PlatdeDNA

The COVID pandemic causes severe acute respiratory distress syndrome (ARDS) with severe respiratory barrier damage, inflammation, edema and often respiratory failure. Platelets are involved in thrombosis and contribute to innate immunity. Platelets expressing ACE2 are abundant in the lungs and upon activation release mitochondrial DNA. We hypothesize that platelets are an important source of extracellular DNA activating the cGAS and STING pathway triggering lung inflammation. Thus, reducing platelets, cell free DNA and/or targeting the cGAS/STING pathway may dampen ARDS. Clinical samples from COVID-19 patients (n = 84) and non-COVID-19 patients (n=17) collected from endotracheal aspirates, plasma and PBMC will be analyzed for platelet counts and activation, self-DNA levels in the aspirates and in plasma and correlated with clinical parameters and survival. Experimental studies of in vitro activated platelets and in vivo SARS-CoV-2 infection in a novel huACE2 KI mice will address the following aspects of platelet-related questions: i) DNA release by in vitro activated platelets; ii) activation of platelet-derived DNA on cGAS/STING reporter and gene deficient mice; iii) selective platelets depletion affecting sterile and SARS-CoV-2 infection induced ARDS; iv) effect of pharmacological inhibition of cGAS/STING in experimental ARDS. Our consortium of two French teams and two international collaborators, which are experts in lung inflammation, virus infection, innate immunity, molecular and cell biology, will address these issues using advanced models, clinical samples and pluridisciplinary and cutting-edge technologies. The data may be exploited to develop innovative therapeutic options for severe COVID-19.