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

描述（由申请人提供）：大约有800万到1200万人感染了克氏锥虫（恰加斯病的病原体），每年大约有1万人死亡。恰加斯病导致多达30%的感染者心肌病，并经常导致心源性猝死。在艾滋病毒流行的背景下，出现了一种新的临床综合征，称为再激活恰加斯病，其特点是高水平寄生虫血症、脑膜脑炎和死亡率高达80%。恰加斯病再激活的危险因素没有很好地表征，对恰加斯病再激活的遗传和免疫决定因素的研究同样缺乏，而且迫切需要。克氏锥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。克氏锥虫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HIV/T的临床特征和发病机制的理解。cruzi-coinfection。她将利用自己的流行病学技能和先前研究恰加斯病的经验，解决人们对这一综合征知之甚少的方面，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。克氏杆菌合并感染：(1)确定导致克氏锥虫重新激活的免疫缺陷；(2)确定克氏锥虫合并感染

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.