<scp>COVID</scp>‐19: A Global Threat to the Nervous System

Koralnik, Igor J.; Tyler, Kenneth L.

doi:10.1002/ana.25807

Cited by 427 publications

(460 citation statements)

References 77 publications

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“…The host's pro-inflammatory response, particularly in cases of aggressive inflammatory phenotypes, strongly contributes to disease prognosis. Neurological observations as nausea, headache, anosmia, myalgia, impaired consciousness, and acute cerebrovascular diseases have also been reported in some COVID-19 patients 17,35,36 . It is clear that much remains unknown about the pathophysiology of SARS-CoV-2 infection not only in periphery organ systems but specially in regard to the CNS.…”

Section: Discussionmentioning

confidence: 88%

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier

Buzhdygan

DeOre

Baldwin‐Leclair

et al. 2020

Preprint

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As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system includes neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-COV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is expressed throughout various caliber vessels in the frontal cortex. Additionally, ACE2 was also detectable in primary human brain microvascular endothelial (hBMVEC) maintained under cell culture conditions. Analysis for cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48hr exposure window. However, when the viral spike proteins were introduced into model systems that recapitulate the essential features of the Blood-Brain Barrier (BBB), breach to the barrier was evident in various degrees depending on the spike protein subunit tested. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluid model of the human BBB, a platform that most closely resembles the human physiological conditions at this CNS interface. Subsequent analysis also showed the ability for SARS-CoV-2 spike proteins to trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.

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Section: Discussionmentioning

confidence: 88%

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier

Buzhdygan

DeOre

Baldwin‐Leclair

et al. 2020

Preprint

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“…For example, transferrin is produced in the brain [18], and high transferrin levels have been associated with hypercoagulability and ischemic stroke [19]. Stroke is a significant complication in COVID-19 [20], and much more common than in influenza patients [21]. Both ischemic and haemorrhagic strokes are observed in COVID-19 patients [20].…”

Section: Discussionmentioning

confidence: 99%

“…Stroke is a significant complication in COVID-19 [20], and much more common than in influenza patients [21]. Both ischemic and haemorrhagic strokes are observed in COVID-19 patients [20]. Notably, transferrin may not only contribute to ischemic strokes via inducing coagulation [19], it may also increase the brain injury associated with haemorrhagic strokes by facilitating cellular iron uptake [22].…”

Section: Discussionmentioning

confidence: 99%

COVID-19-related coagulopathy – Is transferrin a missing link?

McLaughlin

Bechtel

Bojkova

et al. 2020

Preprint

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SARS-CoV-2 is the causative agent of COVID-19. Severe COVID-19 disease has been associated with disseminated intravascular coagulation and thrombosis, but the mechanisms underlying COVID-19-related coagulopathy remain unknown. Since the risk of severe COVID-19 disease is higher in males than in females and increases with age, we combined proteomics data from SARS-CoV-2-infected cells with human gene expression data from the Genotype-Tissue Expression (GTEx) database to identify gene products involved in coagulation that change with age, differ in their levels between females and males, and are regulated in response to SARS-CoV-2 infection. This resulted in the identification of transferrin as a candidate coagulation promoter, whose levels increases with age and are higher in males than in females and that is increased upon SARS-CoV-2 infection. A systematic investigation of gene products associated with the GO term "blood coagulation" did not reveal further high confidence candidates, which are likely to contribute to COVID-19-related coagulopathy. In conclusion, the role of transferrin should be considered in the course of COVID-19 disease and further examined in ongoing clinic-pathological investigations.

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“…In COVID-19 patients, magnetic resonance imaging detected lesions that are compatible with a microvascular pathology [17][18][19][20][21] . Autopsy studies have con rmed this interpretation 17,[22][23][24] . However, the mechanisms that lead to small vessel disease in COVID-19 are still unclear.…”

Section: Introductionmentioning

confidence: 83%

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

Wenzel¹,

Lampe²,

Mueler-Fielitz³

et al. 2020

Preprint

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Several lines of evidence suggest that neurological symptoms in COVID-19 patients are partially due to damage to small vessels. However, the potential mechanisms are unclear. Here, we show that brain endothelial cells express SARS-CoV-2 receptors. The main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of NF-κB signaling. By ablating NEMO, Mpro induces the death of human brain endothelial cells and a microvascular pathology in mice that is similar to what we find in the brain of COVID-19 patients. Importantly, the inhibition of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Our data suggest RIPK as a therapeutic target to treat the neuropathology of COVID-19.

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COVID‐19: A Global Threat to the Nervous System

Cited by 427 publications

References 77 publications

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier

COVID-19-related coagulopathy – Is transferrin a missing link?

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

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