Employing Genetic and Genomic Surveillance to Reveal Mechanisms of Malaria Parasite Persistance

利用遗传和基因组监测揭示疟原虫持续存在的机制

• 批准号: 10452223
• 负责人: Amy Kristine Bei
• 金额: $ 7.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-28 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452223
• 关键词: 5 year old; Affect; Africa; Africa South of the Sahara; Anopheles Genus; Anti-malarial drug resistance; Antibody Response; Antigenic Diversity; Antigenic Variation; Antigens; B-Lymphocyte Epitopes; Biological Assay; Biology; Cause of Death; Cells; Child; Clinical; Collaborations; Communicable Diseases; Communities; Complex; Country; Culicidae; Data; Department chair; Development; Disease Outbreaks; Drug resistance; Endemic Diseases; Epitopes; Erythrocytes; Evolution; Exposure to; Family; Female; Flow Cytometry; Frequencies; Genes; Genetic; Genetic Variation; Genomic approach; Genomics; Genotype; Goals; Growth; High-Throughput Nucleotide Sequencing; Hospitals; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunoglobulin G; Immunoglobulins; Immunology; In Vitro; Individual; Infection; Infectious Diseases Research; Institutes; Institution; International; Intervention; Knowledge; Laboratories; Ligands; Light; Longitudinal cohort; Longitudinal cohort study; Malaria; Malaria Vaccines; Measures; Membrane; Mentors; Mentorship; Molecular; Molecular Genetics; Monitor; National Institute of Allergy and Infectious Disease; Parasites; Parasitic infection; Parasitology; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Plasmodium falciparum; Play; Population; Population Genetics; Positioning Attribute; Prevalence; Process; Public Health; Public Health Schools; Research; Research Activity; Research Personnel; Resources; Role; Scientist; Seasons; Senegal; Standardization; Surface Antigens; Systems Biology; Techniques; Technology; Testing; The science of Mycology; Time; Training; Training Activity; Transcript; Tropical Disease; United States; United States National Institutes of Health; Universities; Vaccines; Variant; Virulence; analytical tool; attributable mortality; base; career; cohesion; experience; feeding; genomic epidemiology; immune resistance; innovation; male; member; programs; spatiotemporal; tool; transcriptomics; transmission process; vector mosquito; vector transmission

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.

抽象的 在此K01的支持下，Amy Bei博士将追求自己的职业目标，以进行尖端的热带 与疟疾的常驻科学家密切合作，美国和海外的疾病研究 流行国家。 Bei博士的研究重点是应用国际公共卫生，并在交叉路口 种群遗传学，基因组学，流行病学，分子遗传学和免疫学之间。她会使用 转化系统生物学方法是研究抗原多样性对免疫逃避和的影响 向量传输。这里提出的指导和培训将促进她向独立的过渡 研究人员致力于为疟疾提供有效，多样性传播疫苗的目标。 作为两个科学社区的成员，Bei博士为活动的活动做出了贡献 HTHCSPH和Broad Institute的哈佛大学疟疾倡议提供了技术创新和 为了增加她作为科学家的成长所需的科学资源，以及大疟疾研究的成长 塞内加尔达卡（Dakar）社区，由大学Cheikh Anta大学的巴斯德·达卡（Pasteur Dakar）代表 Diop，国家疟疾控制计划和路径：Macepa。总部设在勒丹特医院 博士的实验室。 Daouda Ndiaye和Souleymane Mboup，Bei博士指导了疟疾培训和 过去5年的研究活动。 Bei博士将评估遗传多样性对发展的影响 疟疾特有西非地方性媒介传播的免疫力和动态，同时获得专业知识 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Dyann Wirth博士的专家指导下，免疫学和传染性部门主席 哈佛公共卫生学院的疾病，疟疾生物学领导者，拥有丰富的经验 研究寄生虫遗传学，阐明耐药性的机制以及发展晚期基因组 方法；塞内加尔导师Daouda Ndiaye博士，LE寄生虫学杂志实验室负责人 Dantec医院，公认的感染性疾病的领导者，研究抗疟疾耐药性和 疟疾寄生虫多样性； LMVR疟疾免疫学部分负责人Carole Long博士Carole Long，Niaid， NIH兼疟疾疫苗参考中心主任；以及联合官员Rick Fairhurst博士 疟疾发病机理和人类免疫单位，LMVR，NIAID，NIH。两个副官员都有广泛的 进行纵向队列研究，标准化免疫和耐药性测定以及 评估疟疾疫苗。 抗原多样性在免疫逃避中起主要作用，可能损害 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是 越来越多地感染了人口中的多个人。这种独特的观察提供了前所未有的 测试个人是否对具有变异的寄生虫基因型产生变异的免疫力 以前暴露了。或者，这种持续存在的寄生虫基因型可能优先 传输到蚊子载体，或者可能在无症状储层中过度代表。这样的假设可以 仅在疾病流行环境中进行测试，在该环境中可以纵向监测患者 基因型可以实时跟踪时空，并具有牢固的免疫和传播相关性 可以在体内测量。 Bei博士将评估自然获得的IgG对特定寄生虫的效应子功能 生长抑制分析（GIA），变异表面抗原（VSA）识别测定法和基因型 随着时间的流逝，在塞内加尔的纵向队列中以及寄生虫的探测性吞噬作用测定 蚊虫的传播潜力。拟议的研究需要尖端的凝聚力 基因组技术，是一种纵向队列的良好特征，遵循感染进化和免疫力 开发，标准化测定，以作为免疫保护和传播的体外相关性，以及 与地方性国家科学家和机构的紧密联系。 Bei博士在将这些结合起来的独特位置 调查寄生虫多样性对保护性发展的含义的关键要求 免疫。最终，这种知识对于开发多样性转换疟疾疫苗至关重要。

项目成果

Assessing the functional impact of PfRh5 genetic diversity on ex vivo erythrocyte invasion inhibition.

• DOI: 10.1038/s41598-021-81711-9
• 发表时间: 2021-01-26
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Moore AJ;Mangou K;Diallo F;Sene SD;Pouye MN;Sadio BD;Faye O;Mbengue A;Bei AK
• 通讯作者: Bei AK

Structure-guided insights into potential function of novel genetic variants in the malaria vaccine candidate PfRh5.

• DOI: 10.1038/s41598-022-23929-9
• 发表时间: 2022-11-12
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Mangou, Khadidiatou;Moore, Adam J.;Thiam, Laty Gaye;Ba, Aboubacar;Orfano, Alessandra;Desamours, Ife;Ndegwa, Duncan Ndungu;Goodwin, Justin;Guo, Yicheng;Sheng, Zizhang;Patel, Saurabh D.;Diallo, Fatoumata;Sene, Seynabou D.;Pouye, Mariama N.;Faye, Awa Thioub;Thiam, Alassane;Nunez, Vanessa;Diagne, Cheikh Tidiane;Sadio, Bacary Djilocalisse;Shapiro, Lawrence;Faye, Ousmane;Mbengue, Alassane;Bei, Amy K.
• 通讯作者: Bei, Amy K.

Plasmodium falciparum genomic surveillance reveals spatial and temporal trends, association of genetic and physical distance, and household clustering.

• DOI: 10.1038/s41598-021-04572-2
• 发表时间: 2022-01-18
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Sy M;Deme AB;Warren JL;Early A;Schaffner S;Daniels RF;Dieye B;Ndiaye IM;Diedhiou Y;Mbaye AM;Volkman SK;Hartl DL;Wirth DF;Ndiaye D;Bei AK
• 通讯作者: Bei AK