Spike protein multiorgan tropism suppressed by antibodies targeting SARS-CoV-2

Brady, Molly; McQuaid, Conor; Solorzano, Alexander; Johnson, Angelique; Combs, Abigail; Venkatraman, Chethana; Rahman, Akib; Leyva, Hannah; Kwok, Wingchi E.; Wood, Ronald W.; Deane, Rashid

doi:10.1038/s42003-021-02856-x

Cited by 10 publications

(17 citation statements)

References 112 publications

(158 reference statements)

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“…This finding has been frequently reported in COVID-19 patients with neurological symptoms (Jarius et al, 2022). It has been related to several mechanisms such as a direct viral infection, non-specific inflammatory damage (Perico et al, 2020;Varga et al, 2020;Huang et al, 2021), a virus-induced anti-endothelial autoimmunity (Shi et al, 2022), and hypoxia-related alterations (Ackermann et al, 2020;Buja et al, 2020). However, an increase in the CSF/blood-albumin-ratio might also be caused by changes in the CSF production and resorption (Pellegrini, 2020;McMahon et al, 2021) or viral infection of the choroid plexus (Yang et al, 2021).…”

Section: Discussionmentioning

confidence: 59%

“…There is some evidence pointing to a viral neurotropism ( Paterson et al, 2020 ; de Erausquin et al, 2021 ), virus-induced inflammatory state (refereed as a cytokine storm) ( Deleidi and Isacson, 2012 ; Butowt et al, 2021 ; Yang et al, 2021 ) and systemic post-infectious inflammation ( McQuaid et al, 2021 ). Nevertheless, the virus’ presence in the human brain has still to be demonstrated ( von Weyhern et al, 2020 ; Brady et al, 2021 ; McQuaid et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Brain cortical alterations in COVID-19 patients with neurological symptoms

Sanabria‐Diaz

Etter²,

Melie‐García³

et al. 2022

Front. Neurosci.

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BackgroundGrowing evidence suggests that the central nervous system is affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), since infected patients suffer from acute and long-term neurological sequelae. Nevertheless, it is currently unknown whether the virus affects the brain cortex. The purpose of this study was to assess the cortical gray matter volume, the cortical thickness, and the cortical surface area in a group of SARS-CoV-2 infected patients with neurological symptoms compared to healthy control subjects. Additionally, we analyzed the cortical features and the association with inflammatory biomarkers in the cerebrospinal fluid (CSF) and plasma.Materials and methodsThirty-three patients were selected from a prospective cross-sectional study cohort during the ongoing pandemic (August 2020–April 2021) at the university hospitals of Basel and Zurich (Switzerland). The group included patients with different neurological symptom severity (Class I: nearly asymptomatic/mild symptoms, II: moderate symptoms, III: severe symptoms). Thirty-three healthy age and sex-matched subjects that underwent the same MRI protocol served as controls. For each anatomical T1w MPRAGE image, regional cortical gray matter volume, thickness, and surface area were computed with FreeSurfer. Using a linear regression model, cortical measures were compared between groups (patients vs. controls; Class I vs. II–III), with age, sex, MRI magnetic field strength, and total intracranial volume/mean thickness/total surface area as covariates. In a subgroup of patients, the association between cortical features and clinical parameters was assessed using partial correlation adjusting for the same covariates. P-values were corrected using a false discovery rate (FDR).ResultsOur findings revealed a lower cortical volume in COVID-19 patients’ orbitofrontal, frontal, and cingulate regions than in controls (p < 0.05). Regional gray matter volume and thickness decreases were negatively associated with CSF total protein levels, the CSF/blood-albumin ratio, and CSF EN-RAGE levels.ConclusionOur data suggest that viral-triggered inflammation leads to neurotoxic damage in some cortical areas during the acute phase of a COVID-19 infection in patients with neurological symptoms.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Brain cortical alterations in COVID-19 patients with neurological symptoms

Sanabria‐Diaz

Etter²,

Melie‐García³

et al. 2022

Front. Neurosci.

