Exploring the roles of acquired immunity and functional constraint in sculpting malaria antigenic diversity in a longitudinal cohort

探索获得性免疫和功能限制在纵向队列中塑造疟疾抗原多样性中的作用

• 批准号: 10465075
• 负责人: Daniel E Neafsey
• 金额: $ 29.04万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10465075
• 关键词: Adult; Age; Alleles; Amino Acids; Antigen Targeting; Antigenic Diversity; Antigenic Variation; Antigens; Biological Assay; Biological Process; Blood; Blood specimen; CRISPR/Cas technology; Child; Clinical; Communicable Diseases; Complement; Data; Development; Disadvantaged; Ecology; Epidemiology; Equilibrium; Erythrocytes; Evolution; Exhibits; Genes; Genetic; Genetic Polymorphism; Genome; Genotype; Geographic Locations; Growth; Haplotypes; Human; Immune; Immunity; Immunoglobulin G; Immunologics; Impairment; In Vitro; Individual; Infection; Linkage Disequilibrium; Longitudinal cohort; Malaria; Malaria Vaccines; Mali; Measures; Mediating; Modeling; Molecular; Molecular Epidemiology; Morbidity - disease rate; Natural Selections; Parasites; Participant; Plasma; Plasmodium falciparum; Plasmodium falciparum genome; Population; Population Heterogeneity; Positioning Attribute; Probability; Protein Subunits; Proteins; Role; Sampling; Seasons; Signal Transduction; Structure; Subunit Vaccines; Surveys; Systems Development; Testing; Vaccination; Vaccines; Variant; Work; acquired immunity; age group; age stratification; base; circumsporozoite protein; cohort; cross immunity; density; design; epidemiological model; fitness; genome sequencing; genome-wide; genomic data; infancy; malaria infection; malaria transmission; mathematical model; mortality; next generation sequencing; pathogen; pressure; protein function; recurrent infection; transmission process; vaccine development; whole genome

Malaria parasite antigenic diversity is driven by acquired immunity and bounded by functional constraints. The interplay between these forces, if better understood, could accelerate vaccine development. The genome of Plasmodium falciparum, the eukaryotic parasite that causes the most lethal form of human malaria, exhibits a strong signature of evolutionary interaction with human hosts. While most of the genome exhibits low population diversity, several hundred genes encoding antigenic proteins harbor very high levels of variation resulting from immune-mediated balancing selection. Humans do not develop sterilizing immunity to infection with P. falciparum parasites, but develop naturally acquired immunity (NAI) through recurrent infection that reduces parasite density in the blood, and thus morbidity and mortality. For natural selection to maintain antigenic variability in parasite populations, it must confer a fitness advantage, such that parasites harboring certain variants enjoy enhanced probability of successful transmission to another human host. We recently generated PCR- based next-generation sequencing data from more than 5000 clinical samples to demonstrate that vaccination with the RTS,S/AS01 malaria vaccine, a protein subunit vaccine targeting the circumsporozoite protein (CSP), results in a reduction of subsequent blood-stage infections harboring a CSP genotype identical to the vaccine strain. This indicates that immunity conferred by the vaccine was transiently sterilizing in some individuals, but in an allele-specific manner. To explore whether NAI structures antigenic diversity in a manner similar to the RTS,S vaccine on a much larger set of antigens, and whether some observed variants impair antigen function, we propose to genetically profile parasite antigens in blood samples from different age groups, collected deeply within a single transmission season and longitudinally across transmission seasons in Mali, using whole-genome sequencing surveys. Using mathematical models, we will elucidate the mechanistic forces structuring antigenic diversity by generating detailed molecular epidemiological profiles of all malaria infections in multiple age groups within one transmission season (AIM 1), across multiple transmission seasons (AIM 2), and we will evaluate the functional constraints on malaria parasite antigen polymorphism through growth efficiency/inhibition assays (AIM 3). This work will provide a new means of ranking vaccine targets that is complementary to existing rankings, and inform polyvalent development strategies for existing vaccine targets known to exhibit allele-specific protection. Our findings will clarify a fundamental phenomenon relevant to many infectious disease systems and vaccine development efforts.

疟疾寄生虫抗原多样性由获得性免疫驱动，并受功能性免疫限制。 约束如果更好地理解这些力量之间的相互作用， 发展恶性疟原虫的基因组是一种真核寄生虫， 致命形式的人类疟疾，表现出与人类宿主进化相互作用的强烈特征。 虽然大多数基因组表现出低群体多样性，但编码抗原性的数百个基因， 由于免疫介导的平衡选择，蛋白质具有非常高水平的变异。 人类不会对恶性疟原虫感染产生杀菌免疫，但会产生 自然获得性免疫（NAI）通过反复感染，减少血液中的寄生虫密度， 从而导致发病率和死亡率。自然选择维持寄生虫的抗原变异性 种群，它必须赋予健身优势，这样，寄生虫窝藏某些变种享受 增加了成功传播到另一个人类宿主的可能性。我们最近做了PCR- 基于来自5000多个临床样本的下一代测序数据， RTS，S/AS 01疟疾疫苗，一种针对 环子孢子蛋白（CSP），导致随后的血液阶段感染的减少， CSP基因型与疫苗株相同。这表明疫苗所赋予的免疫力 在某些个体中短暂绝育，但以等位基因特异性的方式。为了探索NAI是否 以类似于RTS，S疫苗的方式在更大的一组 抗原，以及一些观察到的变异是否会损害抗原功能，我们建议从遗传学上 分析来自不同年龄组的血液样本中的寄生虫抗原， 传播季节和纵向跨越传播季节在马里，使用全基因组 排序调查。使用数学模型，我们将阐明机械力结构 抗原多样性，生成详细的分子流行病学概况， 一个传播季节内的多个年龄组（AIM 1），跨多个传播季节 (AIM 2），我们将评估疟原虫抗原多态性的功能限制 通过生长效率/抑制测定（AIM 3）。这项工作将提供一种新的排名手段 疫苗目标是对现有排名的补充，并为多价开发提供信息 针对已知表现出等位基因特异性保护的现有疫苗靶标的策略。我们的调查结果将澄清 这是与许多传染病系统和疫苗开发相关的基本现象， 努力