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，并且是由感染红细胞（RBC）引起的， 原生动物疟原虫属（Plasmodium spp.）寄生虫恶性疟原虫可以获得高寄生虫生物量， 循环导致严重的发病率和死亡率。血液阶段的寄生虫对红细胞有严格的细胞向性， 与红细胞中的许多分子决定因子相互作用，用于生产性感染和传播。 允许寄生虫在不同类型的红细胞中繁殖和持续存在的寄生虫多态性， 控制和消灭疟疾的挑战。这包括侵入性裂殖子形式利用 红细胞上的不同受体，称为入侵途径。我们将利用前沿遗传学的力量， 确定介导恶性疟原虫细胞嗜性的两个关键特征的分子决定因素：红细胞年龄 RBC种类偏好我们发现不同的恶性疟原虫株在这些方面有显著差异， 偏好，并假设这种变异背后的寄生虫多态性是至关重要的， 恶性疟原虫在人群中的出现和持续，是致病的关键决定因素 和传输。我们将采用正向遗传学方法来鉴定多态性和相关基因， 与RBC年龄和物种偏好，特别是批量Segregant分析（BSA）的后代，从遗传 具有不同入侵偏好的恶性疟原虫亲本系的杂交。反向遗传学方法将是 用于候选基因中天然存在的多态性的功能分析，无论是单个的还是多个。 组合.总之，这些研究将提供一个全面的了解的分子基础， 恶性疟原虫的细胞嗜性，集中在红细胞年龄和物种偏好。从长远来看，我们 希望我们的研究将阐明持久性，致病性和 恶性疟原虫在寄生虫种群中的传播，为公共卫生干预措施和疫苗接种提供信息 发展