Dendritic Cell Response to Microsporidians

描述（由申请人提供）：微孢子虫感染仍然是免疫功能低下患者，特别是艾滋病患者的一个问题，导致腹泻和体重减轻等症状。然而，在HIV阴性和免疫活性的患者中也发现了这种感染引起的并发症，包括旅行者腹泻患者和老年人。老年人群对微孢子虫感染的易感性增加可以解释为伴随衰老的免疫反应性恶化。然而，尚未对老年人或动物模型中针对微孢子虫的先天免疫应答进行深入分析，并且几乎不存在与先天免疫应答相关的研究。本实验室以兔脑炎原虫为模型微孢子虫，发现与幼龄小鼠相比，9月龄动物的树突状细胞（DCs）不能启动抗E.兔子然而，用重组IL-15治疗恢复了老年DC产生针对病原体的T细胞免疫的能力。此外，给老年动物施用外源性IL-15使它们能够在口服E.兔子挑战。因此，在衰老开始时，原发性免疫缺陷似乎发生在DC失去其引发T细胞抗感染应答的能力，而不是改变T细胞功能。了解参与DC反应下调的机制和能够恢复其功能的因子对于为老年人群产生成功的寄生虫免疫抑制剂至关重要。该应用需要三个具体目标：1）E.将进行家兔感染。将确定鼠DC开始发展这种缺陷的年龄，并将分析参与老年小鼠中DC应答抑制的机制。2)IL-15在恢复正常DC抗E.将研究兔子。这种细胞因子逆转DC群体内缺陷的机制将被确定，IL-15在用纯化的E.将评价兔蛋白。3)从小鼠获得的结果与人和非人DC中针对该B类原生动物产生的先天免疫应答的相关性。这一特定的目标将决定衰老是否会导致先天性DC对E. IL-15是否能恢复ARC功能。

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.