Dendritic Cell Response to Microsporidians

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DESCRIPTION (provided by applicant): Microsporidial infections continue to be a problem for immunocompromised patients, particularly those with AIDS, leading to symptoms like diarrhea and weight loss. However, complications due to this infection have also been identified in patients who are HIV negative and immunocompetent, including individuals with traveler's diarrhea, and in the elderly. Increased susceptibility of the elderly population to microsporidial infection can be explained by the deterioration in immune responsiveness that accompanies aging. However, in depth analysis of innate immune responses against microsporidians in aging humans or in animal models have not been performed and studies related to innate immune response almost non-existent. Using Encephalitozoon cuniculi as the model microsporidian, our laboratory has shown that compared to young mice, dendritic cells (DCs) from 9-month-old animals are unable to prime antigen-specific T cell response against E. cuniculi. However, treatment with recombinant IL-15 restores the ability of older DCs to generate T cell immunity against the pathogen. Moreover, administration of exogenous IL-15 to older animals enables them to survive an oral E. cuniculi challenge. Thus on the onset of aging, a primary immune defect seems to occur with DCs losing their ability to prime a T cell response against infection rather than altered T cell function. Understanding the mechanism involved in the down-regulation of DC response and factors which are able to restore their function is critical for generating successful parasitic immunotherapeutic agents for the aged population. This application entails three specific aims: 1) Age related kinetics of DC response during E. cuniculi infection will be performed. The age at which murine DCs begin to develop this defect will be determined and the mechanism involved in the suppression of DC response in the older mice will be analyzed. 2) The role of IL-15 in the restoration of normal DC response against E. cuniculi will be studied. The mechanism by which this cytokine reverses the defect within the DC population will be determined and importance of IL-15 in the successful vaccination of older mice with purified E. cuniculi protein will be evaluated. 3) Correlation of the results obtained from mice to the innate immune responses generated against this category B protozoon in both humans and non-human DCs. This specific aim will determine if aging results in poor innate DC response to E. cuniculi and whether IL-15 can restores ARC function.