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“…In addition, in cases where traces of SARS-CoV-2 RNA or proteins were found within the brain, they did not correlate with neurological symptoms 10 . Moreover, in mice, SARS-CoV-2 spike protein accumulates in several regions of the body, including the choroid plexus, but is not detected in the brain parenchyma or CSF 11 . It is thus very unlikely that direct viral damage to the brain is the leading cause of cognitive deficits following COVID-19.…”

Section: Sars-cov-2 Neurotropism In the Choroid Plexusmentioning

confidence: 98%

The type I interferon antiviral response in the choroid plexus and the cognitive risk in COVID-19

2023

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“…While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily elicits respiratory infectious coronavirus disease-19 (COVID-19) ( Bchetnia et al, 2020 ), many non-respiratory organs are also affected, including the brain ( Huang et al, 2020 ; Mao L. et al, 2020 ; Moriguchi et al, 2020 ; Saleki et al, 2020 ; Brady et al, 2021 ; McQuaid et al, 2021 ), heart ( Dhakal et al, 2020 ; Puntmann et al, 2020 ; Perez-Bermejo et al, 2021 ), kidneys ( Fanelli et al, 2020 ; Martinez-Rojas et al, 2020 ), and liver ( Mao R. et al, 2020 ; Wang et al, 2020 ; Zhong et al, 2020 ; Marjot et al, 2021 ). This may suggest that there is also viral distribution from the blood during the pathogenesis of this disease.…”

Section: Introductionmentioning

confidence: 99%

“…SARS-CoV-2 has been detected in brains of severely infected deceased people, however, it is unclear as to how it gets there and if this leads to significant viral neuro-invasion ( McQuaid et al, 2021 ). Recombinant spike proteins have been used to study viral behavior by using in vitro models of brain endothelial cells and in vivo studies ( Buzhdygan et al, 2020 ; Brady et al, 2021 ; Rhea et al, 2021 ). While it was reported that SP interacts with the brain endothelial cells, this was independent of ACE2, in mice ( Rhea et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Uptake of severe acute respiratory syndrome coronavirus 2 spike protein mediated by angiotensin converting enzyme 2 and ganglioside in human cerebrovascular cells

McQuaid

Solorzano²,

Dickerson³

et al. 2023

Front. Neurosci.

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IntroductionThere is clinical evidence of neurological manifestations in coronavirus disease-19 (COVID-19). However, it is unclear whether differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/spike protein (SP) uptake by cells of the cerebrovasculature contribute to significant viral uptake to cause these symptoms.MethodsSince the initial step in viral invasion is binding/uptake, we used fluorescently labeled wild type and mutant SARS-CoV-2/SP to study this process. Three cerebrovascular cell types were used (endothelial cells, pericytes, and vascular smooth muscle cells), in vitro.ResultsThere was differential SARS-CoV-2/SP uptake by these cell types. Endothelial cells had the least uptake, which may limit SARS-CoV-2 uptake into brain from blood. Uptake was time and concentration dependent, and mediated by angiotensin converting enzyme 2 receptor (ACE2), and ganglioside (mono-sialotetrahexasylganglioside, GM1) that is predominantly expressed in the central nervous system and the cerebrovasculature. SARS-CoV-2/SPs with mutation sites, N501Y, E484K, and D614G, as seen in variants of interest, were also differentially taken up by these cell types. There was greater uptake compared to that of the wild type SARS-CoV-2/SP, but neutralization with anti-ACE2 or anti-GM1 antibodies was less effective.ConclusionThe data suggested that in addition to ACE2, gangliosides are also an important entry point of SARS-CoV-2/SP into these cells. Since SARS-CoV-2/SP binding/uptake is the initial step in the viral penetration into cells, a longer exposure and higher titer are required for significant uptake into the normal brain. Gangliosides, including GM1, could be an additional potential SARS-CoV-2 and therapeutic target at the cerebrovasculature.

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Spike protein multiorgan tropism suppressed by antibodies targeting SARS-CoV-2

Cited by 10 publications

References 112 publications

Brain cortical alterations in COVID-19 patients with neurological symptoms

Brain cortical alterations in COVID-19 patients with neurological symptoms

The type I interferon antiviral response in the choroid plexus and the cognitive risk in COVID-19

Uptake of severe acute respiratory syndrome coronavirus 2 spike protein mediated by angiotensin converting enzyme 2 and ganglioside in human cerebrovascular cells

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