptoms of anxiety and cognitive dysfunction. 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 5 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 non-canonical 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 are also likely to contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

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