Key Determinants Of The Natural History Of Leishmania major Infection

描述(申请人提供)：人畜共患皮肤利什曼病(ZCL)是一种在北非和中东高度流行的疾病，由大利什曼原虫引起。TMRC计划有三个主要目标：1-描述流行地区主要乳杆菌感染的自然历史，特别是关于无症状感染，疾病的严重性和疾病复发的风险；2-分析媒介(沙蝇唾液)、寄生虫(种内多态)或宿主免疫反应(先天或适应性)的特定因素在ZCL临床表现中的各自作用，特别强调识别免疫相关因素，以防止初级感染、疾病发生或复发；3-加强良好的流行病学临床和实验室实践在计划实施的所有级别的应用。为了达到这些目标，我们将在ZCL流行的地区进行一次大规模的临床前瞻性调查。将对所有登记的个体进行广泛的临床和免疫学调查，以准确定义他们的利什曼病感染的临床病史(包括LST反应性)以及他们对媒介唾液成分和寄生虫抗原的体外免疫反应，然后在接下来的两年里对队列成员中出现的所有ZCL病例进行积极检测。可以从活跃的皮损生长的利什曼原虫分离株将在功能水平上进行广泛调查，以确定由于毒力因子的差异表达而导致的种内多样性。这项研究将绘制L在该地区重大感染的自然历史图景。此外，该计划产生的临床、免疫学和寄生虫学信息将被整合到多参数分析中。这将允许识别保护的免疫相关因素，考虑到主要L的种内功能多态和储藏者多样性的最终影响。这些数据对于开发和评估有效的疫苗或抗利什曼药物至关重要。 项目1：L.重大感染：自然历史和耐药性决定因素(Ben Salah，A.) 项目1说明(由申请人提供)：流行病源地主要乳杆菌感染的易感性/抗药性和自然病史的决定因素包括与环境和宿主有关的风险因素。我们的长期目标是阐明主要利什曼原虫感染的自然历史，并考虑影响暴露的环境因素的混杂效应，权衡宿主相关危险因素在皮肤利什曼病(CL)发病和严重程度中的相对重要性。具体的假设是，主要利什曼原虫感染的自然病史和皮肤利什曼病的临床表现根据过去的传播史和研究地区的生物区类型而不同。除了传播前的利什曼宁皮肤试验(LST)外，与宿主相关的免疫替代物可以解释对该病的抵抗力，并可作为疫苗现场评估的疗效标准。在这些观察的基础上，项目1的重点是通过基于人群的前瞻性队列研究来完善流行病学参数的估计以及疾病的临床描述和传播动力学，以提高对利什曼原虫(L.)重大感染及其决定因素。具体目标是： 1.阐明了大型钩端螺旋体感染的流行病学参数。我们将采用利什曼宁皮肤试验(LST)和临床观察，比较CL与无症状感染(LST？)的发生率。在一项为期两年的前瞻性研究中，为了确定：i)LST阳性的患病率，ii)LST的转换率和复发率，iii)有症状/无症状感染的发生率，iv)疾病的严重程度，v)复发率，vi)LST阳性的预测价值和保护分数。 2.评价免疫宿主相关因素和环境因素对该病自然病程和临床表现的相对重要性。这些因素包括沙蝇LST、沙蝇唾液抗原的细胞毒性免疫反应和抗体、水库到定殖区的距离、栖息地及其化合物的特征、社会经济因素和主要沙蝇毒株的致病特性。 3.制定和验证皮肤损伤严重程度和由此产生的疤痕质量的量表。量表项目包括溃疡大小、颜色(色素沉着减少、色素沉着、正常皮肤)和身高。

DESCRIPTION (provided by applicant): Zoonotic Cutaneous Leishmaniasis (ZCL) is a disease highly prevalent in North Africa and Middle East that is caused by Leishmania major. The TMRC program has three main goals :1-Describe the natural history of L. major infection as expressed in an endemic area especially with regard to asymptomatic infection .disease severity and risk of disease recurrence; 2-Analyse the respective roles of factors specific of the vector(sand fly saliva ),or the parasite(intraspecies polymorphism) or the host immune response(innate or adaptative), in the clinical expression of ZCL with special emphasis on the identification of immune correlates of protection against primoinfection, disease occurrence or recurrence; 3-Reinforce the application of Good Epidemiological Clinical and Laboratory Practices at all levels of programme implementation. In order to reach these goals, we shall conduct a large clinical prospective survey in a region endemic for ZCL. All enrolled individuals will be extensively investigated, clinically and immunologically, in order to accurately define their clinical history with regard to leishmania infection (including LST reactivity) as well as their in vitro immune responses to vector saliva components and parasite antigens at baseline Then an active detection of all ZCL cases, that will emerge among the cohort members will be conducted during the two following years .Leishmania isolates that could be grown from active lesions will be extensively investigated at the functional level in order to identify intraspecies diversity due to differential expression of virulence factors. The study will draw a picture of the natural history of L major infection in the region. In addition the clinical, immunological and parasitological informations generated by the program will be integrated into a multiparametric analysis. This will permit to identify immune correlates of protection that take into consideration the eventual effects of intraspecies functional polymorphism of L major and reservoir diversity. These data are of crucial importance for the development and evaluation of effective vaccines or antileishmanial drugs. PROJECT 1: L. major infection: Natural History and Determinants of Resistance (Ben Salah, A.) PROJECT 1 DESCRIPTION (provided by applicant): Determinants of susceptibility/resistance and natural history of L. major infection in endemic foci include environmental and host related risk factors. Our long term goal is to elucidate the natural history of L. major infection and to weight the relative importance of host related risk factors of cutaneous leishmaniasis (CL) emergence and severity considering the confounding effect of environmental factors influencing exposure. The specific hypothesis is that the natural history of L. major infection and the clinical expression of cutaneous leishmaniasis varies according to past history of transmission and to the type of biotope in the study area. Host related immunological surrogates of protection other than leishmanin skin test (LST) prior to transmission might explain resistance to the disease and might be used as efficacy criteria in the context of vaccines' evaluation in the field. Based on these observations the focus of project 1 is to refine by a prospective cohort population based study the estimation of the epidemetric parameters and clinical description of disease and transmission dynamics to improve the understanding of natural history of Leishmania (L.) major infection and its determinants. The specific aims are to: 1. Elucidate epidemetric parameters of L. major infection. We will use leishmanin skin test (LST) and clinical observations, the incidence of CL versus asymptomatic infection (LST???) in a two years prospective study in order to determine: i) the prevalence of LST positivity, ii) the rate of conversion and reversion of LST, iii) the incidence of symptomatic / asymptomatic infection, iv) the score severity of disease, v) the rate of recurrence, vi) the predictive value and the protection fraction of LST positivity. 2. To evaluate the relative importance of immune host related factors and environmental on the natural history and clinical expression of the disease. These include LST, cytotoxic immune response and antibodies against sand flies' saliva antigens, distance to colonized area by reservoirs, characteristics of dwelling and its compound, socio-economic factors and pathogenic properties of L. major isolates. 3. To develop and validate scales for severity of cutaneous lesions and quality of resulting scars. The scale items include size of the ulcer, color (hypopigmentation, hyperpigmentation, normal skin) and height.