Role of ERK1/2 signaling in SARS-CoV-2 -induced dysregulated immunity and lung pathology.

Project Summary (Abstract): Emerging and re-emerging respiratory viruses such as SARS-CoV, MERS-CoV, SARS-CoV-2, and avian and swine influenza viruses continue to pose a significant challenge to public health. These highly pathogenic viruses successfully evade host immunity and replicate to high titers, causing excessive inflammation, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and fatal pneumonia. However, the host and virus factors that facilitate impaired antiviral response and excessive inflammation (dysregulated immunity) that lead to ALI and lung pathology are not known. In novel preliminary findings, we identify that toll-like receptor (TLR)-extracellular regulated kinase (ERK)1/2 activity is central to SARS- CoV-2 and viral-RNA-induced dysregulated lung immunity. Notably, blocking ERK1/2 activity not only reduced SARS-CoV-2-induced inflammatory cytokine production but also enhanced antiviral IFN-I response. Therefore, based on our strong preliminary data, we hypothesize that myeloid cell-intrinsic TLR- ERK1/2 signaling promotes pathogenic lung inflammation and suppresses antiviral immunity. The primary objective of the proposed study is to demonstrate the critical role of myeloid-cell TLR-ERK1/2 signaling in SARS-CoV-2-induced dysregulated immunity, acute lung injury (ALI), and lung pathology, and to evaluate the therapeutic potential of blocking ERK1/2 activity in suppressing lethal inflammation while enhancing antiviral. We will define the role of myeloid cell-intrinsic TLR-ERK1/2 activity in SARS-CoV-2-induced lung injury and pathology (Aim 1), demonstrate the role of myeloid cell intrinsic TLR-ERK1/2 activation in the dysregulation of SARS-CoV-2-specific lung T cell response (Aim 2), and test the therapeutic potential of blocking ERK1/2 signaling with or without antivirals in reducing lung injury and protecting mice from lethal SARS-CoV-2 infection (Aim 3). The results obtained from this study will provide a foundation for identifying specific targets to moderate lung inflammation and injury, which in combination with antivirals, can be used to improve ALI, ARDS, and clinical outcomes.