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

Abstract

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion 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. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

TOM70 in Glial Cells as a Potential Target for Treatment of COVID-19

“…Consistent with this, the receptors involved in SARS-CoV-2 infection including ACE2 were seen to be expressed in the cells of the neurovascular unit, especially in astrocytes and microglial cells (Torices et al, 2021). Recent studies also showed that human pericyte-like cells from brain organoids and endothelial cells from mouse cerebral microvessels can be infected by SARS-CoV-2 (Wang et al, 2021;Wenzel et al, 2021). Interestingly, it was verified that ACE2 was predominantly localized in the pericytes from the mouse microvessels (Wenzel et al, 2021).…”

“…Recent studies also showed that human pericyte-like cells from brain organoids and endothelial cells from mouse cerebral microvessels can be infected by SARS-CoV-2 (Wang et al, 2021;Wenzel et al, 2021). Interestingly, it was verified that ACE2 was predominantly localized in the pericytes from the mouse microvessels (Wenzel et al, 2021). Further studies showed that SARS-CoV-2 is able to directly infect neural stem cell-derived astrocytes (Crunfli et al, 2020) and hamster astrocytes (de Oliveira et al, 2021), and that SARS-CoV-2 spike protein was present in different cells from brain of patients, the majority of these cells being astrocytes (Crunfli et al, 2020).…”

Effects of Covid-19 on the human central olfactory system: a natural pre-post experiment

“…A more straightforward mechanism that might explain the link between the fast changes in OB volume that olfactory training is known to induce is potential changes in the OBs vascularization. Recent data suggest that nearly all individuals infected by the SARS-CoV-2 virus, regardless of whether symptomatic or not, experience endothelial cell death which cause microvascular damage to tissue along the olfactory pathway (Meinhardt et al, 2021;Wenzel et al, 2021). Given the flexibility of the OBs vascularization and close link to amount of olfactory input (Korol & Brunjes, 1992), this suggest that olfactory training might help alleviate OB morphological loss due to COVD-19.…”

The Sexual Long COVID (SLC): Erectile Dysfunction as a Biomarker of Systemic Complications for COVID-19 Long Haulers

“…As previously reported, fatigue, headache and “brain fog” are undoubtedly the most common symptoms of long COVID, with an estimated prevalence 58%, 44%, and 27% prevalence 5 , 14 , 29 , 42 . Fatigue is more than a mere state of tiredness: it is a persistent state of weariness taking a heavy toll on physical and mental energy, often reported by patients for several weeks following the acute phase of COVID-19, independently of the severity of the disease 5 , 14 , 29 , 43 .…”

“…As SARS-CoV-2 has been identified in the cerebrospinal fluid 40 , 41 , encephalitis following direct viral neuronal damage has been included among the complications of COVID-19. SARS-CoV-2 has also been proven able to infect brain endothelial cells, resulting in microvascular pathology occurring in brain vessels which can also influence the blood-brain barrier 42 .…”