Immunologic consequences of highly effective antimalarial chemoprevention

描述(由申请人提供)：这是为加州大学旧金山分校传染病研究员Prasanna Jagannathan博士申请K23奖项，他在以患者为导向的现场抗疟疾免疫研究中确立了自己的年轻研究员地位。这项K23奖项将为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中IL-10特异性反调节机制和疟疾特异性T细胞反应的发展的影响，以及(2)确定这些反应是否与预防后续疟疾相关。为了实现这些目标，Jagannathan博士组建了一个指导团队，由主要导师、传染病儿科转化免疫学研究专家Margaret Feeney博士和三名共同导师组成：疟疾流行病学家Grant Dorsey博士和将从其获得K23样本的母公司临床试验的PI；疟疾寄生虫学和抗疟疾耐药性专家Philip Rosenthal博士；以及艾滋病毒、结核病和疟疾临床研究的国际领导者Diane Havlir博士。抗疟疾化学预防是预防疟疾高度流行地区儿童因疟疾死亡和发病的一种新方法，但有人担心，这将推迟获得抗疟疾免疫。最近在小鼠和人类身上的研究挑战了这一范式，并表明选择性地阻断抗疟疾药物的血液期感染可能矛盾地促进杀菌抗疟免疫的发展。利用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博士将检验这一中心假设，即化学预防抑制IL-10介导的反调节机制的产生，并允许发展多功能的疟疾特异性CD4+T细胞反应。具体地说，他将使用多参数流式细胞术(AIM 2)比较随机接受有效疟疾化学预防和不接受化学预防的儿童的T细胞和其他免疫细胞群产生的IL-10(AIM 1)和疟疾特异性T细胞对整个寄生虫抗原的反应。在第三个目标中，他将对IL-10的产生和疟疾特异性T细胞反应之间的联系进行小组内分析，以及这些反应是否随后与疟疾未来发病率的降低有关。通过有重点的辅导培训和课程作业，候选人将发展翻译免疫学、临床研究设计以及在资源有限的情况下进行疟疾翻译研究的高级技能。在完成时 在这一奖项中，Jagannathan博士将很好地开发R01应用程序，以进一步确定疟疾保护性免疫的相关性和机制。疟疾项目每年造成近100万人死亡，其中大部分是非洲婴儿和儿童。在流行环境中对儿童进行抗疟疾化学预防是一种有希望的战略，但人们仍然担心其对获得抗疟疾免疫的影响。通过利用现场随机化学预防试验中收集的样本研究儿童对疟疾有效免疫的相关性，这项建议有可能为未来抗疟疾化学预防战略、疫苗和其他免疫调节方法的设计提供信息。

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. Project Narrative Malaria is responsible for nearly 1 million deaths/year, mostly among African infants and children. Antimalarial chemoprevention for children in endemic settings is a promising strategy, but concerns remain about its effect on the acquisition of antimalarial immunity. Through studying correlates of effective immunity to malaria in children utilizing samples collected as part of a field-based, randomized trial of chemoprevention, this proposal has the potential to inform the design of future strategies for antimalarial chemoprevention, vaccines, and other immunomodulatory approaches.