Morphological, cellular, and molecular basis of brain infection in COVID-19 patients
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- Fernanda Crunfli
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Victor C. Carregari
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Flavio P. Veras
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Lucas S. Silva
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Mateus Henrique Nogueira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- André Saraiva Leão Marcelo Antunes
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Pedro Henrique Vendramini
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Aline Gazzola Fragnani Valença
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Caroline Brandão-Teles
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Giuliana da Silva Zuccoli
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Guilherme Reis-de-Oliveira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Lícia C. Silva-Costa
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Verônica Monteiro Saia-Cereda
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Bradley J. Smith
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Ana Campos Codo
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Gabriela F de Souza
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Stéfanie P. Muraro
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Pierina Lorencini Parise
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Daniel A. Toledo-Teixeira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Ícaro Maia Santos de Castro
- University of São Paulo, São Paulo, 05508-220, Brazil
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- Bruno Marcel Melo
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Glaucia M. Almeida
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Egidi Mayara Silva Firmino
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Isadora Marques Paiva
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Bruna Manuella Souza Silva
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Rafaela Mano Guimarães
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Niele D. Mendes
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Raíssa L. Ludwig
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Gabriel P. Ruiz
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Thiago L. Knittel
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Gustavo G. Davanzo
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Jaqueline Aline Gerhardt
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Patrícia Brito Rodrigues
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Julia Forato
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Mariene Ribeiro Amorim
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Natália S. Brunetti
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Matheus Cavalheiro Martini
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Maíra Nilson Benatti
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Sabrina S. Batah
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Li Siyuan
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Rafael B. João
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Ítalo K. Aventurato
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Mariana Rabelo de Brito
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Maria J. Mendes
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Beatriz A. da Costa
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Marina K. M. Alvim
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- José Roberto da Silva Júnior
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Lívia L. Damião
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Iêda Maria P. de Sousa
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Elessandra D. da Rocha
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Solange M. Gonçalves
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Luiz H. Lopes da Silva
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Vanessa Bettini
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Brunno M. Campos
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Guilherme Ludwig
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Lucas Alves Tavares
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Marjorie Cornejo Pontelli
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Rosa Maria Mendes Viana
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Ronaldo B. Martins
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Andre Schwambach Vieira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- José Carlos Alves-Filho
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Eurico Arruda
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Guilherme Gozzoli Podolsky-Gondim
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Marcelo Volpon Santos
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Luciano Neder
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- André Damasio
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Stevens Rehen
- D'Or Institute for Research and Education, 04502001, Brazil
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- Marco Aurélio Ramirez Vinolo
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Carolina Demarchi Munhoz
- University of São Paulo, São Paulo, 05508-220, Brazil
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- Paulo Louzada-Junior
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Renê Donizeti Oliveira
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Fernando Q. Cunha
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Helder I. Nakaya
- University of São Paulo, São Paulo, 05508-220, Brazil
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- Thais Mauad
- University of São Paulo, São Paulo, 05508-220, Brazil
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- Amaro Nunes Duarte-Neto
- University of São Paulo, São Paulo, 05508-220, Brazil
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- Luiz Fernando Ferraz da Silva
- University of São Paulo, São Paulo, 05508-220, Brazil
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- Marisa Dolhnikoff
- University of São Paulo, São Paulo, 05508-220, Brazil
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- Paulo Hilario Nascimento Saldiva
- University of São Paulo, São Paulo, 05508-220, Brazil
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- Alessandro S. Farias
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Fernando Cendes
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Pedro Manoel M. Moraes-Vieira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Alexandre T. Fabro
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- Adriano Sebollela
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- José L. Proença-Modena
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Clarissa L. Yasuda
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Marcelo A. Mori
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, 13083862, Brazil
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- Thiago M. Cunha
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, 14049900, Brazil
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- 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>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 119 (35), e2200960119-, 2022-08-11
Proceedings of the National Academy of Sciences