Interactions between Leishmania and the Immune Response

描述(申请人提供)：不同种类的利什曼原虫分布在不同的身体部位，导致不同的疾病后果。查加西原虫是南美洲引起内脏利什曼病的原虫，可引起从无症状感染到潜在致命内脏利什曼病的各种表现，并扩散到肝脏、骨髓和脾。利什曼原虫的显著特征。它们通过受感染的宿主悄悄传播的能力、它们在特定组织中“归宿”的倾向以及它们在哺乳动物组织中以无症状形式持续存在的倾向。调节传播、归位和持久性的因素还没有被很好地理解。特别是，宿主免疫(包括免疫衍生免疫)如何改变寄生虫在体内的传播尚不清楚。寄生虫本身可以改变局部免疫因素的分子机制才刚刚开始被理解。我们推断，宿主和寄生虫因素都必须促进寄生虫通过受感染宿主的传播。我们研究利什曼原虫的能力。由于难以检测到寄生虫感染的“沉默”阶段，动物模型中的感染一直受到阻碍。在这一应用中，我们建议探索生物发光体外成像系统(MS)在检测发光寄生虫感染宿主时的应用。这种方法，以及实时聚合酶链式反应和传统的显微镜方法，将与免疫调节研究相结合，以跟踪寄生虫在感染过程中的传播情况。这一应用的总体假设是，围绕入侵寄生虫的局部宿主免疫微环境，以及影响这种即时免疫环境的寄生虫因素，都将决定寄生虫是否从接种部位逃逸，扩散到内脏器官，并在宿主组织中长期存在。利用MS定位感染的小鼠体内的L.c/iagas/，我们将达到以下目的：(1)建立一个模型来追踪寄生虫在体内的传播和持续，并测试哪些宿主因素影响L.chagasi感染的传播、定位和长期维持。(2)确定调节局部细胞因子和巨噬细胞激活的寄生虫因素是否影响查加西乳杆菌的建立和全身传播。(3)确定免疫对查加西钩端螺旋体的建立和系统传播的影响。利什曼病是宿主和寄生虫之间动态相互作用的结果，两者都改变了对方的功能和生存。通过本申请中描述的研究，我们希望描绘出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.