Intra-species diversity among L. major isolates as determinant of ZCL polymorphis

L. Major 分离株的种内多样性是 ZCL 多态性的决定因素

• 批准号: 7284546
• 负责人: Dhafer Laouini
• 金额: $ 7.59万
• 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: 2007-10-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284546
• 关键词: Benign; Clinical; Complement; Condition; Country; Cutaneous; Cutaneous Leishmaniasis; Cytolysis; Data; Disease; Disease Outcome; Disease Resistance; Gene Expression; Genes; Genetic Polymorphism; Genetic Variation; Goals; Growth; Healed; Human; Immune; Immune response; In Vitro; Inbred Strains Mice; Individual; Infection; Infection prevention; Kinetics; Leishmania; Leishmania major; Lesion; Middle East; Mus; Natural History; Northern Africa; Outcome; Parasites; Pathogenicity; Pharmaceutical Preparations; Phenotype; Play; Predisposition; Prospective Studies; Proteins; Proteomics; Recording of previous events; Residual state; Resistance; Risk; Role; Role playing therapy; Severities; Testing; Transcript; Tunisia; Vaccines; Virulence; Virulence Factors; Visceral; base; cohort; follow-up; healing; improved; macrophage; programs; prospective; transcriptomics; vector

Zoonotic Cutaneous Leishmaniasis (ZCL) is a disease highly prevalent in North Africa and Middle East that is caused by Leishmania major There is an urgent need for improved non toxic antileishmanial drugs and for effective vaccines that could prevent infection or symptomatic disease. The TMRC proposal aims at describing the natural history of L. major infection in Tunisia and identifying immune correlates of protection that takes into consideration the eventual effects of intraspecies polymorphism of L major and reservoir diversity The specific hypothesis is that genetic variation among L. major might act, in concert with the host immune response, to determine the outcome of infection. The specific aims of project 3 are to:1)Screen individuals with past history of ZCL, for the persistence of residual parasites in healed lesions.2) Establish a bank of L. major isolates from the ZCL lesions that will develop during the prospective follow up of a cohort of individuals exposed to the risk of infection. 3) Evaluate comparatively the intra-species functional diversity of these isolates using five experimental approaches: i- Kinetics of in vitro parasite growth in culture, ii- In vitro resistance to complement lysis, iii- In vitro infectivity to murine or human macrophages. iv- Experimental pathogenicity in inbred mouse strains, v- Quantification of the transcripts of a set ofpre- selected genes expressed in indicator human macrophages infected by the various isolates. 4) Select a subset of L. major isolates on the basis of the functional tests described above and analyze their proteomicand transcriptomic profiles to identify proteins differentially expressed among isolates. Data on L. major diversity generated by project 3 will be correlated to the clinical and immunological base line informations on individuals from whom the parasites were obtained (project 1 and project 2). Parasite strains with diverse functional phenotypes may help to identify virulence factors that might play key roles in host-parasite interactions and immune response . It will contribute to generate a holistic view on the natural history of ZCL considering the effect of the agent and to better understand the determinants of resistance to the disease.

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， 是由利什曼原虫引起的，迫切需要改进的无毒抗利什曼原虫药物， 寻找可以预防感染或症状性疾病的有效疫苗。屯门公路资源中心的建议旨在 描述了L.突尼斯的主要感染和确定保护的免疫相关性 考虑到L major和reservoir种内多态性的最终影响， 多样性的具体假设是，L.少校可能会和主人一起行动 免疫反应来决定感染的结果项目3的具体目标是：1）筛选 有ZCL既往史的个体，在愈合的病变中残留寄生虫的持续存在。2）建立一个 L银行来自ZCL病变的主要分离株，将在队列的前瞻性随访期间形成 暴露在感染风险中的个人。3)比较评价种内功能 这些分离物的多样性使用五种实验方法：i-培养物中体外寄生虫生长的动力学， ii-对补体裂解的体外抗性，iii-对鼠或人巨噬细胞的体外感染性。iv- 在近交系小鼠品系中的实验致病性，v-一组前 在被各种分离株感染的指示人巨噬细胞中表达的选定基因。4)选择一个 L的子集。主要分离株的基础上，上述功能测试，并分析其 蛋白质组学和转录组学谱，以鉴定分离株之间差异表达的蛋白质。 L.的数据。项目3产生的主要多样性将与临床和免疫学基础相关 关于获得寄生虫的个体的行信息（项目1和项目2）。寄生虫 具有不同功能表型的菌株可能有助于鉴定可能在以下方面发挥关键作用的毒力因子： 宿主-寄生虫相互作用和免疫反应。它将有助于形成一种关于自然的整体观， ZCL的历史，考虑到药物的影响，并更好地了解耐药性的决定因素 对疾病的影响