Host cellular network governing the development of post SARS-CoV-2 tissue sequelae

Summary/Abstract The aftermath of the COVID-19 pandemic presents a significant public health challenge with over 60 million individuals globally affected by post-acute sequelae of SARS-CoV-2 infection (PASC). Through comparative single cell RNA-seq analysis, our prelim research has provided insights into the exuberant interactions of between monocyte-derived macrophages and lung resident T cells, mediated by the cytokine IFN-γ, in contributing to the development of respiratory PASC. Importantly, we found that the neutralization of IFN-γ ameliorated immune anomalies and chronic tissue sequelae after acute SARS-CoV-2 infection. Despite these advancements, critical knowledge gaps remain. The direct roles of T cell-derived IFN-γ in regulating post SARS-CoV-2 chronic diseases are yet to be fully understood. Our established post-viral tissue sequelae models are still relatively transient compared to human sequelae. Furthermore, the intricacies of the IFN-γ -STAT1 pathway in macrophages driving persistent tissue sequelae, and the potential of pharmacologically targeting this pathway to mitigate chronic sequelae post-infection are areas that need exploration. This grant application aims to address these gaps through three specific aims: Aim 1. To elucidate the roles of T cell-derived IFN-γ in post SARS-CoV-2 tissue sequelae. Aim 2. To determine the roles of persistent macrophage STAT1 signaling in driving post SARS-CoV-2 tissue sequelae. Aim 3. To examine the IFN-γ-STAT1-SPP1 axis in tissue inflammation and fibrosis post SARS-CoV-2 infection. The successful completion of this study promises to significantly advance our understanding of the cellular and molecular mechanisms driving respiratory PASC development. Moreover, it will open new avenues for developing effective therapeutics for PASC, addressing a crucial unmet clinical need.