Interactions between Leishmania and the Immune Response

描述（由申请人提供）：不同的利什曼原虫种原生动物定位于不同的身体部位，导致各种疾病结果。L.恰加斯原虫是在南美洲引起内脏利什曼病的原生动物，引起从无症状感染到可能致命的内脏利什曼病的各种表现，并传播到肝脏、骨髓和脾脏。利什曼原虫的显著特征。它们能够通过感染的宿主无声地传播，它们倾向于“归巢”到它们可以复制的特定组织，以及它们倾向于在哺乳动物组织中以无症状的形式持续存在。调节传播、归巢和持久性的因素还不清楚。特别是，宿主免疫（包括免疫源性免疫）改变寄生虫在体内传播的方式尚不清楚。寄生虫自身可以通过其改变局部免疫因子的分子机制才刚刚开始被理解。我们的理由是，宿主和寄生虫的因素必须有助于这种贩运的寄生虫通过受感染的主机。我们在动物模型中研究利什曼原虫感染的能力受到了检测寄生虫感染“沉默”阶段的困难的阻碍。在此应用程序中，我们建议探索实用的生物发光体外成像系统（MS）检测发光寄生虫，因为它们感染的主机。这种方法，以及真实的时间PCR以及常规的显微镜方法，将与免疫调节的研究相结合，以跟踪寄生虫在整个感染过程中的运输。本申请的总体假设是，入侵寄生虫周围的局部宿主免疫微环境和影响该直接免疫环境的寄生虫因素将决定寄生虫是否从接种部位逃逸，传播到内脏器官，并在宿主组织中长期存在。利用MS对L. c/iagas/在感染的小鼠宿主内，我们将致力于以下目标：（1）建立一个模型来跟踪寄生虫在体内的传播和持久性，并测试哪些宿主因素影响L.恰加斯病感染(2)确定调节局部细胞因子和巨噬细胞活化的寄生虫因子是否影响L.查加斯。(3)确定免疫接种对L.查加斯。利什曼病是宿主和寄生虫之间动态相互作用的结果，每一种都会改变另一种的功能和生存。通过本申请中描述的研究，我们希望描述决定感染最终结果的关键特征。

DESCRIPTION (provided by applicant): Different Leishmania species protozoa localize in different body locations, leading to a variety of disease outcomes. L. chagasi, the protozoan causing visceral leishmaniasis in South America, causes manifestations ranging from asymptomatic infection to potentially fatal visceral leishmaniasis, with dissemination to the liver, bone marrow and spleen. Remarkable features of the Leishmania spp. are their ability to disseminate silently through infected hosts, their propensity to "home" to particular tissues where they can replicate, and their propensity to persist in an asymptomatic form in mammalian tissues. Factors that regulate dissemination, homing, and persistence are not well understood. In particular, the way in which host immunity, including immunization-derived immunity, modifies the travels of parasites through the body is not known. The molecular mechanisms through which the parasite itself can modify the local immune factors are just beginning to be understood. We reason that both host and parasite factors must contribute to this trafficking of parasites through an infected host. Our ability to study Leishmania sp. infections in animal models have been hampered by difficulties in detecting the "silent" stages of parasite infection. During this application we propose to explore the utility of bioluminescence in vitro imaging system (MS) to detect luminescent parasites as they infect a host. This method, and real time PCR as well as conventional microscopic methods, will be coupled with studies of immune modulation to follow the trafficking of parasite throughout infection. The overall hypothesis of this application is that both the local host immune microenvironment surrounding the invading parasite, and parasite factors influencing this immediate immune environment, will determine whether the parasite escapes from the site of inoculation, disseminates to visceral organs, and persists long-term in host tissues. Using MS to localize L. c/iagas/within the infected murine host, we will address the following aims: (1) Develop a model to track parasite dissemination and persistence in vivo, and test which host factors influence dissemination, localization, and long-term maintenance of L. chagasi infection. (2) Determine whether parasite factors that modulate local cytokines and macrophage activation influence the establishment and systemic dissemination of L. chagasi. (3) Determine the effects of immunization on the establishment and systemic dissemination of L. chagasi. Leishmaniasis is the result of a dynamic interaction between host and parasite, with each modifying the functions and survival of the other. Through studies described in this application we hope to delineate critical features that determine the ultimate outcome of the infection.