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

  • Fernanda Crunfli
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Victor C. Carregari
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Flavio P. Veras
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Lucas S. Silva
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Mateus Henrique Nogueira
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • André Saraiva Leão Marcelo Antunes
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Pedro Henrique Vendramini
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Aline Gazzola Fragnani Valença
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Caroline Brandão-Teles
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Giuliana da Silva Zuccoli
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Guilherme Reis-de-Oliveira
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Lícia C. Silva-Costa
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Verônica Monteiro Saia-Cereda
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Bradley J. Smith
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Ana Campos Codo
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Gabriela F de Souza
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Stéfanie P. Muraro
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Pierina Lorencini Parise
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Daniel A. Toledo-Teixeira
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Ícaro Maia Santos de Castro
    University of São Paulo, São Paulo, 05508-220, Brazil
  • Bruno Marcel Melo
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Glaucia M. Almeida
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Egidi Mayara Silva Firmino
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Isadora Marques Paiva
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Bruna Manuella Souza Silva
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Rafaela Mano Guimarães
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Niele D. Mendes
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Raíssa L. Ludwig
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Gabriel P. Ruiz
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Thiago L. Knittel
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Gustavo G. Davanzo
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Jaqueline Aline Gerhardt
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Patrícia Brito Rodrigues
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Julia Forato
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Mariene Ribeiro Amorim
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Natália S. Brunetti
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Matheus Cavalheiro Martini
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Maíra Nilson Benatti
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Sabrina S. Batah
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Li Siyuan
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Rafael B. João
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Ítalo K. Aventurato
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Mariana Rabelo de Brito
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Maria J. Mendes
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Beatriz A. da Costa
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Marina K. M. Alvim
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • José Roberto da Silva Júnior
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Lívia L. Damião
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Iêda Maria P. de Sousa
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Elessandra D. da Rocha
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Solange M. Gonçalves
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Luiz H. Lopes da Silva
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Vanessa Bettini
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Brunno M. Campos
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Guilherme Ludwig
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Lucas Alves Tavares
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Marjorie Cornejo Pontelli
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Rosa Maria Mendes Viana
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Ronaldo B. Martins
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Andre Schwambach Vieira
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • José Carlos Alves-Filho
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Eurico Arruda
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Guilherme Gozzoli Podolsky-Gondim
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Marcelo Volpon Santos
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Luciano Neder
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • André Damasio
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Stevens Rehen
    D'Or Institute for Research and Education, 04502001, Brazil
  • Marco Aurélio Ramirez Vinolo
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Carolina Demarchi Munhoz
    University of São Paulo, São Paulo, 05508-220, Brazil
  • Paulo Louzada-Junior
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Renê Donizeti Oliveira
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Fernando Q. Cunha
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Helder I. Nakaya
    University of São Paulo, São Paulo, 05508-220, Brazil
  • Thais Mauad
    University of São Paulo, São Paulo, 05508-220, Brazil
  • Amaro Nunes Duarte-Neto
    University of São Paulo, São Paulo, 05508-220, Brazil
  • Luiz Fernando Ferraz da Silva
    University of São Paulo, São Paulo, 05508-220, Brazil
  • Marisa Dolhnikoff
    University of São Paulo, São Paulo, 05508-220, Brazil
  • Paulo Hilario Nascimento Saldiva
    University of São Paulo, São Paulo, 05508-220, Brazil
  • Alessandro S. Farias
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Fernando Cendes
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Pedro Manoel M. Moraes-Vieira
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Alexandre T. Fabro
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Adriano Sebollela
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • José L. Proença-Modena
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Clarissa L. Yasuda
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Marcelo A. Mori
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
  • Thiago M. Cunha
    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
  • Daniel Martins-de-Souza
    Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil

抄録

<jats:p>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.</jats:p>

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