Encephalitozoan cuniculi-Host immunity and pathogenesis

描述（由申请方提供）：微孢子虫是人类免疫缺陷（HIV）感染患者体内重要的原生动物寄生虫。最近的一项研究表明，高达40%的艾滋病相关性脑炎患者正在脱落微孢子虫。这些寄生虫最近也被牵连到引起疾病的非艾滋病毒感染的旅行者和免疫功能正常的老年人。针对这些病原体产生的宿主免疫反应仍然研究不足。有限的研究与Enc。一种可以在实验室中容易地培养的微孢子虫，强调了T细胞在保护免受寄生虫侵害中的重要性。与免疫活性动物不同，T细胞缺陷小鼠无法解决感染。我们的实验室已经证明，在T细胞亚群中，CD8+细胞毒性T淋巴细胞在通过腹膜内途径施用的对兔艾美耳球虫的保护中起主导作用。然而，在口腔感染期间，CD4和CD8 + T细胞都有助于对抗寄生虫的保护性免疫。由于微孢子虫是经口获得的，因此关键是要表征针对感染引起的肠道免疫应答并理解保护机制。我们实验室最近的研究表明，经口感染家兔肠球菌可诱导肠道内强烈且延长的上皮内淋巴细胞（IEL）反应。从感染动物中分离的IEL表现出强烈的抗原特异性细胞毒性和细胞因子应答。因此，IEL似乎在针对寄生虫的粘膜免疫应答中发挥重要作用。了解IEL介导的保护作用的动力学和机制将为产生针对这些病原体的免疫抑制剂奠定基础。该提案包括三个具体目标。在第一个具体目标中，诱导IEL对Enc的反应。将评价家兔感染。将测定来自派尔集合淋巴结的树突状细胞（DC）在肠道中引发IEL应答中的作用。最后，研究派伊尔斑DCs和IEL反应的机制。在第二个具体目标中，不同IEL亚群在调节针对Enc的粘膜免疫中的作用。将测定家兔感染。将评价IEL介导的抗寄生虫保护机制。在第三个特定目标中，将分析针对病原体的长期IEL应答。我们的初步数据表明，免疫IEL在兔肠球菌感染的小鼠持续很长一段时间。将评价感染动物中长期抗原特异性IEL（记忆IEL）的形成和持续性机制。

DESCRIPTION (Provided by applicant): Microsporidia are important protozoan parasites in human immunodeficiency (HIV) infected patients. A recent study showed up to 40% of patients with AIDS associated diarrheas were shedding microsporidia. These parasites have also been recently implicated in causing illness to non-HIV-infected travelers and immunocompetent elderly individuals. The host immune response generated against these pathogens remains understudied. The limited studies available with Enc. cuniculi, a microsporidia that can be easily cultured in the laboratory, have emphasized the importance of T cells in the protection against the parasite. T cell deficient mice, unlike the immunocompetent animals are unable to resolve the infection. Our laboratory has demonstrated that among the T cell subsets, CD8+ cytotoxic T lymphocytes play a dominant role in protection against E.cuniculi administered via intraperitoneal route. However, during an oral infection both CD4 and CD8+ T cells contribute to protective immunity against the parasites. As microsporidia are acquired orally, it is critical that the gut immune response evoked against the infection be characterized and mechanism of protection understood. Recent studies from our laboratory have shown that per oral Enc.cuniculi infection induces a strong and prolonged intraepithelial lymphocyte (IEL) response in the gut. IELs isolated from the infected animals exhibit strong antigen-specific cytotoxicity and cytokine response. Thus IELs appear to play an important role in mucosal immune response against the parasite. Understanding the kinetics and mechanism of IEL mediated protection will form a basis for generating immunotherapeutic agents against these pathogens. The proposal comprises of three specific aims. In the first specific aim the induction of IEL response to Enc. Cuniculi infection will be evaluated. Role of dendritic cells (DCs) from the Peyer's patches in priming IEL response in the gut will be assayed. Finally the mechanism by which Peyer's patch DCs and IEL response will be studied. In the second specific aim, the role of different IEL subsets in the regulation of mucosal immunity against Enc. cuniculi infection will be assayed. The mechanism of IEL mediated protection against the parasite will be evaluated. In the third specific aim long-term IEL response against the pathogen will be analyzed. Our preliminary data suggests that immune IELs in the Enc.cuniculi infected mice persist for a long period. Development and mechanism of persistence of long-term antigen specific IELs (memory IELs) in the infected animals will be evaluated.