Immune & Inflammatory Response in L (Viannia) Infection

(Viannia)亚属的利什曼原虫流行于整个拉丁美洲。该亚属可引起自限性皮肤、慢性皮肤粘膜和皮肤病以及无症状感染。虽然免疫介导的超敏反应和炎症反应是由该菌引起的人类皮肤疾病的特征，并且可能是治疗上可以干预的，但涉及疾病的发病机制、寄生虫的持久性和疾病的再激活的机制尚不清楚。感染和疾病(皮肤粘膜、慢性和非皮肤粘膜)中混合Th1/Th2反应的证据 无症状)表明疾病的发病机制与旧大陆截然不同 皮肤营养物种。对人类免疫反应在发病机制中的理解以及感染的持久性一直受到以下因素的限制：1)获得定义良好的离散临床表型的机会有限；2)适用于人类感染的方法分辨率低；3)缺乏基因定义的、遗传和免疫可操作的实验模型。我们将使用高分辨率技术(实时聚合酶链式反应、微阵列、细胞学、靶向基因缺失)临床不同的、地方性暴露的人群和实验感染BALB/c和敲除小鼠，以了解宿主在慢性和复发性疾病以及寄生虫持续存在时的反应。研究的最终目标是确定疾病发病机制中可干预的先天、炎症和适应性过程。具体目标是：1)确定Th1/Th2极化是否发生并与华支睾吸虫感染的结局有关；2)确定慢性或复发性利什曼病和无症状感染的个体中Mif低表达和高表达的频率，并确定这些等位基因是否与感染结局相关；3)确定促进人巨噬细胞对华支睾吸虫感染的体外易感性的机制及其与临床表型的关系；3)使用华支睾吸虫的小鼠模型来分析宿主的反应。

Leishmania of the (Viannia) subgenus are prevalent throughout Latin America. This subgenus causes self-limited cutaneous, chronic mucocutaneous and cutaneous disease, and asymptomatic infection. Although immune mediated hypersensitivity and the inflammatory response are hallmarks of human dermal disease caused by this L. Viannia, and may be therapeutically intervenable, the mechanisms involved in pathogenesis, parasite persistence and reactivation of disease are inadequately understood. Evidence of mixed Th1/Th2 responses throughout the spectrum of infection and disease (mucocutaneous, chronic and asymptomatic) indicates that disease pathogenesis involves distinct mechanisms from Old World dermatotrophic species. Understanding of the human immune response in pathogenesis, and persistence of infection has been constrained by:1) limited access to well defined, discrete clinical phenotypes; 2) low resolution of methods applicable in human infection; 3) lack of genetically defined, genetically and immunologically manipulatable experimental models. We will use high resolution technologies (RealTime PCR, microarray, cytometry, targeted gene deletion) clinically disparate, endemically exposed populations and experimentally infected BALB/c and knock out mice to understand the host response in chronic and recurrent disease, and parasite persistence.The ultimate goal of the research is to identify intervenable innate, inflammatory and adaptive processes of disease pathogenesis. Specific Aims are:1 )To determine if Th1/Th2 polarization occurs and is linked to the outcome of infection by L. Viannia; 2) Define the frequency of low and high expression Mif alleles in individuals with chronic or recurrent leishmaniasis and asymptomatic infection, and determine if these alleles are associaed with outcome of infection; 3) Determine the mechanisms that propiciate in vitro susceptibility of human macrophages to L. Viannia infection, and their relationship to clinical phenotype; 4.) Use murine models of L. Viannia to dissect the host response.