Role of Complement Activation in Severe COVID-19

PROJECT ABSTRACT We recently developed sub-lethal lethal mouse model of Covid-19 (K18-hACE2). We infected these mice with influenza virus or sublethal SARS-CoV-2 infected K18-hACE2 mice to study pathobiology of Covid-mild 19 disease and to identify treatment modalities for long Covid. These studies revealed that both influenza and sub-lethal dose of SARS-CoV-2 causes transients weight loss and damage lung epithelial cells as expected. However, influenza induced inflammation was resolved by proliferation of basal lung epithelial cells organized into pod structure and lung regeneration while sub-lethal SARS-CoV-2 induced inflammation resulted in lung fibrosis. At the molecular level influenza infection induced expression of Keratin genes (Krt5, 15, 16) at dramatically higher levels compared to sub-lethal dose of SARS-CoV-2, consistent with tissue repair in lungs of influenza but fibrosis in the lungs of sub-lethal SARS-CoV-2 infected mice. Importantly, influenza induced much stronger interferon response while SARS-CoV-2 induced much stronger cytokine response, complement response, and fibrosis. These data indicate that a more robust innate immune response, attenuated cytokine and complement response, and activation of pro-resolving molecules may help reduce the mortality and morbidity of SARS-CoV- 2. Omega 3 polyunsaturated fatty acids (n-3 PUFAs) fulfil these criteria because they activate direct anti-viral response proteins and are the precursors of the pro-resolving lipid mediators that favor tissue repair. Indeed, n-3 PUFAs reduce lung fibrosis induced by various chemical and environmental assaults. In this supplemental proposal we will feed sub-lethal SARS-CoV-2 infected mice with n-3 PUFA or n-6 PUFA (control) supplemented diets to test the hypothesis that n-3 PUFAs will improve innate immune response to SARS-CoV-2 infection by moderating the initial injury as determined by weight loss and initial lung injury. We hypothesis further that by increasing tissue and blood concentration of pro-resolving lipid mediators, n-3 PUFAs will promote tissue repair over fibrosis in mice infected with sub-lethal dose of SARS-CoV-2. If these studies are successful they will open a path for human clinical studies aimed at using n-3 PUFAs as nutritional substances to reduce morbidity of long Covid, either alone or in combination with other agents such as complement inhibitors.