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

Crunfli, Fernanda; Carregari, Victor Corasolla; Veras, Flávio P.; Vendramini, Pedro Henrique; Valença, Aline Gazzola Fragnani; Antunes, André Saraiva Leão Marcelo; Brandão‐Teles, Caroline; Zuccoli, Giuliana S.; Reis‐de‐Oliveira, Guilherme; Silva-Costa, Lícia C.; Saia-Cereda, Verônica M.; Smith, Bradley J.; Codo, Ana Campos; Souza, Gabriela Fabiano de; Muraro, Stéfanie Primon; Parise, Pierina Lorencini; Toledo-Teixeira, Daniel A.; Castro, Ícaro Maia Santos de; Melo, Bruno Marcel Silva de; Almeida, Gláucia Maria; Firmino, Egidi Mayara Silva; Paiva, Isadora Marques; Silva, Bruna Manuella Souza; Guimarães, Rafaela Mano; Mendes, Niele Dias; Ludwig, Raissa G.; Ruiz, Gabriel Palermo; Knittel, Thiago L; Davanzo, Gustavo Gastão; Gerhardt, Jaqueline Aline; Rodrigues, Patrícia Brito; Forato, Julia; Amorim, Mariene R.; Silva, Natália Brunetti; Martini, Matheus Cavalheiro; Benatti, Maíra Nilson; Batah, Sabrina Setembre; Siyuan, Li; João, Rafael Batista; Silva, Lucas Scárdua; Nogueira, Mateus Henrique; Aventurato, Ítalo Karmann; Brito, Mariana Rabelo de; Alvim, Marina K. M.; Júnior, José Roberto da Silva; Damião, Lívia Liviane; Sousa, Iêda Maria Pereira de; Rocha, Elessandra Dias da; Gonçalves, Solange Maria; Silva, Luiz Henrique Lopes da; Bettini, Vanessa; Campos, Brunno Machado de; Ludwig, Guilherme; Tavares, Lucas Alves; Pontelli, Marjorie Cornejo; Viana, Rosa Maria Mendes; Martins, Ronaldo B.; Vieira, André Schwambach; Alves‐Filho, José C.; Arruda, Eurico; Podolski-Gondim, Guilherme; Santos, Marcelo Volpon; Neder, Luciano; Cendes, Fernando; Louzada‐Júnior, Paulo; Oliveira, Renê Donizeti Ribeiro de; Cunha, Fernando Q.; Damásio, André; Vinolo, Marco Aurélio Ramirez; Munhoz, Carolina Demarchi; Rehen, Stevens; Nakaya, Helder I.; Mauad, Thaís; Duarte‐Neto, Amaro Nunes; Silva, Luiz Fernando Ferraz da; Dolhnikoff, Marisa; Saldiva, Paulo Hilário Nascimento; Farias, Alessandro S.; Moraes‐Vieira, Pedro M.; Fabro, Alexandre Todorovic; Sebollela, Adriano; Proença-Módena, José Luiz; Yasuda, Clarissa L.; Mori, Marcelo A.; Cunha, Thiago M.; Martins-de-Souza, Daniel

doi:10.1101/2020.10.09.20207464

Cited by 68 publications

(61 citation statements)

References 120 publications

(242 reference statements)

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“…Our findings suggest that developing astrocytes are particularly vulnerable to SARS-CoV-2, however another recent study indicates that adult astrocytes may also be susceptible to infection and that other coronavirus receptors, like CD147, are abundant in mature astrocytes ( 11 , 30 ). We observe an increase in CD147 expression upon infection, suggesting a potential positive feedback loop, as observed in case of ACE2 in lung alveolosphere infection ( 34 ).…”

Section: Discussioncontrasting

confidence: 50%

“…We observed no increase in apoptosis in primary cortical cultures 72 hours post-infection in dsRNA+ GFAP+ cells ( Figure 3A ). In a recent study of adult post-mortem samples, infected astrocytes were observed to have impaired protein folding, translation initiation, and metabolic function ( 11 ). We investigated the impact of SARS-CoV-2 on cellular stress by evaluating the abundance of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) gene, ARCN1.…”

Section: Resultsmentioning

confidence: 99%

“…Studies of postmortem brain tissue from COVID-19 patients have observed widespread inflammation in the brainstem characterized by infiltration of immune cells including microglia and T cells, as well as infection of cranial nerves, microvascular injury, fibrinogen leakage, and extensive astrogliosis (9,10). Moreover, viral RNA has recently been observed in cortical astrocytes from post-mortem patient tissue (11).…”

mentioning

confidence: 99%

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Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Andrews

Mukhtar

Eze

et al. 2021

Preprint

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. It proves fatal for one percent of those infected. Neurological symptoms, which range in severity, accompany a significant proportion of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized primary human cortical tissue and stem cell-derived cortical organoids. We find significant and predominant infection in cortical astrocytes in both primary and organoid cultures, with minimal infection of other cortical populations. Infected astrocytes had a corresponding increase in reactivity characteristics, growth factor signaling, and cellular stress. Although human cortical cells, including astrocytes, have minimal ACE2 expression, we find high levels of alternative coronavirus receptors in infected astrocytes, including DPP4 and CD147. Inhibition of DPP4 reduced infection and decreased expression of the cell stress marker, ARCN1. We find tropism of SARS-CoV-2 for human astrocytes mediated by DPP4, resulting in reactive gliosis-type injury.

