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

被引：155

作者：

Crunfli, Fernanda ^{[1
]}

Carregari, Victor C. ^{[1
]}

Veras, Flavio P. ^{[2
]}

Silva, Lucas S. ^{[1
]}

Nogueira, Mateus Henrique ^{[1
]}

Leao Marcelo Antunes, Andre Saraiva ^{[1
]}

Vendramini, Pedro Henrique ^{[1
]}

Fragnani Valenca, Aline Gazzola ^{[1
]}

Brandao-Teles, Caroline ^{[1
]}

Zuccoli, Giuliana da Silva ^{[1
]}

Reis-de-Oliveira, Guilherme ^{[1
]}

Silva-Costa, Licia C. ^{[1
]}

Saia-Cereda, Veronica Monteiro ^{[1
]}

Smith, Bradley J. ^{[1
]}

Codo, Ana Campos ^{[1
]}

de Souza, Gabriela F. ^{[1
]}

Muraro, Stefanie P. ^{[1
]}

Parise, Pierina Lorencini ^{[1
]}

Toledo-Teixeira, Daniel A. ^{[1
]}

Santos de Castro, Icaro Maia ^{[3
]}

Melo, Bruno Marcel ^{[2
]}

Almeida, Glaucia M. ^{[2
]}

Silva Firmino, Egidi Mayara ^{[2
]}

Paiva, Isadora Marques ^{[2
]}

Souza Silva, Bruna Manuella ^{[2
]}

Guimaraes, Rafaela Mano ^{[2
]}

Mendes, Niele D. ^{[2
]}

Ludwig, Raissa L. ^{[1
]}

Ruiz, Gabriel P. ^{[1
]}

Knittel, Thiago L. ^{[1
]}

Davanzo, Gustavo G. ^{[1
]}

Gerhardt, Jaqueline Aline ^{[1
]}

Rodrigues, Patricia Brito ^{[1
]}

Forato, Julia ^{[1
]}

Amorim, Mariene Ribeiro ^{[1
]}

Brunetti, Natalia S. ^{[1
]}

Martini, Matheus Cavalheiro ^{[1
]}

Benatti, Maira Nilson ^{[2
]}

Batah, Sabrina S. ^{[2
]}

Li Siyuan

Joao, Rafael B. ^{[1
]}

Aventurato, Italo K. ^{[1
]}

de Brito, Mariana Rabelo ^{[1
]}

Mendes, Maria J. ^{[1
]}

da Costa, Beatriz A. ^{[1
]}

Alvim, Marina K. M. ^{[1
]}

da Silva Junior, Jose Roberto ^{[1
]}

Damiao, Livia L. ^{[1
]}

de Sousa, Ieda Maria P. ^{[1
]}

da Rocha, Elessandra D. ^{[1
]}

机构：

[1] Univ Estadual Campinas, Inst Biol, Dept Biochem & Tissue Biol, BR-13083862 Campinas, Brazil

[2] Univ Sao Paulo, Ribeirao Preto Med Sch, BR-14049900 Ribeirao Preto, Brazil

[3] Univ Sao Paulo, BR-05508220 Sao Paulo, Brazil

[4] DOr Inst Res & Educ, BR-04502001 Sao Paulo, SP, Brazil

[5] Univ Fed Rio de Janeiro, Inst Biomed Sci, BR-21941590 Rio De Janeiro, Brazil

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2022年 / 119卷 / 35期

关键词：

SARS-CoV-2; COVID-19; neurological symptoms; astrocytes; NRP1; RESPIRATORY SYNDROME CORONAVIRUS; SARS-COV-2; NEUROTROPISM; CEREBROSPINAL-FLUID; CORTICAL THICKNESS; ENERGY-METABOLISM; GLUCOSE; GLUTAMATE; LACTATE; ASTROCYTES; TRANSPORT;

D O I：

10.1073/pnas.2200960119

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

共 98 条

[1] Neurological Complications Associated with the Blood-Brain Barrier Damage Induced by the Inflammatory Response During SARS-CoV-2 Infection [J].