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

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 spectru...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS Jg. 119; H. 35; S. e2200960119
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 30.08.2022
Schlagworte:
Astrocytes - pathology
Astrocytes - virology
Brain - pathology
Brain - virology
Central Nervous System Viral Diseases - etiology
Central Nervous System Viral Diseases - pathology
COVID-19 - complications
COVID-19 - pathology
Humans
Post-Acute COVID-19 Syndrome
SARS-CoV-2
COVID-19
neurological symptoms
NRP1
SARS-CoV-2
astrocytes
ISSN:1091-6490, 1091-6490
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Zusammenfassung: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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.2200960119