Key Determinants Of The Natural History Of Leishmania major Infection

描述（由申请人提供）：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，由利什曼原虫引起。TMRC项目有三个主要目标：1 .描述流行地区主要乳杆菌感染的自然历史，特别是在无症状感染方面。疾病严重程度和疾病复发风险；2 .分析媒介（沙蝇唾液）、寄生虫（种内多态性）或宿主免疫反应（先天或适应性）的特异性因子在ZCL临床表达中的各自作用，特别强调识别免疫相关因子对原感染、疾病发生或复发的保护；在规划实施的所有层面加强流行病学临床和实验室良好操作规范的应用。为了达到这些目标，我们将在ZCL流行的地区进行大规模的临床前瞻性调查。所有入选的个体将进行广泛的临床和免疫学调查，以便准确地确定他们的利什曼原虫感染的临床病史（包括LST反应性）以及他们对载体唾液成分和寄生虫抗原的体外免疫反应基线。在接下来的两年里，将对所有将在队列成员中出现的ZCL病例进行主动检测。将在功能水平上广泛研究可从活动性病变中生长的利什曼原虫分离株，以确定由于毒力因子的差异表达而导致的种内多样性。这项研究将描绘出该地区L型病毒感染的自然历史。此外，该程序产生的临床、免疫学和寄生虫学信息将被整合到多参数分析中。这将允许识别考虑到L主的种内功能多态性和库多样性的最终影响的保护的免疫相关因素。这些数据对于开发和评价有效的疫苗或抗利什曼药物至关重要。

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.