Toll-like receptor interactions and their contribution to airway inflammation

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Respiratory viral infections elicit acute exacerbations of chronicairway inflammatory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. However,the molecularmechanisms thatunderlie these exacerbations are poorly understood. Evidencesuggests that impairment of innate immune responses mediated by Toll-like (TLR)receptors is involved.Microbial components bind TLRs triggering signaling cascades that induce expression ofgenes involvedin inflammation. The central hypothesis of this proposal is that viral activation of TLRS sensitizes airway epithelial cells to TLR2 stimuli and desensitizes them to TLRS stimuli and this modified sensitivity alters the inflammatory response of the airways to allergen and bacterial challenge. To test this hypothesis, the effect of TLRS activation on TLR2 and TLRS expression and innate immunefunction will be examined using human airway epithelial cells. Moreover,exacerbation of airway inflammation in response to TLRS activation will be studied in wild-type and TLRS-deficient mice treated with TLR2 or TLRS ligands to investigate the molecular mechanisms involved in altered sensitivity to allergens and microorganisms that activate these receptors. Additionally, the effects of Alternaria alternata, a fungus detected by TLR2 and known to induce acute asthmatic episodes, alongwith Burkholderia cenocepacia,an opportunistic bacterium that activated TLRS and causes pulmonary infection in individuals with cystic fibrosis will be used to explore the role ofTLR2, TLRS, and TLRS receptors in airway inflammation. As our understanding of these interactions on the development of inflammatory airway disease improves, novel interventions designed to modulate the host response to these exposures can be implemented to alleviate the damage caused by chronic inflammation. This Career DevelopmentAward proposal was designed to advance my research trainingtowards becoming an independent scientist. To accomplish this goal 1 have received the support of three established investigators at the Universityof Minnesota and the Mayo Clinic that will serve as co-sponsors, along with consultants to assist me in my career development. I have developed a research project based on experiments I performed in the RELEVANCE (See instructions): Respiratory viral infections elicit acute exacerbations of airway diseases (asthma, COPD and CF). However, molecular mechanisms underlying these exacerbations are poorly understood. Evidence suggests impair- ment of innate immune responses mediated by Toll-like (TLR) receptors is involved. This proposal characterizes the effects of TLRS activation on the expression and function of TLR2 and TLRS. Understanding these interactions may lead to novel interventions to combat these diseases.