MECHANISTIC STUDIES OF THE INTRAVASCULAR INNATE IMMUNE SYSTEM (IIIS) IN COVID19 AND ARDS OF OTHER ORIGIN

The aim of this application is to characterize the generalized intravascular innate immune system (IIIS) activation in COVID-19.

The rationale for this is to identify the mechanisms of the respiratory distress syndrome and indirectly the collateral damages in other organs associated with COVID-19 and identify new targets for therapeutic intervention in patients with COVID-19 ARDS.Supported by a previous COVID-specific VR grant, we have investigated biomarkers of IIIS activation in the first 66 COVID-19 patients with ARDS-like disease admitted to the ICU in Uppsala University Hospital in the start of the pandemic, both cross-sectionally and longitudinally.

We found a massive activation of the IIIS, in particular of the kinin/kallikrein system leading to an overreactive conjunct thromboinflammation.Now we aim to extend our previous studies to e.g. i) compare IIIS in short- and long-term COVID-19 and in other types of ARDS; ii) perform in vivo testing of inhibitors of IIIS in a pig ARDS model; iii) perform basic studies of the interaction between the IIIS and virusproteins and virus-infected (damaged) cells.This project identifies IIIS biomarkers and IIIS points of regulation to be used in the clinic, and it also paves the way for testing already licensed orphan drugs such as Firazyr (icantibant; BKR2 inhibitor), Takhzyro and Kalbitor (Lanadelumab and Ecallantide; both kallikrein inhibitors) or drugs that have already passed the phase I stage (e.g.

AMY-101; C3 inhibitor).