ABSTRACT
Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we show that SARS-CoV-2 is detectable in postmortem vagus nerve specimen together with inflammatory cell infiltration derived primarily from monocytes. This is associated with a decreased respiratory rate in non-survivors of critical COVID-19. Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction.
Subject(s)
COVID-19 , Inflammation , Vagus Nerve Diseases , Primary DysautonomiasABSTRACT
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.