Encephalitozoan cuniculi-Host immunity and pathogenesis

描述(申请人提供)：微孢子虫是人类免疫缺陷病毒(HIV)感染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%的艾滋病相关性腹泻患者正在排出微孢子虫。这些寄生虫最近也被认为是导致未感染艾滋病毒的旅行者和具有免疫能力的老年人患病的原因。针对这些病原体产生的宿主免疫反应仍未得到充分研究。Enc提供的有限研究。楔形虫是一种很容易在实验室中培养的微孢子虫，它强调了T细胞在抵御寄生虫方面的重要性。T细胞缺陷的小鼠，不像免疫能力强的动物，无法解决感染问题。我们的实验室已经证明，在T细胞亚群中，CD8+细胞毒性T细胞在通过腹膜途径给药对鸡传染性支气管炎的保护作用中占主导地位。然而，在口腔感染期间，CD4和CD8+T细胞都有助于对寄生虫的保护性免疫。由于微孢子虫是通过口服获得的，因此对感染引起的肠道免疫反应的特征和保护机制的了解是至关重要的。我们实验室最近的研究表明，经口感染楔形线虫可诱导肠道内强烈而持久的上皮内淋巴细胞(IEL)反应。从感染动物中分离的IEL具有较强的抗原特异性细胞毒作用和细胞因子反应。因此，IEL似乎在针对寄生虫的粘膜免疫反应中发挥着重要作用。了解IEL介导的保护的动力学和机制将为开发针对这些病原体的免疫治疗剂奠定基础。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。将对钩体感染进行评估。将分析Peyer氏结中的树突状细胞(DC)在肠道中启动IEL反应中的作用。最后对Peyer‘s斑块DC和IEL响应的机制进行了研究。在第二个特定目标中，不同的IEL亚群在调节黏膜免疫抗Enc中的作用。将检测楔形虫感染情况。将评估IEL介导的对寄生虫的保护机制。在第三个特定目标中，将分析针对病原体的长期IEL反应。我们的初步数据表明，感染楔形线虫的小鼠体内的免疫IEL持续了很长一段时间。将评估长期抗原特异性IEL(记忆性IEL)在感染动物中的发展和持续机制。

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.