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

描述(申请人提供)：约有800万至1200万人感染克氏锥虫寄生虫，这是恰加斯病的病原体，每年约有10,000人死亡。恰加斯病在高达30%的感染者中会导致心肌病，并经常导致心脏性猝死。在艾滋病毒流行的背景下，出现了一种名为复活型恰加斯病的新的临床综合征，其特征是高水平的寄生虫血症、脑膜脑炎和高达80%的死亡率。重新激活恰加斯病的风险因素尚未得到很好的描述，对重新激活恰加斯病的遗传和免疫决定因素的研究也同样缺乏，而且迫切需要。克氏毛滴虫的遗传多样性可能影响恰加斯病的临床表现和宿主免疫反应。克氏毛滴虫的感染可以是多克隆的，但多克隆感染的频率和特定克隆在恰加斯病表现中的作用尚不清楚。在这个项目中，候选人建议提高对艾滋病毒/支原体混合感染的临床特征和发病机制的了解。她将利用她的流行病学技能和先前研究恰加斯病的经验，解决这种综合征鲜为人知的方面，同时通过精心设计的教育计划和指导团队学习尖端实验室和分析技术。候选人建议解决艾滋病毒/克鲁兹支原体混合感染的三个方面：(1)确定导致克鲁兹支原体重新激活的免疫缺陷，(2) 评价克氏锥虫遗传多样性在复活型恰加斯病发病机制中的作用，以及(3)确定复活型恰加斯病的临床和实验室预测因子，并开发一种算法来区分复活型恰加斯病和脑弓形虫病。这一结果将提高对艾滋病毒/克氏锥虫混合感染的认识，指导艾滋病毒/克氏支原体混合感染患者的临床治疗，并为未来对恰加斯病的遗传和免疫学决定因素的研究提供信息。这位候选人致力于学术医学的职业生涯，并得到了她的导师和她在北卡罗来纳大学教堂山分部的大力支持。她被提供了一个助理教授的职位，并保证实验室和办公空间以及75%的受保护的研究时间。这项建议包括一个全面的教学计划和指导团队，以指导候选人的研究，并为她提供成为艾滋病毒/克鲁兹支原体混合感染专家所需的主题和技术知识。她将在流行病学技能、临床经验的基础上，与导师Steven Meshnick博士和Jonathan Juliano博士一起研究疟疾。她的导师团队的其他成员罗伯特·吉尔曼博士和卡林·伯恩博士是恰加斯病专家，他们将帮助她将这些技能应用于克氏锥虫，并在玻利维的研究地点提供导师。在K23奖项的过程中获得的教学课程、指导以及实际的实验室、临床和现场经验将为候选人提供多样化的技能集，使她能够成为致病媒介传播传染病的独立研究员和专家。

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.