Role of Interleukin-3 and Basophils in a Mouse Model of Cutaneous Leishmaniasis

描述（由申请方提供）：皮肤利什曼病是一种由利什曼原虫属原虫寄生虫引起的媒介传播传染病，是全球最重要的被忽视的传染病之一。目前，82个国家（大多数是发展中国家）的1 000万人受到感染。受感染者在身体暴露部位出现一处或多处溃疡性皮肤损伤，造成严重残疾和永久性疤痕。用导致人类皮肤利什曼病的两种主要物种之一的硕大利什曼原虫感染小鼠是用于研究体内免疫的各个方面的完善的实验模型。大多数感染L.主要发展局部病变，几周后自愈。然而，某些小鼠品系-例如BALB/c小鼠-不能控制感染并发展进行性病变和全身性疾病。对L.小鼠中的主要感染与导致疾病的白细胞介素（IL）-4驱动的Th 2应答的优势相对于促进愈合和寄生虫清除的IL- 12驱动的干扰素-3（INF-3）主导的Th 1应答强烈相关。在机制上，INF-3触发巨噬细胞中诱导型一氧化氮合酶（iNOS）操作的杀利什曼系统，导致抗性表型，而IL-4使该机制失活，导致易感表型。最近在小鼠中的研究已经确定了IL-4产生的嗜碱性粒细胞在促进Th 2型免疫应答中的关键但以前未被认识的作用。此外，许多研究报道IL-3可促进嗜碱性粒细胞扩增并增强嗜碱性粒细胞细胞因子的产生，并且IL-3的产生与BALB/c小鼠对L.少校然而，IL-3和IL-4产生嗜碱性粒细胞在皮肤利什曼病的确切作用尚未得到解决。因此，我们建议利用令人兴奋的机会来分析IL-3和嗜碱性粒细胞在皮肤利什曼病小鼠模型中的作用。具体而言，我们将使用BALB/c IL-3缺陷小鼠、嗜碱性粒细胞耗竭的野生型小鼠和骨髓来源的嗜碱性粒细胞纯化群体来检验两个主要但相关的假设：1）IL-3的产生加剧了疾病的严重性，如通过病变大小、寄生虫负荷、T细胞细胞因子产生和炎性效应细胞浸润和功能的测量所反映的，2）嗜碱性粒细胞在感染后迁移到引流淋巴结和皮肤损伤处，被L.主要抗原，并释放Th 2-促进细胞因子如IL-4，其导致BALB/c小鼠产生无效的Th 2免疫应答，导致它们对感染的易感性。 公共卫生相关性： 人类皮肤利什曼病仍然是世界范围内最重要的传染病之一。该项目的总体目标是确定被称为嗜碱性粒细胞的白色血细胞和白细胞介素-3蛋白在对原生动物寄生虫利什曼原虫的免疫应答中的作用。我们相信这些研究对于确定疫苗，治疗和诊断的有意义的目标至关重要。

DESCRIPTION (provided by applicant): Cutaneous leishmaniasis, a vector-borne infectious disease caused by protozoan parasites of the genus Leishmania, is one of the most important neglected infectious diseases worldwide. Currently, 10 million people in 82 (mostly developing) countries are infected. Those infected develop one or more ulcerative skin lesions on the exposed parts of the body, causing serious disability and permanent scarring. Infection of mice with Leishmania major, one of the two main species that causes human cutaneous leishmaniasis, is a well- established experimental model used to study various aspects of immunity in vivo. Most mouse genotypes infected with L. major develop localized lesions that heal spontaneously after a few weeks. However, certain mouse strains - such as BALB/c mice - fail to control infection and develop progressive lesions and systemic disease. The genetic predisposition for susceptibility or resistance to L. major infection in mice strongly correlates with the dominance of an interleukin (IL)-4-driven Th2 response that causes disease versus an IL- 12-driven, interferon-3 (INF-3)-dominated Th1 response that promotes healing and parasite clearance. Mechanistically, INF-3 triggers inducible nitric oxide synthase (iNOS)-operated leishmanicidal systems in macrophages, resulting in the resistant phenotype, while IL-4 inactivates that mechanism resulting in a susceptible phenotype. Recent studies in mice have now defined a critical but previously unrecognized role for IL-4-producing basophils in promoting Th2-type immune responses. Furthermore, a number of studies have reported that IL-3 can promote basophil expansion and enhance basophil cytokine production, and that IL-3 production correlates with susceptibility of BALB/c mice to infection with L. major. However, the precise role of IL-3 and IL-4-producing basophils in cutaneous leishmaniasis has yet to be addressed. We therefore propose to take advantage of exciting opportunities to analyze the role of IL-3 and basophils in a mouse model of cutaneous leishmaniasis. Specifically, we will use BALB/c IL-3-deficient mice, wild-type mice depleted of basophils, and purified populations of bone marrow-derived basophils to test two major but related hypotheses: 1) that IL-3 production exacerbates the severity of disease as reflected by measures of lesion size, parasite burden, T cell cytokine production, and inflammatory effector cell infiltration and function, and 2) that basophils undergo migration to draining lymph nodes and cutaneous lesions in response to infection, become innately activated by L. major antigens, and release Th2-promoting cytokines such as IL-4 that result in BALB/c mice mounting an ineffective Th2 immune response responsible for their susceptibility to infection. PUBLIC HEALTH RELEVANCE: Human cutaneous leishmaniasis continues to rank among the most important infectious diseases on a worldwide basis. The overall goal of this project is to determine the role of white blood cells called basophils and the protein interleukin-3 in the immune response to the protozoan parasite Leishmania major. We believe these studies to be critical to identifying meaningful targets for vaccines, therapeutics, and diagnostics.