Employing genetic and genomic surveillance to reveal mechanisms of malaria parasite persistence

摘要 在K 01的支持下，Amy Bei博士将追求她的职业目标，进行尖端的热带 在美国和海外的疾病研究，在密切合作，与驻地科学家在疟疾 流行国家。贝博士的研究重点是应用国际公共卫生， 群体遗传学、基因组学、流行病学、分子遗传学和免疫学之间的联系。她会用一个 翻译系统生物学方法来研究抗原多样性对免疫逃避的影响， 病媒传播这里建议的指导和培训将有助于她过渡到一个独立的 研究人员，致力于一个有效的，超越多样性的疟疾疫苗的目标。 作为两个科学界的资深成员，贝博士为联合国的活动做出了贡献。 哈佛疟疾倡议在HTHCSPH和布罗德研究所，提供技术创新和 科学资源需要增加她作为一个科学家的成长，以及那些更大的疟疾研究 塞内加尔达喀尔社区，由达喀尔巴斯德研究所、Chédérique Anta大学 Diop，National Malaria Control Program，and PATH：MACEPA.虽然总部设在Le Dantec医院， 在Daouda Ndiaye博士和Souleymane Mboup博士的实验室里，贝博士指导了疟疾培训， 过去五年的研究活动。贝博士将评估遗传多样性对发展的影响， 免疫力和病媒传播动态，同时获得 处理复杂的基因组和转录组数据所需的分析工具。她将进行这些研究 在美国导师，免疫学和传染病系主任Dyann Wirth博士的专家指导下， 他是哈佛公共卫生学院疟疾生物学领域的领导者，在 研究寄生虫遗传学，阐明耐药机制，开发先进的基因组 方法;塞内加尔导师Daouda Ndiaye博士，Le寄生虫学-真菌学实验室主任 Dantec医院是抗疟药物耐药性传染病研究领域公认的领导者， 疟疾寄生虫多样性;共同导师Carole Long博士，疟疾免疫学科科长，LMVR，NIAID， 美国国立卫生研究院和疟疾疫苗参考中心主任;和共同导师里克费尔赫斯特博士，主任 疟疾发病机制和人类免疫单位，LMVR，NIAID，NIH。两位导师都有广泛的 在进行纵向队列研究、标准化免疫和耐药性检测方面的专业知识，以及 评估疟疾疫苗。 抗原多样性在免疫逃避中起着重要作用，可能损害免疫系统的发展。 天然或疫苗诱导的保护性免疫。在塞内加尔，发现具有相同基因型的寄生虫， 越来越多地感染人群中的多个个体。这一独特的观察提供了前所未有的 有机会测试个体是否对他们所感染的寄生虫基因型产生变异特异性免疫力 以前暴露过。可替代地或另外地，这样的持续寄生物基因型可以优选地 传播给蚊媒或可能在无症状宿主中过度存在。这些假设可以 仅在可以纵向监测患者的疾病流行环境中进行检测， 基因型可以在时空上实时跟踪，免疫和传播的可靠相关性 可以离体测量。贝博士将评估自然获得的IgG对特定寄生虫的效应功能 生长抑制试验（GIA）、变异表面抗原（VSA）识别试验中的基因型，以及 调理吞噬试验，随着时间的推移，在塞内加尔纵向队列，以及寄生虫的 传播潜力的按蚊。拟议的研究需要凝聚尖端的 基因组技术，一个充分表征的纵向队列，以跟踪感染演变和免疫 开发标准化测定，作为免疫保护和传播的体外相关物，以及 与地方病流行国家的科学家和机构有着密切的联系。贝博士是独一无二的定位，联合收割机， 研究寄生虫多样性对发展保护性 免疫力最终，这些知识对于开发一种超越多样性的疟疾疫苗至关重要。

Abstract With the support of this K01, Dr. Amy Bei will pursue her career goal of conducting cutting-edge tropical diseases research in the United States and overseas, in close collaboration with resident scientists in malaria endemic countries. Dr. Bei's research focuses on applied international public health, and lies at the intersection between population genetics, genomics, epidemiology, molecular genetics, and immunology. She will use a translational systems biology approach to study the impact of antigenic diversity on immune evasion and vector transmission. The mentorship and training proposed here will facilitate her transition to an independent researcher, working towards the goal of an effective, diversity-transcendent vaccine for malaria. As an established member of two scientific communities, Dr. Bei contributes to the activities of the Harvard Malaria Initiative at HTHCSPH and the Broad Institute, which provide the technical innovation and scientific resources needed to augment her growth as a scientist, and to those of the greater malaria research community of Dakar, Senegal, which is represented by the Institute Pasteur Dakar, University Cheikh Anta Diop, National Malaria Control Program, and PATH: MACEPA. While based at Le Dantec Hospital in the laboratories of Drs. Daouda Ndiaye and Souleymane Mboup, Dr. Bei has guided both malaria training and research activities for the past 5 years. Dr. Bei will assess the impact of genetic diversity on the development of immunity and dynamics of vector transmission in malaria endemic West Africa, while gaining expertise in the analytical tools needed to process complex genomic and transcriptomic data. She will conduct these studies under the expert guidance of U.S. mentor Dr. Dyann Wirth, Department Chair of Immunology and Infectious Diseases at the Harvard School of Public Health, a leader in malaria biology with extensive experience in studying parasite genetics, elucidating mechanisms of drug resistance, and developing advanced genomic approaches; Senegal mentor Dr. Daouda Ndiaye, Chief of the Laboratory of Parasitology-Mycology at Le Dantec Hospital, a recognized leader in infectious diseases research on antimalarial drug resistance and malaria parasite diversity; co-mentor Dr. Carole Long, Chief of the Malaria Immunology Section, LMVR, NIAID, NIH and director of the Malaria Vaccine Reference Center; and co-mentor Dr. Rick Fairhurst, Chief of the Malaria Pathogenesis and Human Immunity Unit, LMVR, NIAID, NIH. Both co-mentors have extensive expertise in performing longitudinal cohort studies, standardizing immune and drug resistance assays, and evaluating malaria vaccines. Antigenic diversity plays a major role in immune evasion, potentially compromising the development of natural or vaccine induced protective immunity. In Senegal, parasites with identical genotypes are found to increasingly infect multiple individuals in the population. This unique observation provides an unprecedented opportunity to test if individuals develop variant-specific immunity to the parasite genotypes to which they have been previously exposed. Alternatively or additionally, such persisting parasite genotypes may preferentially transmit to the mosquito vector or may be overrepresented in asymptomatic reservoirs. Such hypotheses can only be tested in a disease endemic setting in which patients can be monitored longitudinally, parasite genotypes can be tracked spatiotemporally in real-time, and robust correlates of immunity and transmission can be measured ex vivo. Dr. Bei will assess the effector function of naturally acquired IgG to specific parasite genotypes in growth inhibition assays (GIAs), variant surface antigen (VSA) recognition assays, and opsonophagocytosis assays, over time in a Senegalese longitudinal cohort, as well as the parasites' transmission potential for Anopheles mosquitoes. The proposed studies require the cohesion of cutting-edge genomic technologies, a well characterized longitudinal cohort to follow infection evolution and immunity development, standardized assays to serve as in vitro correlates of immune protection and transmission, and strong ties to endemic country scientists and institutions. Dr. Bei is uniquely positioned to combine these critical requirements to investigate the implications of parasite diversity on the development of protective immunity. Ultimately, this knowledge will be essential to developing a diversity-transcendent malaria vaccine.