tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2022 Aug 30;119(35):e2200960119.
doi: 10.1073/pnas.2200960119. Epub 2022 Aug 11.
Morphological, cellular, and molecular basis of brain infection in COVID-19 patients
Fernanda Crunfli[SUP] 1 [/SUP], Victor C Carregari[SUP] 1 [/SUP], Flavio P Veras[SUP] 2 [/SUP], Lucas S Silva[SUP] 1 [/SUP], Mateus Henrique Nogueira[SUP] 1 [/SUP], André Saraiva Leão Marcelo Antunes[SUP] 1 [/SUP], Pedro Henrique Vendramini[SUP] 1 [/SUP], Aline Gazzola Fragnani Valença[SUP] 1 [/SUP], Caroline Brandão-Teles[SUP] 1 [/SUP], Giuliana da Silva Zuccoli[SUP] 1 [/SUP], Guilherme Reis-de-Oliveira[SUP] 1 [/SUP], Lícia C Silva-Costa[SUP] 1 [/SUP], Verônica Monteiro Saia-Cereda[SUP] 1 [/SUP], Bradley J Smith[SUP] 1 [/SUP], Ana Campos Codo[SUP] 1 [/SUP], Gabriela F de Souza[SUP] 1 [/SUP], Stéfanie P Muraro[SUP] 1 [/SUP], Pierina Lorencini Parise[SUP] 1 [/SUP], Daniel A Toledo-Teixeira[SUP] 1 [/SUP], Ícaro Maia Santos de Castro[SUP] 3 [/SUP], Bruno Marcel Melo[SUP] 2 [/SUP], Glaucia M Almeida[SUP] 2 [/SUP], Egidi Mayara Silva Firmino[SUP] 2 [/SUP], Isadora Marques Paiva[SUP] 2 [/SUP], Bruna Manuella Souza Silva[SUP] 2 [/SUP], Rafaela Mano Guimarães[SUP] 2 [/SUP], Niele D Mendes[SUP] 2 [/SUP], Raíssa L Ludwig[SUP] 1 [/SUP], Gabriel P Ruiz[SUP] 1 [/SUP], Thiago L Knittel[SUP] 1 [/SUP], Gustavo G Davanzo[SUP] 1 [/SUP], Jaqueline Aline Gerhardt[SUP] 1 [/SUP], Patrícia Brito Rodrigues[SUP] 1 [/SUP], Julia Forato[SUP] 1 [/SUP], Mariene Ribeiro Amorim[SUP] 1 [/SUP], Natália S Brunetti[SUP] 1 [/SUP], Matheus Cavalheiro Martini[SUP] 1 [/SUP], Maíra Nilson Benatti[SUP] 2 [/SUP], Sabrina S Batah[SUP] 2 [/SUP], Li Siyuan[SUP] 2 [/SUP], Rafael B João[SUP] 1 [/SUP], Ítalo K Aventurato[SUP] 1 [/SUP], Mariana Rabelo de Brito[SUP] 1 [/SUP], Maria J Mendes[SUP] 1 [/SUP], Beatriz A da Costa[SUP] 1 [/SUP], Marina K M Alvim[SUP] 1 [/SUP], José Roberto da Silva Júnior[SUP] 1 [/SUP], Lívia L Damião[SUP] 1 [/SUP], Iêda Maria P de Sousa[SUP] 1 [/SUP], Elessandra D da Rocha[SUP] 1 [/SUP], Solange M Gonçalves[SUP] 1 [/SUP], Luiz H Lopes da Silva[SUP] 1 [/SUP], Vanessa Bettini[SUP] 1 [/SUP], Brunno M Campos[SUP] 1 [/SUP], Guilherme Ludwig[SUP] 1 [/SUP], Lucas Alves Tavares[SUP] 2 [/SUP], Marjorie Cornejo Pontelli[SUP] 2 [/SUP], Rosa Maria Mendes Viana[SUP] 2 [/SUP], Ronaldo B Martins[SUP] 2 [/SUP], Andre Schwambach