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

描述(申请人提供)：皮肤利什曼病(CL)在西非有很长的历史，但在该地区是较少被认识的寄生虫感染之一。这种疾病流行于北部的撒哈拉沙漠国家，从西非到东非的萨赫勒地带。目前，还没有针对这种疾病的疫苗。然而，研究一直表明，在幼稚宿主中，沙蝇唾液通常会增强利什曼原虫的传染性，而在啮齿动物感染模型中，对全唾液或特定唾液蛋白的适应性免疫反应通常可以预防皮肤和内脏利什曼病。在拟议的工作中，将对西非3个具有不同流行病学和生态环境的地点进行皮肤利什曼病感染的强度和流行率、沙蝇媒介种群动态和疾病发病机制的比较，重点是寄生虫和宿主因素以及对候选疫苗(特别是沙蝇蛋白)的免疫反应。支持这一建议的假设是，寄生虫、媒介和人类接触其他寄生虫感染(如微丝虫感染)的组合决定了候选疫苗的免疫调节效果，特别是沙蝇蛋白。该建议旨在1)了解西非不同疫区皮肤利什曼病及其媒介的基本流行病学；2)了解对这种疾病的抗药性/易感性的机制；3)评估微丝虫感染如何改变人类对沙蝇唾液蛋白的免疫反应；4)加强当地对未来疫苗试验的研究能力。 相关性：这项提议与公共卫生直接相关，因为利什曼病在全球造成巨大损失。它的目标是研究皮肤利什曼病的流行病学和传播，以及在很大程度上被忽视的一个组成部分：沙蝇蛋白的免疫调节。 项目1：皮肤利什曼病流行病学 项目负责人：奥斯曼·法耶，医学博士 (申请人提供的描述)：利什曼病是一种通过媒介传播的疾病，通过感染利什曼原虫的血吸虫沙蝇叮咬传播给宿主。皮肤利什曼病(CL)在西非有很长的历史，但在该地区是一种鲜为人知的寄生虫感染。研究一直表明，在幼稚宿主中，沙蝇唾液通常会增强利什曼原虫的传染性，而在啮齿动物感染模型中，对全唾液或特定唾液蛋白的适应性免疫反应通常可以预防皮肤和内脏利什曼病。在拟议的工作中，将对西非三个具有不同流行病学和生态环境的地点进行皮肤利什曼病感染的强度和流行率、沙蝇媒介种群动态和疾病发病机制的比较，重点是寄生虫和宿主因素以及对候选疫苗(特别是沙蝇蛋白)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)，并确定在马里和加纳CL的经典和隐蔽疫源地流行的利什曼原虫的特征；2)将人类对沙蝇唾液蛋白的特异性免疫反应与CL的结果相关联。在目标1中，我们将可能描述新种利什曼原虫的特征，这些新种的寄生虫来自于感染者出现无症状CL的地方，并将其与经典的CL焦点进行比较。我们还将在目标2中首次确定沙蝇唾液细胞免疫是否可以影响流行人群的CL结局。 相关性：该项目是整个提案的核心，因为它将评估人类接触沙蝇媒介叮咬(项目2)、寄生虫和对沙蝇唾液蛋白的免疫反应(项目3)与疾病的关系。了解这些关系对于疫苗开发和控制策略的现场试验非常重要。

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.