Morphological, cellular and molecular basis of brain infection in COVID-19 patients
Authors: Crunfli Fernanda , Carregari Victor Corasolla , Veras Flavio Protasio , Vendramini Pedro Henrique , Valença Aline Gazzola Fragnani , Antunes André Saraiva Leão Marcelo , Brandão-Teles Caroline , da Silva Zuccoli Giuliana , Reis-de-Oliveira Guilherme , Silva-Costa Lícia C. , Saia-Cereda Verônica Monteiro , Smith Bradley Joseph , Codo Ana Campos , de Souza Gabriela Fabiano , Muraro Stéfanie Primon , Parise Pierina Lorencini , Toledo-Teixeira Daniel A. , de Castro Ícaro Maia Santos , Melo Bruno Marcel Silva , Almeida Glaucia M. , Firmino Egidi Mayara Silva , Paiva Isadora Marques , Silva Bruna Manuella Souza , Guimarães Rafaela Mano , Mendes Niele D. , Ludwig Raíssa Guimarães , Ruiz Gabriel Palermo , Knittel Thiago Leite , Davanzo Gustavo Gastão , Gerhardt Jaqueline Aline , Rodrigues Patrícia Brito , Forato Julia , Amorim Mariene Ribeiro , Silva Natália Brunetti , Martini Matheus Cavalheiro , Benatti Maíra Nilson , Batah Sabrina , Siyuan Li , João Rafael Batista , Silva Lucas Scardua , Nogueira Mateus Henrique , Aventurato Ítalo Karmann , de Brito Mariana Rabelo , Alvim Marina Koutsodontis Machado , da Silva Júnior José Roberto , Damião Lívia Liviane , de Sousa Iêda Maria Pereira , da Rocha Elessandra Dias , Gonçalves Solange Maria , da Silva Luiz Henrique Lopes , Bettini Vanessa , de Campos Brunno Machado , Ludwig Guilherme , Tavares Lucas Alves , Pontelli Marjorie Cornejo , Viana Rosa Maria Mendes , Martins Ronaldo , Vieira Andre S. , Alves-Filho José Carlos , Arruda Eurico , Podolski-Gondim Guilherme , Santos Marcelo Volpon , Neder Luciano , Cendes Fernando , Louzada-Junior Paulo , Oliveira Renê Donizeti , Cunha Fernando Queiroz , Damásio André , Vinolo Marco Aurélio Ramirez , Munhoz Carolina Demarchi , Rehen Stevens K. , Nakaya Helder I , Mauad Thais , Duarte-Neto Amaro Nunes , da Silva Luiz Fernando Ferraz , Dolhnikoff Marisa , Saldiva Paulo , Farias Alessandro S. , Moraes-Vieira Pedro Manoel M. , Fabro Alexandre Todorovic , Sebollela Adriano S. , Módena José Luiz Proença , Yasuda Clarissa Lin , Mori Marcelo A. , Cunha Thiago Mattar , Martins-de-Souza Daniel 
Published: October 2020

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.