Sunday, May 11, 2025
5/11/2025
Roles of human surfactant collectin variants in the susceptibility of COVID-19 - More than 4.8 million people have died due to coronavirus disease 2019 (COVID-19) in less than two years. COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Morbidity and mortality following SARS-CoV-2 infection are predominantly due to a robust influx of inflammatory cells and cytokines into the lungs resulting in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Individuals exhibited different degree of disease severity after SARS-CoV-2 infection. Human Surfactant proteins A and D (hSP-A and hSP-D), two members of C-type lectin (surfactant collectin), are pattern recognition proteins, and they play a critical role as a first-line host defense and innate immunity in the mucosal surfaces of the lung and other organs. Our preliminary data and recent in vitro studies demonstrated that hSP-A and hSP-D can bind to SARS-CoV-2 Spike protein and inhibit viral entry and replication in lung epithelial cells. Interestingly, the genes of hSP-A and hSP-D are highly polymorphic, and several genetic variants (alleles) for each of them have been identified in the general population. However, the mechanistic roles of hSP- A and hSP-D genetic variants in the pathogenesis of COVID-19 are unknow. The long-term goal is to determine the roles of hSP-A and hSP-D genetic variants in susceptibility and severity to SARS-CoV-2-induced ALI/ARDS and to develop novel variant-specific therapeutic drug for the treatment of COVID-19. This proposal aims to determine molecular interaction of surfactant collection and Spike protein, and define the mechanistic roles of hSP-A and hSP-D genetic variants causing individual susceptibilities to COVID-19. Our central hypothesis is that hSP-A and hSP-D genetic variants differentially influence susceptibility and severity to SARS-CoV-2-induced ALI/ARDS by inhibiting SARS-CoV-2 infectivity and modulating mucosal innate immunity and pathophysiology. Recently, we have generated a new double-humanized transgenic (double-hTG) mouse model, which express human angiotensin-converting enzyme-2 (SARS-CoV-2 cognate receptor) and hSP-A or hSP-D genetic variant. This double-hTG model provides us with a powerful tool to study the innate immune response and mechanistic roles of hSP-A and hSP-D variants following SARS-CoV-2 infection. We propose two specific aims to test our hypothesis: Aim 1: Study the interactions of hSP-A or hSP-D genetic variants with SARS-CoV-2 spike protein and the inhibitory effect on viral entry and replication in lung epithelial cells. Aim 2: Define the differential roles of hSP-A genetic variants in inhibiting viral infectivity and modulating SARS-CoV-2-induced ALI through regulating TLRs/NF-kB/IFN signaling in a double-hTG mouse model. The proposal is strongly supported by our preliminary data and available novel double-hTG model suitable for COVID-19 study. We expect that the successful completion of the proposed studies will establish a novel COVID-19 murine model, and have a better understanding of the innate immune roles of hSP-A and hSP-D in COVID-19 pathogenesis that is crucial to develop novel immunomodulatory therapies and personalized medicine.
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