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

Wenzel, J., Lampe, J., Müller-Fielitz, H., et al. SARS-CoV -2 main protease M causes microvascular brain pathology by cleaving NEMO in pro-brain endothelial cells. Nat Neurosci (2021). https://doi.org/10.1038/s41593-021-00926-1

Commentary

COVID-19 has been described as capable of injuring small blood vessels in the brain and causing neurological symptoms.

This study was designed to describe the structural changes in cerebral small blood vessels in patients with COVID-19 and to elucidate the potential mechanisms underlying vascular lesions.

In the brains of individuals and animal models infected with SARS-CoV-2, an increased number of empty basement membrane tubes, representing the remnants of lost capillaries, were observed.

This provided evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M pro) cleaves NEMO, an essential modulator of nuclear factor-κB. Ablation of NEMO triggers the death of M pro human brain endothelial cells and the development of filamentous blood vessels in mice.

Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, prevents NEMO ablation-induced vascular rarefaction and disruption of the blood-brain barrier, and importantly, pharmacological inhibitors of M-preventive RIPK signaling prevent pro-induced microvascular pathology.

These results suggest that RIPK is a potential therapeutic target for treating COVID-19 neuropathology.