Malaria parasite determinants of host cell tropism

疟疾寄生虫宿主细胞趋向性的决定因素

• 批准号: 10522253
• 负责人: Manoj T Duraisingh
• 金额: $ 83.78万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522253
• 关键词: Age; Binding; Biomass; Blood; Blood Circulation; Candidate Disease Gene; Cell surface; Cells; Cellular Tropism; Cessation of life; Disease; Erythrocytes; Exhibits; Family; Genes; Genetic Crosses; Genetic Polymorphism; Glycophorin; Gorilla gorilla; Growth; Hemoglobinopathies; Heterogeneity; Human; Individual; Infection; Intervention; Ligands; Malaria; Maps; Mediating; Molecular; Morbidity - disease rate; Natural Selections; Parasites; Parasitic infection; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Plasmodium; Plasmodium falciparum; Population; Process; Proliferating; Proteins; Public Health; Quantitative Trait Loci; Recombinants; Reticulocytes; Role; Scourge; Sickle Hemoglobin; Staging; Therapeutic Intervention; Tropism; Variant; blood group; cell age; cell type; design; disorder control; forward genetics; genetic approach; loss of function; member; mortality; preference; public health intervention; receptor; reverse genetics; therapy development; transmission process; vaccine development

PROJECT SUMMARY Malaria continues to be a major scourge of humanity, and is caused by infection of red blood cells (RBCs) by the protozoan Plasmodium spp. parasites. Plasmodium falciparum can achieve high parasite biomasses in the circulation causing severe morbidity and mortality. Blood-stage parasites have a strict cellular tropism for RBCs, interacting with numerous molecular determinants in the RBCs for productive infection and transmission. Parasite polymorphisms that allow parasites to propagate and persist in different types of RBCs present a major challenge to malaria control and elimination. This includes the ability of the invasive merozoite forms to use different receptors on RBCs, known as invasion pathways. We will leverage the power of forward genetics to identify the molecular determinants mediating two key features of the cellular tropism of P. falciparum: RBC age and RBC species preference. We have found that different P. falciparum strains vary significantly in these preferences, and hypothesize that the parasite polymorphisms underlying this variation are critical to the emergence and persistence of P. falciparum in human populations, and are key determinants of pathogenesis and transmission. We will employ a forward genetics approach to identify polymorphisms and genes associated with RBC age and species preference, specifically Bulk Segregant Analysis (BSA) of progeny from genetic crosses of P. falciparum parental lines with varying invasion preferences. Reverse genetics approaches will be used for the functional analysis of naturally occurring polymorphisms in candidate genes, both singly and in combination. Together these studies will provide a comprehensive understanding of the molecular basis of cellular tropism in P. falciparum parasites, focused on RBC age and species preference. In the long-term we hope that our studies will elucidate the critical interactions required for the persistence, pathogenicity and transmission of P. falciparum in parasite populations, to inform public health interventions and inform vaccine development.

项目摘要 疟疾仍然是人类的主要祸害，是由红细胞感染（RBC）引起的 原生动物疟原虫属。寄生虫。恶性疟原虫可以实现高寄生虫生物量 循环引起严重的发病率和死亡率。血液阶段寄生虫对RBC具有严格的细胞向热量， 与RBC中的许多分子决定因素相互作用，以进行生产感染和传播。 允许寄生虫传播和持续在不同类型的RBC中的寄生虫多态性呈现主要 挑战疟疾控制和消除。这包括侵入性梅罗洛氏形式使用的能力 RBC上的不同受体，称为入侵途径。我们将利用远期遗传学的力量 识别介导恶性疟原虫细胞向性质的两个关键特征：RBC年龄的两个关键特征 和RBC物种偏好。我们发现，不同的恶性疟原虫菌株在这些菌株中有很大差异 偏好，并假设这种变化的寄生虫多态性对 恶性疟原虫在人类种群中的出现和持久性，是发病机理的关键决定因素 和传输。我们将采用一种远期遗传学方法来识别相关的多态性和基因 随着RBC的年龄和物种偏好，特别是遗传学中后代的批量隔离分析（BSA） 恶性疟原虫亲戚的杂交，具有不同的入侵偏好。反向遗传学方法将是 用于单独和在候选基因中自然发生的多态性的功能分析 组合。这些研究将共同​​提供对分子基础的全面理解 恶性疟原虫寄生虫中的细胞向热，重点是RBC年龄和物种偏好。从长远来看 希望我们的研究能阐明持久性，致病性和 在寄生虫种群中传播恶性疟原虫，以告知公共卫生干预措施并通知疫苗 发展。