Vieira[SUP] 1 [/SUP], José Carlos Alves-Filho[SUP] 2 [/SUP], Eurico Arruda[SUP] 2 [/SUP], Guilherme Gozzoli Podolsky-Gondim[SUP] 2 [/SUP], Marcelo Volpon Santos[SUP] 2 [/SUP], Luciano Neder[SUP] 2 [/SUP], André Damasio[SUP] 1 [/SUP], Stevens Rehen[SUP] 4 5 [/SUP], Marco Aurélio Ramirez Vinolo[SUP] 1 [/SUP], Carolina Demarchi Munhoz[SUP] 3 [/SUP], Paulo Louzada-Junior[SUP] 2 [/SUP], Renê Donizeti Oliveira[SUP] 2 [/SUP], Fernando Q Cunha[SUP] 2 [/SUP], Helder I Nakaya[SUP] 3 [/SUP], Thais Mauad[SUP] 3 [/SUP], Amaro Nunes Duarte-Neto[SUP] 3 [/SUP], Luiz Fernando Ferraz da Silva[SUP] 3 [/SUP], Marisa Dolhnikoff[SUP] 3 [/SUP], Paulo Hilario Nascimento Saldiva[SUP] 3 [/SUP], Alessandro S Farias[SUP] 1 [/SUP], Fernando Cendes[SUP] 1 [/SUP], Pedro Manoel M Moraes-Vieira[SUP] 1 [/SUP], Alexandre T Fabro[SUP] 2 [/SUP], Adriano Sebollela[SUP] 2 [/SUP], José L Proença-Modena[SUP] 1 [/SUP], Clarissa L Yasuda[SUP] 1 [/SUP], Marcelo A Mori[SUP] 1 [/SUP], Thiago M Cunha[SUP] 2 [/SUP], Daniel Martins-de-Souza[SUP] 1 4 [/SUP]
Affiliations
Abstract
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.
Keywords: COVID-19; NRP1; SARS-CoV-2; astrocytes; neurological symptoms.
. 2022 Aug 30;119(35):e2200960119.
doi: 10.1073/pnas.2200960119. Epub 2022 Aug 11.
Morphological, cellular, and molecular basis of brain infection in COVID-19 patients
Fernanda Crunfli[SUP] 1 [/SUP], Victor C Carregari[SUP] 1 [/SUP], Flavio P Veras[SUP] 2 [/SUP], Lucas S Silva[SUP] 1 [/SUP], Mateus Henrique Nogueira[SUP] 1 [/SUP], André Saraiva Leão Marcelo Antunes[SUP] 1 [/SUP], Pedro Henrique Vendramini[SUP] 1 [/SUP], Aline Gazzola Fragnani Valença[SUP] 1 [/SUP], Caroline Brandão-Teles[SUP] 1 [/SUP], Giuliana da Silva Zuccoli[SUP] 1 [/SUP], Guilherme Reis-de-Oliveira[SUP] 1 [/SUP], Lícia C Silva-Costa[SUP] 1 [/SUP], Verônica Monteiro Saia-Cereda[SUP] 1 [/SUP], Bradley J Smith[SUP] 1 [/SUP], Ana Campos Codo[SUP] 1 [/SUP], Gabriela F de Souza[SUP] 1 [/SUP], Stéfanie P Muraro[SUP] 1 [/SUP], Pierina Lorencini Parise[SUP] 1 [/SUP], Daniel A Toledo-Teixeira[SUP] 1 [/SUP], Ícaro Maia Santos de Castro[SUP] 3 [/SUP], Bruno Marcel Melo[SUP] 2 [/SUP], Glaucia M Almeida[SUP] 2 [/SUP], Egidi Mayara Silva Firmino[SUP] 2 [/SUP], Isadora Marques Paiva[SUP] 2 [/SUP], Bruna Manuella Souza Silva[SUP] 2 [/SUP], Rafaela Mano Guimarães[SUP] 2 [/SUP], Niele D Mendes[SUP] 2 [/SUP], Raíssa L Ludwig[SUP] 1 [/SUP], Gabriel P Ruiz[SUP] 1 [/SUP], Thiago L Knittel[SUP] 1 [/SUP], Gustavo G Davanzo[SUP] 1 [/SUP], Jaqueline Aline Gerhardt[SUP] 1 [/SUP], Patrícia Brito Rodrigues[SUP] 1 [/SUP], Julia Forato[SUP] 1 [/SUP], Mariene Ribeiro Amorim[SUP] 1 [/SUP], Natália S Brunetti[SUP] 1 [/SUP], Matheus Cavalheiro Martini[SUP] 1 [/SUP], Maíra Nilson Benatti[SUP] 2 [/SUP], Sabrina S Batah[SUP] 2 [/SUP], Li Siyuan[SUP] 2 [/SUP], Rafael B João[SUP] 1 [/SUP], Ítalo K Aventurato[SUP] 1 [/SUP], Mariana Rabelo de Brito[SUP] 1 [/SUP], Maria J Mendes[SUP] 1 [/SUP], Beatriz A da Costa[SUP] 1 [/SUP], Marina K M Alvim[SUP] 1 [/SUP], José Roberto da Silva Júnior[SUP] 1 [/SUP], Lívia L Damião[SUP] 1 [/SUP], Iêda Maria P de Sousa[SUP] 1 [/SUP], Elessandra D da Rocha[SUP] 1 [/SUP], Solange M Gonçalves[SUP] 1 [/SUP], Luiz H Lopes da Silva[SUP] 1 [/SUP], Vanessa Bettini[SUP] 1 [/SUP], Brunno M Campos[SUP] 1 [/SUP], Guilherme Ludwig[SUP] 1 [/SUP], Lucas Alves Tavares[SUP] 2 [/SUP], Marjorie Cornejo Pontelli[SUP] 2 [/SUP], Rosa Maria Mendes Viana[SUP] 2 [/SUP], Ronaldo B Martins[SUP] 2 [/SUP], Andre Schwambach Vieira[SUP] 1 [/SUP], José Carlos Alves-Filho[SUP] 2 [/SUP], Eurico Arruda[SUP] 2 [/SUP], Guilherme Gozzoli Podolsky-Gondim[SUP] 2 [/SUP], Marcelo Volpon Santos[SUP] 2 [/SUP], Luciano Neder[SUP] 2 [/SUP], André Damasio[SUP] 1 [/SUP], Stevens Rehen[SUP] 4 5 [/SUP], Marco Aurélio Ramirez Vinolo[SUP] 1 [/SUP], Carolina Demarchi Munhoz[SUP] 3 [/SUP], Paulo Louzada-Junior[SUP] 2 [/SUP], Renê Donizeti Oliveira[SUP] 2 [/SUP], Fernando Q Cunha[SUP] 2 [/SUP], Helder I Nakaya[SUP] 3 [/SUP], Thais Mauad[SUP] 3 [/SUP], Amaro Nunes Duarte-Neto[SUP] 3 [/SUP], Luiz Fernando Ferraz da Silva[SUP] 3 [/SUP], Marisa Dolhnikoff[SUP] 3 [/SUP], Paulo Hilario Nascimento Saldiva[SUP] 3 [/SUP], Alessandro S Farias[SUP] 1 [/SUP], Fernando Cendes[SUP] 1 [/SUP], Pedro Manoel M Moraes-Vieira[SUP] 1 [/SUP], Alexandre T Fabro[SUP] 2 [/SUP], Adriano Sebollela[SUP] 2 [/SUP], José L Proença-Modena[SUP] 1 [/SUP], Clarissa L Yasuda[SUP] 1 [/SUP], Marcelo A Mori[SUP] 1 [/SUP], Thiago M Cunha[SUP] 2 [/SUP], Daniel Martins-de-Souza[SUP] 1 4 [/SUP]
Affiliations
- PMID: 35951647
- DOI: 10.1073/pnas.2200960119
Abstract
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.
Keywords: COVID-19; NRP1; SARS-CoV-2; astrocytes; neurological symptoms.