Functional analysis of erythrocyte determinants of malaria infection

疟疾感染红细胞决定因素的功能分析

• 批准号: 8261676
• 负责人: Manoj T Duraisingh
• 金额: $ 40.38万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261676
• 关键词: Affect; Anti-malarial drug resistance; Antimalarials; Binding Proteins; Biochemical; Biological; Blood Circulation; Blood Group Antigens; Blood typing procedure; Cell surface; Cessation of life; Childhood; Clinical; Communicable Diseases; Development; Disease; Drug resistance; Environment; Erythrocytes; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Screening; Glycophorin A; Goals; Growth; Hematopoietic stem cells; Homologous Protein; Human; Human Pathology; Immune; In Vitro; Individual; Infection; Intervention; Knock-out; Lead; Life; Ligands; Malaria; Measures; Membrane Proteins; Molecular Genetics; Parasites; Pathway interactions; Pharmaceutical Preparations; Plasmodium falciparum; Play; Population; Process; Proteins; RNA Interference; Regimen; Relative (related person); Resources; Reticulocytes; Role; Stem cells; Subfamily lentivirinae; Surface; System; Vaccines; Variant; Work; antigen binding; base; blood group; combinatorial; design; erythrocyte receptor; genetic analysis; loss of function; loss of function mutation; member; mortality; mutant; novel; novel strategies; novel therapeutics; parasite invasion; positional cloning; public health relevance; receptor; response; therapeutic target; vaccine candidate; vaccine development

DESCRIPTION (provided by applicant): Malaria remains a major global infectious disease, largely affecting people living in resource poor environments, and is one of the most important causes of childhood mortality. Drug-resistance is constantly undermining the usefulness of antimalarial regimens. There is an urgent need for the development of new therapeutic strategies. Plasmodium falciparum parasites utilize multiple ligand-receptor interactions for the invasion of human erythrocytes. Much work has focused on the characterization of parasite ligands, with the goal of developing them as vaccine candidates. Largely due to the genetic intractabiliy of enucleated human erythrocytes, the function of host human erythrocyte receptors in ligand-receptor interactions has not been comprehensively assessed. We have developed an approach combining an in vitro erythrocyte culture system, which supports P. falciparum invasion and growth, with lentiviral transduction to generate genetically modified erythrocytes. The best characterized ligand-receptor interaction in P. falciparum is that of the ligand EBA-175 and its receptor glycophorin A, with EBA-175 being developed as a vaccine candidate. Using this system, we have achieved knockdown in expression of glycophorin A, genetically demonstrating that it is required for efficient strain-specific parasite invasion. We hypothesize that targeting a limited number of erythrocyte receptors will be sufficient to abrogate P. falciparum invasion in all P. falciparum parasite lines. This project will functionally analyze erythrocyte determinants of the invasion process of P. falciparum. We will use 1) a loss-of- function approach to establish a hierarchy amongst putative erythrocyte receptors for invasion, 2) a combinatorial knockdown approach to identify minimal sets of erythrocyte surface determinants that are essential for invasion and 3) a genetic screen to identify human blood group antigens that are novel determinants of invasion. In the long-term we hope that our studies will provide a functional understanding of critical ligand-receptor interactions for P. falciparum invasion of erythrocytes to inform vaccine development and the design of host-targeted therapeutics. PUBLIC HEALTH RELEVANCE: Malaria parasites interact intimately with molecules on the red blood cell surface of the human host during invasion and growth. The identity of host molecules that are essential for malaria proliferation has remained elusive. We will use a novel approach of genetically manipulating stem cells to study the function of molecules in the host red blood cell. We hypothesize that the identification and analysis of essential host proteins will provide ideal candidates for the development of novel therapeutics and will greatly inform vaccine development.

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