Role of Secretoglobin 1A1 Protein in COVID-19-induced Thrombosis

Severe COVID-19 infection causes coagulopathies leading to stroke, pulmonary embolism, DVT, and disseminated intravascular coagulation (DIC). These complications of COVID-19 infection are often lethal and can lead to permanent disability in survivors. COVID-19-induced coagulopathy is atypical of most respiratory viral infections and it is important to understand the basis for these effects. Secretoglobin 1A1 (SCGB1A1, also known as CC10, CC16, CCSP, and uteroglobin) is a small globular immunomodulatory protein that is highly expressed in normal lungs by Club cells. Club cells are injured during COVID-19 infection, by the extreme inflammatory response and/or by direct viral infection. Club cell depletion results in SCGB1A1 deficiency. SCGB1A1 is important not only in maintaining lung homeostasis, function, and repair, but also circulates in the blood where it likely has additional homeostatic functions. SCGB1A1 is known to inhibit platelet aggregation and Factor XIIIa transglutaminase activity in vitro and may therefore play a role in vascular and/or blood homeostasis particularly as relates to balancing coagulation responses. SCGB1A1 is also known to be chemically modified by exposure to reactive oxygen and nitrogen species (ROS/RNS) during severe inflammatory responses in the lungs and the impact of these modifications on the anti-thrombotic activities of SCGB1A1 merits investigation. The proposed research will investigate the effects of ROS/RNS modification of SCGB1A1 on coagulation and clot formation in vitro, as well as in an animal model, and then will evaluate the potential depletion of SCGB1A1 and ROS/RNS-mediated modifications of native SCGB1A1 in COVID-19 patients and the potentiation of thrombosis in COVID-19 patients.The proposed research would contribute fundamental knowledge to our understanding of how severe inflammation can impact local and systemic coagulation and regulation of vascular permeability through a completely new and unanticipated mechanism. It could lead not only to improved management of conditions like severe COVID-19 infection but also to new therapeutic approaches that could enhance health, lengthen life, and reduce illness and disability.