Immunologic consequences of highly effective antimalarial chemoprevention

描述（由申请人提供）：这是一份为Prasanna Jagannathan博士申请K23奖的申请，Prasanna Jagannathan博士是加州大学旧金山分校的传染病研究员，他是一名以患者为导向、基于实地的抗疟疾免疫研究的年轻研究者。K23奖将为Jagannathan博士提供必要的支持，以实现以下目标：(1)研究抗疟疾化学预防对生活在高流行环境中的儿童il -10特异性反调节机制和疟疾特异性T细胞反应发展的影响，以及(2)确定这些反应是否与随后的疟疾保护相关。为了实现这些目标，Jagannathan博士组建了一个指导团队，其中包括一名主要导师Margaret Feeney博士（传染病儿科转化免疫学研究专家）和三名共同导师：疟疾流行病学家Grant Dorsey博士（将从中获得K23样本的母临床试验的PI）；疟疾寄生虫学和抗疟药物耐药性专家Philip Rosenthal博士；以及艾滋病、结核病和疟疾临床研究的国际领导者黛安·哈夫利尔博士。抗疟化学预防是一种新兴的方式，可防止生活在疟疾高发地区的儿童因疟疾死亡和发病，但令人关切的是，它将推迟获得抗疟免疫。最近对小鼠和人类的研究挑战了这一范式，并表明用抗疟药物选择性地阻断血期感染可能矛盾地促进无菌抗疟免疫的发展。利用正在进行的由美国国立卫生研究院资助的非洲儿童抗疟疾化学预防随机临床试验的样本，Jagannathan博士将检验化学预防抑制IL-10介导的反调节机制的产生并允许发展多功能疟疾特异性CD4+ T细胞反应的中心假设。具体来说，他将比较T细胞和其他免疫细胞群（Aim 1）产生的IL-10和疟疾特异性T细胞对整个寄生虫抗原的反应，使用多参数流式细胞术（Aim 2）随机接受有效的疟疾化学预防或没有化学预防的儿童。在第三个目标中，他将对IL-10产生与疟疾特异性T细胞反应之间的关系进行组内分析，以及这些反应是否随后与未来疟疾发病率的降低有关。通过有指导的培训和课程的重点项目，候选人将发展转化免疫学、临床研究设计和在资源有限的环境中进行疟疾转化研究方面的高级技能。完工时

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Prasanna Jagannathan, a fellow in infectious diseases at the University of California at San Francisco who is establishing himself as a young investigator in patient-oriented, field-based studies of antimalarial immunity. This K23 award will provide Dr. Jagannathan with the support necessary to accomplish the following goals: (1) to study the impact of antimalarial chemoprevention on the development of IL-10-specific counterregulatory mechanisms and malaria-specific T cell responses in children living in high endemicity settings, and (2) to determine whether these responses correlate with protection from subsequent malaria. To achieve these goals, Dr. Jagannathan has assembled a mentoring team comprised of a primary mentor, Dr. Margaret Feeney, an expert in pediatric translational immunologic research in infectious diseases, and three co-mentors: Dr. Grant Dorsey, a malaria epidemiologist and PI of the parent clinical trial from which samples for this K23 will be obtained; Dr. Philip Rosenthal, a expert in malaria parasitology and antimalarial drug resistance; and Dr. Diane Havlir, an international leader of clinical research in HIV, TB, and malaria. Antimalarial chemoprevention is an emerging modality to prevent deaths and morbidity from malaria in children living in highly endemic areas, but there are concerns that it will delay the acquisition of antimalarial immunity. Recent studies in mice and humans have challenged this paradigm, and suggest that selective blockade of blood stage infection with antimalarial drugs may paradoxically enhance the development of sterilizing antimalarial immunity. Leveraging samples from an ongoing, NIH-funded randomized clinical trial of antimalarial chemoprevention in African children, Dr. Jagannathan will test the central hypothesis that chemoprevention suppresses the generation of IL-10 mediated counterregulatory mechanisms and allows for the development of polyfunctional malaria-specific CD4+ T cell responses. Specifically, he will compare IL-10 production by T cells and other immune cell populations (Aim 1) and malaria-specific T cell responses to whole parasite antigens using multiparameter flow cytometry (Aim 2) in children randomized to receive effective malaria chemoprevention or no chemoprevention. In the third aim, he will conduct a within-group analysis of the association between IL-10 production and malaria-specific T cell responses, and whether these responses are subsequently associated with reductions in the future incidence of malaria. Through a focused program of mentored training and coursework, the candidate will develop advanced skills in translational immunology, clinical research design, and the conduct of translational studies of malaria in resource-limited settings. At the completion of this award, Dr. Jagannathan will be well positioned to develop an R01 application to further define correlates and mechanisms of protective immunity to malaria.