Immune & Inflammatory Response in L (Viannia) Infection

免疫

• 批准号: 6970458
• 负责人: Diane McMahon Pratt
• 金额: $ 24.16万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6970458
• 关键词: Colombia; Leishmania; cellular polarity; clinical research; cooperative study; flow cytometry; gene deletion mutation; genetic models; genetic regulation; genetically modified animals; helper T lymphocyte; host organism interaction; human subject; immune response; inflammation; interferon gamma; interleukin 10; interleukin 13; laboratory mouse; leishmaniasis; macrophage; microarray technology; microorganism immunology; migration inhibition factor; phenotype; polymerase chain reaction; skin infection; transcription factor

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.

利什曼原虫（Viannia）亚属在整个拉丁美洲流行。该亚属引起自限性皮肤、慢性粘膜皮肤和皮肤疾病以及无症状感染。虽然免疫介导的超敏反应和炎症反应是由这种L. Viannia，并可能是治疗干预，发病机制，寄生虫的持久性和疾病的再激活所涉及的机制是不充分的理解。在整个感染和疾病谱中混合Th 1/Th 2应答的证据（粘膜皮肤、慢性和慢性感染）。 无症状）表明疾病发病机制涉及与旧世界不同的机制 皮肤营养物种。对发病机制中的人类免疫应答和感染的持续性的理解受到以下限制：1）对明确定义的离散临床表型的有限访问; 2）适用于人类感染的方法的分辨率低; 3）缺乏遗传上定义的、遗传上和免疫学上可操作的实验模型。我们将使用高分辨率技术（实时PCR，微阵列，细胞计数，靶向基因缺失）临床上不同的，地方性暴露的人群和实验感染的BALB/c和敲除小鼠，以了解慢性和复发性疾病的宿主反应，以及寄生虫的持久性。研究的最终目标是确定疾病发病机制的可干预的先天，炎症和适应性过程。具体目的是：1）确定是否存在Th 1/Th 2极化，并与感染的结果由L。Viannia; 2）明确慢性或复发性利什曼病和无症状感染个体中Mif等位基因的低表达和高表达频率，并确定这些等位基因是否与感染结果相关; Viannia感染及其与临床表型的关系; 4.）使用L. Viannia对解剖宿主的反应。