Fig. 2

(Key Figure) The cellular virus invasion (SARS-CoV-2) with viral hijacking and amplification of the nuclear factor kappa B (NF-κB) pathway for its replication with additional excessive release of pro-inflammatory cytokines (cytokine storm). In the normal cell cycle, subunits (p65, p50 or p52, c-Rel, RelA or RelB) of the transcriptional factor of numerous pro-inflammatory cytokines (NF-κB) are bound by inhibitor proteins of NF-κB subunits (IκB) in the cytoplasm, which leads to regulation of NF-κB production. After cellular virus invasion (SARS-CoV-2) via the ACE 2 receptor, the virus amplifies the activity of the IκB kinase complex (IKK) catalyzing the proteolytic degradation of IκB by the proteasome. This in turn leaves free NF-κB subunits to translocate unrestricted to the nucleus, where they form NF-κB. NF-κB binds to nuclear DNA in order to enhance virus replication as well as the synthesis and release of pro-inflammatory cytokines (i.e. IL 6, IL 8, TNF α). Vagally secreted acetylcholine (ACh) binds to α7 nicotinic acetylcholine receptors (α7nAchRs) at the cellular surface, blocking the NF-κB action and controlling both, virus replication and release of pro-inflammatory cytokines. Afferent vagal nerve stimulation leads to rebalanced vagal representation in a hypersympathetic, imbalanced autonomic nervous system (ANS), which can be seen in several medical conditions, and during stress in general, but also along the course of critical illness such as severe forms of COVID-19 itself