Saturday, September 7, 2024
9/7/2024
Project Summary/Abstract Human coronavirus (hCoV) induces excessive inflammation and impairs interferon (IFN) responses, often referred to as 'dysregulated immunity,' which is associated with fatal pneumonia. However, the specific virus and host factors that cause dysregulated lung immunity and lethal pneumonia are not well defined, constituting a significant knowledge gap. Our work in mouse models of hCoVs has shown that impaired or delayed IFN-I and excessive myeloid cell responses cause excessive lung inflammation, acute lung injury, and fatal pneumonia. Notably, myeloid cell depletion reduces lung inflammation and pathology and improved survival. However, the key host factors that drive hCoV-induced acute lung injury and pathology are not well understood. RNA viruses such as hCoVs elicit myeloid cell inflammation primarily through TLR/TRAF6/NF-kB or MAPK activation. Of note, TRAF6 is a common adapter molecule upstream of both NF-kB and MAPK. Therefore, TRAF6 is an attractive target to moderate hCoV-induced excessive lung inflammation without disturbing the antiviral TRAF3/IRF/IFN pathway. Here, we show that TRAF6 is central to myeloid cell-mediated inflammatory response, and the abrogation of TRAF6 activity significantly reduces hCoV-induced inflammatory cytokine production. Remarkably, TRAF6 inhibition enhances antiviral IFN-I response in macrophages. Based on our published and preliminary data, we hypothesize that myeloid cell intrinsic TRAF6 activity promotes excessive lung inflammation, suppresses antiviral immunity, causing lung pathology. The primary objective of the proposed exploratory grant application is to define the critical role of myeloid-cell TRAF6 signaling in SARS- CoV-2-induced dysregulated immunity, acute lung injury, and lung pathology. We will also define the mechanistic basis for TRAF6-mediated dysregulated immunity during SARS-CoV-2 infection. Establishing the central role of TRAF6 signaling in dysregulated immunity will allow us to evaluate novel therapeutics targeting TRAF6 activity to suppress excessive lung inflammation while enhancing antiviral immunity.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
