Key Determinants Of The Natural History Of Leishmania major Infection

利什曼原虫重度感染自然史的关键决定因素

• 批准号: 7677367
• 负责人: AFIF BEN SALAH
• 金额: $ 50.27万
• 依托单位: INSTITUT PASTEUR DE TUNIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677367
• 关键词: Key; Determinants; Natural; History; Leishmania

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.

描述（由申请方提供）：人畜共患皮肤利什曼病（ZCL）是一种由硕大利什曼原虫引起的在北非和中东高度流行的疾病。 TMRC计划有三个主要目标：1-描述L的自然历史。在流行地区表现为严重感染，特别是无症状感染。疾病严重程度和疾病复发的风险; 2-分析媒介特有因素的各自作用（沙蝇唾液），或寄生虫（种内多态性）或宿主免疫反应（先天或适应性），在ZCL的临床表现中，特别强调识别保护免受初次感染、疾病发生或复发的免疫相关性; 3.在方案执行的所有各级加强流行病学临床和实验室良好做法的应用。 为了达到这些目标，我们将在ZCL流行的地区进行一项大规模的临床前瞻性调查。所有入组的个体将进行广泛的临床和免疫学研究，以准确确定其关于利什曼原虫感染的临床病史（包括LST反应性）以及它们在基线时对载体唾液组分和寄生虫抗原的体外免疫应答。然后对所有ZCL病例进行主动检测，将在接下来的两年中进行队列成员中出现的利什曼原虫分离株的功能水平的广泛研究，以确定种内多样性是由于毒力因子的差异表达。 该研究将描绘该地区L主要感染的自然历史。此外，该程序生成的临床、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主要和水库多样性的种内功能多态性的最终影响的保护的免疫相关性。这些数据对于有效疫苗或抗利什曼病药物的开发和评价至关重要。 项目1：L.主要感染：耐药性的自然史和决定因素（Ben Salah，A.） 项目1描述（由申请人提供）：L.地方性疫源地的主要感染包括环境和宿主相关的危险因素。我们的长期目标是阐明L.主要感染，并考虑到影响暴露的环境因素的混杂效应，对皮肤利什曼病（CL）出现和严重程度的宿主相关危险因素的相对重要性进行加权。具体的假设是，L.主要感染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小区类型而不同。在传播前，与宿主相关的免疫学保护替代物（而非利什曼菌素皮肤试验（LST））可能解释对疾病的抗性，并可用作疫苗田间评价的有效性标准。基于这些观察结果，项目1的重点是通过一项基于前瞻性队列人群的研究来完善对利什曼原虫（L.）的血液动力学参数的估计以及疾病和传播动力学的临床描述，以提高对利什曼原虫自然史的理解。主要感染及其决定因素。具体目标是： 1.阐明了L.严重感染我们将采用利什曼菌素皮肤试验（LST）和临床观察，比较CL的发生率与无症状感染（LST？）在一项为期两年的前瞻性研究中，以确定：i）LST阳性的患病率，ii）LST的转换和逆转率，iii）有症状/无症状感染的发生率，iv）疾病严重程度评分，v）复发率，vi）LST阳性的预测值和保护分数。 2.评价免疫宿主相关因素和环境因素对该病自然史和临床表现的相对重要性。这些因素包括LST、细胞毒性免疫反应和抗白蛉唾液抗原的抗体、水库与疫区的距离、居民及其复合物的特点、社会经济因素和致病特性。主要分离株。 3.开发和验证皮肤病变严重程度和瘢痕质量的量表。量表项目包括溃疡的大小、颜色（色素沉着减退、色素沉着过度、正常皮肤）和身高。