The pathogenesis of T. cruzi in HIV-infected persons in Bolivia

描述（由申请人提供）：800万至1200万人感染寄生虫克氏锥虫（锥虫病的病原体），每年约有10，000人死亡。恰加斯病在高达30%的感染者中引起心肌病，并经常导致心脏性猝死。在艾滋病流行的背景下，出现了一种新的临床综合征，称为再活化恰加斯病，其特征是高水平的寄生虫血症、脑膜脑炎，死亡率高达80%。查加斯病复发的风险因素尚未得到很好的描述，对查加斯病复发的遗传和免疫决定因素的研究同样缺乏，而且迫切需要。T. cruzi可能影响查加斯病的临床表现和宿主免疫反应。感染T.克氏锥虫病可以是多克隆的，但多克隆感染的频率和特异性克隆在恰加斯病表现中的作用尚不清楚。在这个项目中，候选人建议提高对HIV/T的临床特征和发病机制的理解。克鲁兹合并感染她将利用她的流行病学技能和先前研究恰加斯病的经验，解决对这种综合征知之甚少的方面，同时通过精心设计的教育计划和导师团队学习尖端的实验室和分析技术。候选人提议处理艾滋病毒/艾滋病的三个方面。cruzi合并感染：（1）确定导致T. cruzi，（2）to 评价T. cruzi遗传多样性在再活化恰加斯病发病机制中的作用，以及（3）描述再活化恰加斯病的临床和实验室预测因子，并开发区分再活化恰加斯病和脑弓形虫病的算法。研究结果将提高对艾滋病毒/艾滋病的认识。cruzi合并感染，指导HIV/T的临床管理。cruzi合并感染的患者，并告知未来的研究到南美锥虫病的遗传和免疫决定因素。候选人致力于学术医学的职业生涯，并在她的导师和她在北卡罗来纳大学教堂山分部的目标的大力支持。她已提供了一个职位，助理教授和保证实验室和办公空间，以及75%的保护研究时间。这项建议包括一个全面的教学计划和指导小组，以指导候选人的研究，并向她提供成为艾滋病毒/艾滋病专家所需的主题和技术知识。克氏混合感染。她将利用她的流行病学技能，临床经验，并与导师Steven Meshnick博士和Jonathan Juliano博士一起研究疟疾。罗伯特·吉尔曼博士和卡琳伯尔尼博士是她的导师团队的其他成员，他们是恰加斯病专家，将帮助她将这些技能应用于T。cruzi并在Bolivi的研究地点提供指导。在K23奖项的过程中获得的教学课程，指导和实践实验室，临床和现场经验将为候选人提供多样化的技能，使她能够成为致病媒介传播的传染病的独立调查员和专家。

DESCRIPTION (provided by applicant): Between 8 and 12 million people are infected with the parasite Trypanosoma cruzi, the causative agent of Chagas disease, and approximately 10,000 die each year. Chagas disease causes cardiomyopathy in up to 30% of those infected and often results in sudden cardiac death. In the context of the HIV epidemic, a new clinical syndrome called reactivation Chagas disease has emerged, characterized by high-level parasitemia, meningoencephalitis, and mortality as high as 80%. Risk factors for reactivation Chagas disease are not well characterized, and studies of the genetic and immunological determinants of reactivation Chagas disease are similarly lacking and urgently needed. The genetic diversity of T. cruzi likely influences clinical presentation and host immune response in Chagas disease. Infections with T. cruzi can be multiclonal, but the frequency of multiclonal infections and the role of specific clones in the manifestations of Chagas disease are not known. In this project, the candidate proposes to improve understanding of the clinical features and pathogenesis of HIV/T. cruzi-coinfection. She will draw upon her epidemiological skills and prior experience studying Chagas disease to address poorly understood aspects of this syndrome while learning cutting-edge laboratory and analytic techniques through a thoughtfully designed educational program and mentorship team. The candidate proposes to address three aspects of HIV/T. cruzi coinfection: (1) to define the immunological deficits that lead to reactivation of T. cruzi, (2) to evaluate the role of T. cruzi genetic diversity in the pathogenesis of reactivation Chagas disease, and (3) to characterize the clinical and laboratory predictors of reactivation Chagas disease and develop an algorithm to distinguish reactivation Chagas disease from cerebral toxoplasmosis. The results will improve understanding of HIV/T. cruzi coinfection, guide the clinical management of HIV/T. cruzi-coinfected patients, and inform future studies into the genetic and immunological determinants of Chagas disease. The candidate is committed to a career in academic medicine and is strongly supported in her goals by her mentors and her division at UNC-Chapel Hill. She has been offered a position as Assistant Professor and guaranteed laboratory and office space as well as 75% protected research time. This proposal includes a comprehensive didactic plan and mentorship team to guide the candidate's research and provide her the subject matter and technical knowledge needed to become an expert in HIV/T. cruzi coinfection. She will build upon her epidemiological skills, clinical experience, and work on malaria with mentors Dr. Steven Meshnick and Dr. Jonathan Juliano. Dr. Robert Gilman and Dr. Caryn Bern, the other members of her mentorship team, are Chagas disease experts and will help her apply these skills to T. cruzi and provide mentorship at the study site in Bolivi. The didactic coursework, mentorship, and practical laboratory, clinical, and field experience obtained over the course of the K23 award will provide the candidate with a diverse skill set that will allow her to be an independent investigator and expert in the pathogenesis vector-borne infectious diseases.