Novel role of TLR-ERK1/2 activation in SARS-CoV-2-induced dysregulated immunity 3869

Abstract Description Pathogenic human coronaviruses (hCoVs) cause severe respiratory illness and continue to challenge global public health. These hCoVs suppress anti-viral immunity and elicit excessive inflammation (dysregulated immunity) resulting in acute lung injury and fatal pneumonia. However, the key PAMPs and host factors that facilitate dysregulated immunity are not well understood. Therefore, using murine bone-marrow derived macrophages, we evaluated the mechanistic basis of SARS-CoV-2-induced dysregulated immunity. In novel findings, we show that SARS-CoV-2 structural protein- and viral-RNA-induced toll-like receptor (TLR)-extracellular regulated kinase (ERK)1/2 activity promotes dysregulated immunity in macrophages. Notably, blocking ERK1/2 activity not only reduced inflammatory cytokine response in viral RNA mimic and SARS-CoV-2 structural proteins-stimulated macrophages but also enhanced antiviral IFN-I response, whereas blocking other key inflammatory pathways such as p-38 MAPK, NF-kB, and JNK only suppressed inflammation, highlighting the unique role of ERK1/2 in facilitating hCoV-induced dysregulated immunity. We further show that inhibiting ERK1/2 activity reduced viral titers in SARS-CoV-2 infected human airway epithelial cells and improved survival in MA-CoV-2 infected mice. Collectively, we identify TLR-ERK1/2 signaling as novel pathway that drives SARS-CoV-2-induced dysregulated immunity and blocking this pathway will likely facilitate protective immunity to hCoV infections. Funding Sources NIH R21AI186028-01; NIH R01HL165423-01A1; NIH: P30GM149368-02 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)