Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?

As healthy young adults can die of COVID-19, whereas old COVID-19 patients can have mild symptoms only, genetic variances probably contribute to the severity of this emerging infection. We previously put forward the hypothesis that gain of function variants of TMEM 173, which encodes STING, contribute to COVID-19, since bats are protected from coronaviruses due to loss of function mutations of this gene. The present review detail new arguments for the contribution of the STING pathway to COVID-19, following the description of hyper-coagulability and Kawasaki-like diseases in children with COVID-19. Indeed, Kawasaki disease is induced by overreaction of innate cells following exposition to various viruses, including herpes viruses which trigger STING. It predisposes to diffuse vasculitis and aneurysms, whereas STING is over-expressed in arterial aneurisms. The redness at the inoculation site of bacillus Calmette-Guerin, a specific feature of Kawasaki disease, is reproduced by activation of the STING pathway, which is inhibited upstream by aspirin, intravenous immunoglobulins, and Vitamin-D. SARS-CoV2 binding to ACE2 can lead to excessive angiotensin II signaling, which activates the STING pathway in mice. Overactivation of the STING-pathway promotes hyper-coagulability through release of interferon-β and tissue factor by monocytes-macrophages. Aspirin and dipyridamole, besides their anti-platelet activity, also reduce tissue factor procoagulant activity, and aspirin inhibits the STING pathway upstream of STING. Aspirin and dipyridamole may be used, in combination with drugs blocking downstream the activation of the STING pathway, like inhibitors of IL-6R and JAK/STAT pathways. The risk of bleeding should be low as bleeding has not been reported in severe COVID-19 patients.