SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein

Khaddaj‐Mallat, Rayan; Aldib, Natija; Bernard, Maxime; A, Paquette; Ferreira, Aymeric; Lecordier, Sarah; Saghatelyan, Armen; Flamand, Louis; ElAli, Ayman

doi:10.1016/j.nbd.2021.105561

Cited by 50 publications

(51 citation statements)

References 52 publications

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“…. The expression can be increased with by exposure to the viral S protein, and importantly, potentiated in combination with hypoxia(Khaddaj-Mallat et al, 2021), a mechanism which could account for the modulation of RSFA abnormality by disease severity in our cohort.Given this biological context the correlation of RSFA abnormalities with disease severity is open to two potential interpretations. One possibility is that these changes in cerebrovascular regulatory integrity are the consequence of direct viral invasion; while the other is that these abnormalities are a consequence of the inflammatory host response, which is a consequence of, but may not scale precisely with, viral infection.…”

mentioning

confidence: 63%

“…On the abluminal aspect of the neurovascular interface, pericytes express abundantly the angiotensin-converting enzyme-2 (ACE2) receptor (He et al, 2020). The expression can be increased with by exposure to the viral S protein, and importantly, potentiated in combination with hypoxia (Khaddaj-Mallat et al, 2021), a mechanism which could account for the modulation of RSFA abnormality by disease severity in our cohort.…”

Section: Discussionmentioning

confidence: 87%

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Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study

Tsvetanov

Spindler

Stamatakis

et al. 2022

Preprint

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Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. Here we assess cerebrovascular health in 45 hospitalised patients using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode, as indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. Exploratory analysis suggests that the level of cerebrovascular dysfunction is associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.

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mentioning

confidence: 63%

Section: Discussionmentioning

confidence: 87%

Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study

Tsvetanov

Spindler

Stamatakis

et al. 2022

Preprint

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“…In other conditions, excessive NET formation may cause vascular injury by activating endothelial to mesenchymal transition, triggering death of endothelial cells and vascular smooth muscle cells, and promoting coagulation. (Barbosa et al, 2021;Colmenero et al, 2020;Khaddaj-Mallat et al, 2021;Leppkes et al, 2020;Zuo et al, 2021b) NET complexes have been detected in the circulation of adult patients with severe COVID-19. (Zuo et al, 2020), and widespread occlusion of small vessels by aggregated NETs has been visualized in their lung and kidneys (Radermecker et al, 2020;Schurink et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

Carmona-Rivera¹,

Dobbs²,

Markowitz³

et al. 2022

Preprint

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Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including MIS-C and chilblain-like lesions (CLL), otherwise known as COVID toes, remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

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“…The virus can infect the human CNS, either directly or indirectly via elusive mechanisms, leading to the inflammation of blood vessels and ensuing clotting, seizures, strokes, and hemorrhages. Recent studies showed that the virus entry receptor ACE2 is poorly expressed in neural cells, but highly expressed in brain pericytes, specialized cells that wrap around blood vessels and regulate immune cell entry to the CNS ( 95 ). Indeed, intranasal infection with SARS-CoV-2 induced a prompt hypoxic/ischemic-like pericyte response in the brain of transgenic mice expressing human ACE2 ( 95 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies showed that the virus entry receptor ACE2 is poorly expressed in neural cells, but highly expressed in brain pericytes, specialized cells that wrap around blood vessels and regulate immune cell entry to the CNS ( 95 ). Indeed, intranasal infection with SARS-CoV-2 induced a prompt hypoxic/ischemic-like pericyte response in the brain of transgenic mice expressing human ACE2 ( 95 ). Likewise, immunostaining of human brains demonstrated the presence of viral dsRNA in the vascular wall, perivascular inflammation, and a restricted loss of blood-brain barrier integrity ( 96 ).…”

Section: Discussionmentioning

confidence: 99%

Neurogenesis and Viral Infection

et al. 2022

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Neural stem cells (NSCs) are multipotent stem cells that reside in the fetal and adult mammalian brain, which can self-renew and differentiate into neurons and supporting cells. Intrinsic and extrinsic cues, from cells in the local niche and from distant sites, stringently orchestrates the self-renewal and differentiation competence of NSCs. Ample evidence supports the important role of NSCs in neuroplasticity, aging, disease, and repair of the nervous system. Indeed, activation of NSCs or their transplantation into injured areas of the central nervous system can lead to regeneration in animal models. Viral invasion of NSCs can negatively affect neurogenesis and synaptogenesis, with consequent cell death, impairment of cell cycle progression, early differentiation, which cause neural progenitors depletion in the cortical layer of the brain. Herein, we will review the current understanding of Zika virus (ZIKV) infection of the fetal brain and the NSCs, which are the preferential population targeted by ZIKV. Furthermore, the potential neurotropic properties of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may cause direct neurological damage, will be discussed.

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SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein

Cited by 50 publications

References 52 publications

Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study

Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

Neurogenesis and Viral Infection

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