Cutaneous Leishmaniasis in West Africa: the Parasite, Vector and Disease

描述（由申请人提供）：皮肤利什曼病（CL）在西非有很长的历史，但在该地区较少认识到的寄生虫感染之一。这种疾病是撒哈拉沙漠国家北部的地方病，位于从西非到东非的萨赫勒地带。目前还没有针对这些疾病的疫苗。然而，研究一致表明，白蛉唾液通常增强未感染宿主中利什曼原虫寄生虫的感染性，而对全唾液或不同唾液蛋白的适应性免疫应答通常在啮齿动物感染模型中保护皮肤和内脏利什曼病。在拟议的工作中，将比较西非3个具有不同流行病学和生态环境的地点的皮肤利什曼原虫感染强度和患病率、白蛉病媒种群动态和疾病发病机制，重点是寄生虫和宿主因素以及对候选疫苗（特别是白蛉蛋白）的免疫应答。这一提议的假设是，寄生虫、媒介和人类暴露于其他寄生虫感染（如微丝蚴感染）的组合决定了候选疫苗（特别是白蛉蛋白）的免疫调节作用。该建议旨在：1）了解西非不同疫源地皮肤利什曼病及其病媒的基本流行病学; 2）了解对该疾病的抗性/易感性机制; 3）评估微丝蚴活动性感染如何改变人类对白蛉唾液蛋白的免疫反应; 4）加强当地未来疫苗试验的研究能力。 相关性：这项建议与公共卫生直接相关，因为利什曼病在地球仪上造成巨大损失。它的目标是研究流行病学，皮肤利什曼病的传播和一个在很大程度上被忽视的组成部分：白蛉蛋白的免疫调节。 项目1：皮肤利什曼病流行病学 项目负责人：Ousmane Faye，MD，PhD （由申请方提供的描述）：利什曼病是一种媒介传播的疾病，通过感染利什曼原虫的白蛉叮咬传播给宿主。皮肤利什曼病（CL）在西非有着悠久的历史，但在该地区是一种较少被认识的寄生虫感染。研究一致表明，白蛉唾液通常增强未感染宿主中利什曼原虫寄生虫的感染性，而对全唾液或不同唾液蛋白的适应性免疫应答通常在啮齿动物感染模型中保护皮肤和内脏利什曼病。在拟议的工作中，在西非的三个网站，每个不同的流行病学和生态环境将比较皮肤利什曼原虫感染的强度和患病率，白蛉媒介种群动态，疾病的发病机制，重点是寄生虫和宿主因素和候选疫苗（特别是白蛉蛋白）的免疫反应。该项目旨在1]确定CL的患病率/发病率（感染和疾病），并描述在马里和加纳的CL经典和隐蔽病灶中传播的利什曼原虫寄生虫; 2]将对白蛉唾液蛋白的特异性人类免疫应答与CL结果相关联。在目标1中，我们可能会从感染个体出现无症状CL的部位描述新的利什曼原虫属寄生虫种，并将其与经典CL病灶进行比较。我们还将在目标2中，首次确定白蛉唾液细胞免疫是否会影响地方性人群的CL结果。 相关性：该项目是整个提案的核心，因为它将评估人类暴露于白蛉媒介叮咬（项目2）、寄生虫和对白蛉唾液蛋白的免疫反应（项目3）与疾病之间的关系。了解这些关系对于疫苗开发和控制策略的现场试验是重要的。

DESCRIPTION (provided by applicant): Cutaneous leishmaniasis (CL) has a long history in West Africa, but one of the less recognized parasitic infections in the region. The disease is endemic Saharan desert countries in the North, in Sahelian band from west to East Africa. Currently, there is no vaccine against the diseases. However, studies have consistently shown that sand fly saliva generally enhances infectivity of Leishmania parasites in a naive host while an adaptive immune response to whole saliva or a distinct salivary protein generally protects against both cutaneous and visceral leishmaniasis in rodent models of infection. In the proposed work, 3 sites in West Africa each with distinct epidemiological and ecological environment will be compared with regard to intensity and prevalence of cutaneous leishmania infection, sand fly vector population dynamics, and disease pathogenesis with a focus on parasite and host factors and the immune response to candidate vaccines (sand fly proteins in particular). The hypothesis underlying this proposal is that a combination of parasite, vector, and human exposure to other parasitic infection such as infection with microfilariae determine the immunomodulatory effects of candidate vaccines, specifically sand fly proteins. The proposal seeks to 1] understand the basic epidemiology of cutaneous leishmaniasis and its vector in different foci of West Africa; 2] understand mechanism of resistance/susceptibility to the disease; 3] assess how an active infection with microfilariae alters the human immune response to sand fly salivary proteins and 4] reinforce local research capacity for future vaccine trials. RELEVANCE: This proposal is directly relevant to public health because Leishmaniasis take an enormous toll across the globe. Its goals are to examine the epidemiology, transmission of cutaneous leishmaniasis and a component that has been largely overlooked: the immuno-modulation of sandfly proteins. Project 1: Epidemiology of Cutaneous Leishmaniasis Project Leader: Ousmane Faye, MD, PhD (Description as provided by applicant): Leishmaniasis is a vector-borne disease transmitted to the host via the bite of a Leishmania infected phlebotomine sand fly. Cutaneous leishmaniasis (CL) has a long history in West Africa, but is one of the less recognized parasitic infections in the region. Studies have consistently shown that sand fly saliva generally enhances infectivity of Leishmania parasites in a naive host while an adaptive immune response to whole saliva or a distinct salivary protein generally protects against both cutaneous and visceral leishmaniasis in rodent models of infection. In the proposed work, three sites in West Africa each with distinct epidemiological and ecological environment will be compared with regard to intensity and prevalence of cutaneous leishmania infection, sand fly vector population dynamics, and disease pathogenesis with a focus on parasite and host factors and the immune response to candidate vaccines (sand fly proteins in particular). This project seeks to 1] Determine the prevalence/incidence (of infection and disease) of CL and characterize the Leishmania parasites circulating in Malian and Ghanaian classical and cryptic foci of CL; 2] Correlate specific human immune responses to sand fly salivary proteins with CL outcome. In the Aim 1 we will possibly characterize new species of Leishmania parasites from a site where the infected individuals presented with asymptomatic CL and compare it to a classical CL focus. We will also in Aim 2, for the first time, establish if sand fly salivary cellular immunity can influece the CL outcome in endemic populations. RELEVANCE: This project is at the center of the entire proposal because it will assess the relationship between human exposure to sand fly vector bite (Project 2), the parasite and immune response to sand fly salivary proteins (Project 3) and the disease. Understanding of these relationship is important for vaccine development and field trials of control strategies.