Thrombosis is frequently observed in COVID-19 patients suffering an aggravated disease course (89), and vasculitis resembling Kawasaki disease was specifically observed in children, subsequently to a suspected contact with SARS-CoV-2 (90)

Thrombosis is frequently observed in COVID-19 patients suffering an aggravated disease course (89), and vasculitis resembling Kawasaki disease was specifically observed in children, subsequently to a suspected contact with SARS-CoV-2 (90). COVID-19 and patients with Behcets disease, an autoimmune disorder exhibiting a region-specific prevalence in countries of the former silk road. Molecular mechanisms and clinical indicators suggest reactive oxygen species as trigger factor for severe progression of COVID-19 and establish a link to the innate immune defense against bacteria. The selective pressure exerted by bacterial pathogens may have shaped the genetics of inhabitants at this ancient trade route in favor of bacterial defense, to the detriment of severe COVID-19 progression in the 21th century. RIG-I and viral RNA is dependent on ROS (69) through upregulation of the mitochondria-associated adapter MAVS (70). The activity of complex multiunit enzymes belonging to the NADPH oxidase (NOX)- CID-2858522 and the dual oxidase (DUOX) families, both expressed in airway- and alveolar epithelial cells, is catalyzing the local generation of CID-2858522 ROS subsequent to viral challenges (71). In this review, we hypothesize that a massive increase in production of ROS triggered by assisted ventilation under high oxygen pressure and facilitated by the downregulation of ACE-2 and the viral load leads to a vicious cycle between RIG-I signaling, exacerbated inflammasome activation and ROS production, ending up in a cytokine storm. There is accumulating evidence that the assisted ventilation in patients with COVID-19 does not change the disease course (2, 72). In addition, iron as limiting element for the continuous activity of NOX and DUOX is reduced in its availability by the upregulation of ferritin, in order to avoid accumulation of ROS and thereof cellular toxicity. Indeed, patients presenting a severe form of COVID exhibit high levels of serum ferritin (73C75), suggesting an inflammatory process accompanied by high levels of ROS. Genetics of ROS Generation and Human Sociographic and Linguistic Evolution The key regulatory checkpoints in ROS production are determined by activity and localization of the multiunit enzymes NOX and DUOX. While epithelial cells of the upper respiratory tract express several isoforms of NOX and DUOX, alveolar epithelial cells, macrophages, and vascular endothelial cells express only two isoforms of NOX, namely NOX2 and NOX4 (76). Macrophages and granulocytes require NOX2 for generation of sufficient ROS in lysosomal compartments for the elimination of bacterial pathogens. The significance of NOX2 function for bacterial defense is apparent in patients with chronic granulomatous disease (CGD), where several identified mutations in any of the five subunits of NOX2 lead to high susceptibility for bacterial infection, giving rise to a low life expectancy (77). Since the first description of a genetic mutation in a NOX CID-2858522 subunit as cause for CGD in the 1980s, single FSHR nucleotide polymorphisms (SNPs) in several NOX subunits and in enzymes involved in neutralization of ROS were identified and associated with atherosclerosis (78), type II diabetes mellitus (79), diabetic nephropathy (79), and thrombosis (80). However, besides the relevant SNPs, the genetic background of patients in those studies, as reflected by their ethnicity, seems to have a significant impact on the outcome. Interestingly, the small p22(phox) subunit, shared between NOX 1- 4 enzymes, serves a crucial role in the assembly and intracellular CID-2858522 localization of all other enzymatic subunits and was found to be highly polymorphic with functional differences in ROS generation (81). Consistent with the role of ACE-2 in neutralizing ROS and decreasing angiotensin II, there is evidence that a persistent high activity of angiotensin II is at least in part responsible for the organ injury observed in COVID-19 (82, 83). SARS-CoV-2 downregulates ACE-2 expression after using it for cellular entry, resulting in unopposed angiotensin II accumulation and local RAAS activation (84, 85). The level of plasma angiotensin II correlates with the degree of lung injury and total viral load in COVID-19 patients (83). Before the invention and wide applications of antibiotics in the 1950s, bacterial infection represented the major cause of death in the human population (86). Bacteria and its ability for host adaption has shaped human evolution for thousands of years by maintaining selective pressure on immune function in young individuals before attaining their reproductive age. Polymorphisms in genes associated with functional differences in generation or neutralization of ROS, or its subcellular localization in phagocytes, may had a profound impact on survival and subsequent genetic inheritance during the pre-antibiotic times (.