In a recent Comment published on EBioMedicine entitled “COVID-19 as a STING disorder with delayed oversecretion of Interferon-beta”, Berthelot and Lioté suggests that SARS-CoV-2 firstly inhibits interferon release but the NETs self-DNA induces delayed activation of STING with“cytokine storm”, causing the combination of interstitial lung disease and inflammatory vasculopathy.
The assumption that SARS-CoV-2 had no charge on critical evolution was reported by Zheng et al showing that no significant difference in serum viral loads could be detected between patients with mild or severe disease, while innate immunity pathways activation patterns, specifically neutrophilia and neutrophils/lymphocytes ratio, are significantly increased in critically ill patients.
Neutrophils, through Neutrophil Elastase Traps (NETS), excessively activate STING, inducing further recruitment and the TRL4 activation, with TNFalfa and IL1 release, contributes to subsequent endothelitis, with overexpression of P-Selectin and local prothrombotic conditions.
Furthermore, neutrophil degranulation releases high levels of serine proteases activators, causing a “proteolytic storm” due to significant imbalance of four major proteolytic cascades (coagulation, complement, fibrinolysis and kallikrein) with activators prevalence over SERPIN family inhibitors. This results in uncontrolled proteolytic activation in the lung, in the endothelium and in organs with unhinibited activation of platelets, extrinsic and intrinsic pathway of blood coagulation, complement and fibrinolysis cascades, with extensive cross talk mutually fine-tuning their activation status.
NETS reinforce “Proteolytic storm”, in a feedback loop, disrupting epithelial lining, inducing platelet aggregation, activating new neutrophils recruitment, the intrinsic and extrinsic pathways of coagulation and forming a scaffold for thrombus formation by promoting platelet adhesion, by binding factor XII and supporting its activation through NETosis. At endothelial level, inflammatory vasculopathy, FXIa and α-thrombin reduce ADAMTS13, increasing the release of Ultra Large von Willebrand Factor multimers (ULVWF) by endothelial cells, resulting in persistence of ULVWF strands and causing a further increase in platelet adhesion.
The hypercoagulability, as imbalance of proteases/antiproteases cascades, decrease of ADAMTS13, endotheliopathy, increased platelet activation, ULVWF multimers and NETosis together create a severe thromboembolic environment with microthrombi formation. These microthrombi can become sufficiently large to be released from endothelial cells into the circulation, resulting in embolism or can be physically disrupted (as in forced ventilation) disseminating through general circulation to organs, causing MOF.
The clinical evolution to critical conditions is thus triggered by a “proteolytic storm”, due to serine proteases cascades imbalancing.
The potential efficacy of convalescent plasma cannnot be related to NAbs, but to its ability to reintegrate a physiological balance.