The RFA, Immune Defense Mechanisms at the Mucosa, requests exploratory/developmental research projects that propose to study immune mechanisms at respiratory mucosal surfaces to gain new insights that will facilitate vaccine development to protect mucosal surfaces from infection and inflammation. Antibody producing and memory B cells and T cells populate the lung indicating a capacity to form adaptive immune responses, yet development of respiratory mucosal vaccines has been difficult. A successful mucosal vaccine needs to provide for memory, subsequent recognition, and clearance of pathogens. The lower pulmonary mucosa generally remains sterile in spite of continuous exposure to inhaled microbes. Lung mucosal protection is attributable to the innate and adaptive immune system, cells and molecules, which enhance microbial clearance. There is little knowledge of mucosal properties that lead to reduced microbial clearance. We have identified a property of the mucosal surface that reduces microbial clearance, which could compromise the effectiveness of mucosal vaccines. Resistin-like molecules (RELM peptides) are induced at the mucosal surface by inflammatory stimuli. Using a transgenic mouse model of inducible RELM-? produced in the pulmonary epithelium, we have identified a novel property of RELM-?, which is to cause reduced bacterial clearance from the lung in vivo. These data suggest that antigen challenges may induce RELM peptides leading to reduced microbial clearance. The purpose of this application is gain knowledge of this paradoxical immune response by testing the central hypothesis that RELM peptides prevent efficient elimination of pathogens by inhibiting innate clearance mechanisms. To test this hypothesis we will use RELM-? as a model and (1) determine whether RELM-? affects clearance of pathogens which are targets of mucosal vaccines (Aim 1);(2) determine if RELM-? affects sentinel cells and reduces levels of known innate molecules (Aim 2);(3) determine if levels of RELM-? or RELM-? signaling can be reduced using clinically applicable pharmacological inhibitors (Aim 3). The long-term goal is to gain knowledge of mucosal properties that cause reduced clearance, which ultimately may compromise effectiveness of vaccines.
Individuals with underlying chronic lung or cardiovascular diseases have increased risk of inhaled pathogens escaping lung protective mechanisms causing lung infections and these groups of individuals could benefit from the development of mucosal vaccines against likely lung pathogens. The outcome of the interaction between host and pathogen depends on the balance between mechanisms that enhance microbial killing and those that inhibit clearance. We are seeking to gain knowledge regarding how lung RELM molecules reduce microbial clearance.
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