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Section: Discussioncontrasting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Andrews

Mukhtar

Eze

et al. 2021

Preprint

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“…In the short-term, 20–40% of COVID-19 cases may present with neuropsychiatric complications, such as cerebrovascular events, headache, dizziness, encephalopathies, anosmia, ageusia, and mood problems ( Bo et al, 2020 ; Crunfli et al, 2020 ; Lu et al, 2020 ; Mao et al, 2020 ; Mirfazeli et al, 2020 ; Troyer et al, 2020 ; Varatharaj et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2020 ), see Table 1 . The acute effect of CoV infections on the CNS is manifested in viral encephalitis, infectious toxic encephalopathy, and acute cerebrovascular disease.…”

Section: Neuropsychiatric and Cognitive Effects Of Coronavirus Infectmentioning

confidence: 99%

Neuropsychiatric and Cognitive Sequelae of COVID-19

2021

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Coronavirus disease 2019 (COVID-19) is likely to have long-term mental health effects on individuals who have recovered from COVID-19. Rightly, there is a global response for recognition and planning on how to deal with mental health problems for everyone impacted by the global pandemic. This does not just include COVID-19 patients but the general public and health care workers as well. There is also a need to understand the role of the virus itself in the pathophysiology of mental health disorders and longer-term mental health sequelae. Emerging evidence suggests that COVID-19 patients develop neurological symptoms such as headache, altered consciousness, and paraesthesia. Brain tissue oedema and partial neurodegeneration have also been observed in an autopsy. In addition, there are reports that the virus has the potential to cause nervous system damage. Together, these findings point to a possible role of the virus in the development of acute psychiatric symptoms and long-term neuropsychiatric sequelae of COVID-19. The brain pathologies associated with COVID-19 infection is likely to have a long-term impact on cognitive processes. Evidence from other viral respiratory infections, such as severe acute respiratory syndrome (SARS), suggests a potential development of psychiatric disorders, long-term neuropsychiatric disorders, and cognitive problems. In this paper, we will review and evaluate the available evidence of acute and possible long-term neuropsychiatric manifestations of COVID-19. We will discuss possible pathophysiological mechanisms and the implications this will have on preparing a long-term strategy to monitor and manage such patients.

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“…Neurological manifestations of COVID-19 fueled research on the putative viral infection of the brain. However, absence or low detection of SARS-CoV-2 was described in the cerebrospinal fluid (CSF), and so far many reports have described the presence of SARS-CoV-2 in the brain parenchyma [20,26,41,42]. Here, we bring the attention to SARS-CoV-2 infection in the ChP in its LV lining, and in the frontal cortex of an infant’s brain (S1A Fig), which was confirmed by qRT-PCR for viral RNA (S1B Fig) (pathological analysis of this case was described in detail in [22]).…”

Section: Discussionmentioning

confidence: 99%

Non-permissive SARS-CoV-2 infection in human neurospheres

Pedrosa

Goto‐Silva

Temerozo

et al. 2020

Preprint

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Coronavirus disease 2019 (COVID-19) was initially described as a viral infection of the respiratory tract. It is now known, however, that many other biological systems are affected, including the central nervous system (CNS). Neurological manifestations such as stroke, encephalitis, and psychiatric conditions have been reported in COVID-19 patients, but its neurotropic potential is still debated. Here, we investigate the presence of SARS-CoV-2 in the brain from an infant patient deceased from COVID-19. The susceptibility to virus infection was compatible with the expression levels of viral receptor ACE2, which is increased in the ChP in comparison to other brain areas. To better comprehend the dynamics of the viral infection in neural cells, we exposed human neurospheres to SARS-CoV-2. Similarly to the human tissue, we found viral RNA in neurospheres, although viral particles in the culture supernatant were not infective. Based on our observations in vivo and in vitro, we hypothesize that SARS-CoV-2 does not generate productive infection in developing neural cells and that infection of ChP weakens the blood-cerebrospinal fluid barrier allowing viruses, immune cells, and cytokines to access the CNS, causing neural damage in the young brain.

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

Cited by 68 publications

References 120 publications

Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Neuropsychiatric and Cognitive Sequelae of COVID-19

Non-permissive SARS-CoV-2 infection in human neurospheres

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