Morphological, cellular, and molecular basis of brain infection in COVID-19 patients
Authors: Crunfli Fernanda , Carregari Victor C. , Veras Flavio P. , Silva Lucas S. , Nogueira Mateus Henrique , Antunes André Saraiva Leão Marcelo , Vendramini Pedro Henrique , Valença Aline Gazzola Fragnani , Brandão-Teles Caroline , Zuccoli Giuliana da Silva , Reis-de-Oliveira Guilherme , Silva-Costa Lícia C. , Saia-Cereda Verônica Monteiro , Smith Bradley J. , Codo Ana Campos , de Souza Gabriela F , Muraro Stéfanie P. , Parise Pierina Lorencini , Toledo-Teixeira Daniel A. , Santos de Castro Ícaro Maia , Melo Bruno Marcel , Almeida Glaucia M. , Firmino Egidi Mayara Silva , Paiva Isadora Marques , Silva Bruna Manuella Souza , Guimarães Rafaela Mano , Mendes Niele D. , Ludwig Raíssa L. , Ruiz Gabriel P. , Knittel Thiago L. , Davanzo Gustavo G. , Gerhardt Jaqueline Aline , Rodrigues Patrícia Brito , Forato Julia , Amorim Mariene Ribeiro , Brunetti Natália S. , Martini Matheus Cavalheiro , Benatti Maíra Nilson , Batah Sabrina S. , Siyuan Li , João Rafael B. , Aventurato Ítalo K. , Rabelo de Brito Mariana , Mendes Maria J. , da Costa Beatriz A. , Alvim Marina K. M. , da Silva Júnior José Roberto , Damião Lívia L. , de Sousa Iêda Maria P. , da Rocha Elessandra D. , Gonçalves Solange M. , Lopes da Silva Luiz H. , Bettini Vanessa , Campos Brunno M. , Ludwig Guilherme , Tavares Lucas Alves , Pontelli Marjorie Cornejo , Viana Rosa Maria Mendes , Martins Ronaldo B. , Vieira Andre Schwambach , Alves-Filho José Carlos , Arruda Eurico , Podolsky-Gondim Guilherme Gozzoli , Santos Marcelo Volpon , Neder Luciano , Damasio André , Rehen Stevens , Vinolo Marco Aurélio Ramirez , Munhoz Carolina Demarchi , Louzada-Junior Paulo , Oliveira Renê Donizeti , Cunha Fernando Q. , Nakaya Helder I. , Mauad Thais , Duarte-Neto Amaro Nunes , Ferraz da Silva Luiz Fernando , Dolhnikoff Marisa , Saldiva Paulo Hilario Nascimento , Farias Alessandro S. , Cendes Fernando , Moraes-Vieira Pedro Manoel M. , Fabro Alexandre T. , Sebollela Adriano , Proença-Modena José L. , Yasuda Clarissa L. , Mori Marcelo A. , Cunha Thiago M. , Martins-de-Souza Daniel 
Published: August 2022

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.