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Malaria parasite determinants of host cell tropism

疟疾寄生虫宿主细胞趋向性的决定因素

基本信息

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
项目类别：
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

项目摘要

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.

项目总结