TLR3, TICAM1 and human rhinovirus infection

DESCRIPTION (provided by applicant): TLR3, TICAM1 and human rhinovirus infection Human rhinovirus (RV) infection is associated with the common cold and asthma development and/or exacerbation. To date, we and others have reported a complex of RV-induced epithelial proinflammatory and antiviral pathways, which involve TLR3, RIG1, MDA5 and PKR. Recently, we have shown that TLR3 activation appears to be upstream of all other pathways, and TLR3 desensitization via TICAM1 degradation is critical to antiviral defense by airway epithelium. To further elucidate the underlying mechanism, we propose to first determine the impact of TLR3 desensitization on epithelial anti-viral defense in vitro. In this study, we will determine the kinetics of TICAM1 protein turnover and its downstream cellular antiviral responses induced by dsRNA or by RV. We will also determine the cellular antiviral status during this process. Lastly, we will overexpress TICAM1 to test if this could restore the cellular antiviral response. To evaluate the potential alteration of TLR3 desensitization in asthma, we will determine whether or not Th2-cytokine- treated epithelial cells have altered desensitization, and whether or not human asthmatic epithelial cells are defective in this process as compared to the normal cells. Then, we propose to determine the mechanistic basis of TICAM1 degradation. In this aim, we will test a novel hypothesis that TICAM1 is degraded via chaperone mediated autophagy. This is a high-risk and high-impact project that is well suited for R21 mechanism. If we succeed, we will be able to gain novel insight into the TLR3-TICAM1 mediated airway antiviral defense and to identify a risk factor for asthma exacerbation.