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.

摘要 在这次K01的支持下，贝博士将追求她的职业目标--指挥最前沿的热带 与常驻疟疾科学家密切合作，在美国和海外进行疾病研究 地方病流行国家。贝博士的研究重点是应用国际公共卫生，他的研究处于交叉点 种群遗传学、基因组学、流行病学、分子遗传学和免疫学之间的联系。她将使用一个 翻译系统生物学方法研究抗原多样性对免疫逃逸的影响 传播媒介。这里建议的指导和培训将有助于她过渡到独立的 研究人员正在努力实现一种有效、超越多样性的疟疾疫苗的目标。 作为两个科学界的既定成员，贝博士为 HTHCSPH的哈佛疟疾倡议和布罗德研究所，它们提供了技术创新和 需要科学资源来促进她作为一名科学家的成长，以及那些更广泛的疟疾研究 塞内加尔达喀尔社区，由谢赫·安塔大学巴斯德·达喀尔研究所代表 DIOP，国家疟疾控制计划，路径：MACEPA。在法国的Le Dantec医院工作期间 Daouda Ndiaye博士和Souley mane Mboup博士的实验室，贝博士指导了疟疾培训和 过去5年的研究活动。贝博士将评估遗传多样性对发展的影响 研究疟疾流行西非的免疫和媒介传播动力学，同时获得 需要分析工具来处理复杂的基因组和转录组数据。她将进行这些研究 在美国免疫学和感染学系主任Dyann Wirth博士的专家指导下 疾病在哈佛大学公共卫生学院，疟疾生物学的领导者，具有丰富的经验 研究寄生虫遗传学，阐明耐药机制，发展先进基因组学 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 丹泰克医院，公认的传染病研究的领导者，抗疟疾药物耐药性和 疟疾寄生虫多样性；共同导师Carole Long博士，NIAID LMVR疟疾免疫科主任， NIH和疟疾疫苗参考中心主任；以及共同导师Rick Fairhurst博士， 疟疾发病和人类免疫学研究所，NIAID，NIH。两位共同导师都有广泛的 在执行纵向队列研究、标准化免疫和耐药性分析方面的专业知识，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，潜在地损害了 自然或疫苗诱导的保护性免疫。在塞内加尔，具有相同基因型别的寄生虫被发现 越来越多地感染人口中的多个人。这一独特的观察提供了前所未有的 测试个体是否对其所具有的寄生虫基因型产生变异型特异性免疫的机会 之前被曝光过。可替换地或另外地，这种持久性寄生虫基因型可以优先 传播到蚊子媒介或可能在无症状的水库中出现过多。这样的假设可以 只能在疾病流行的环境中进行测试，在这种环境中，可以对患者进行纵向监测，寄生虫 可以在时空上实时跟踪基因类型，并与免疫和传播密切相关 可以在体外测量。贝博士将评估自然获得的免疫球蛋白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 吞噬细胞分析，随着时间的推移，在塞内加尔纵向队列中，以及寄生虫 按蚊的传播潜力。拟议的研究需要尖端技术的凝聚力 基因组技术，跟踪感染进化和免疫的特征良好的纵向队列 发展、标准化检测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密切联系。贝博士的独特之处在于将这些 调查寄生虫多样性对保护性疾病发展的影响的关键要求 豁免权。归根结底，这些知识将对开发一种超越多样性的疟疾疫苗至关重要。

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