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Malaria variant surface antigen expression and vulnerability to disease in Malian children with Hemoglobin C trait

具有血红蛋白 C 特征的马里儿童的疟疾变异表面抗原表达和疾病易感性

基本信息

批准号：
10642903
负责人：
Mark A Travassos
金额：
$ 34.04万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642903
关键词：
5 year old Acute Affect Africa South of the Sahara Antibody Response Antigen Presentation Antigens Attenuated Binding Blood CD36 gene Child Clinical Convalescence Custom Data Development Disease Endothelium Epitopes Erythrocyte Membrane Erythrocytes Falciparum Malaria Family Genetic Polymorphism Genetic Transcription Goals Hemoglobin Hemoglobin C Hemoglobinopathies Human Genome Immune Evasion Immune system Incidence Individual Infant Infection Label Link Longitudinal Studies Longitudinal cohort study Malaria Malaria Vaccines Mali Maps Measures Mediating Membrane Membrane Proteins Parasites Pathogenesis Plasmodium falciparum Play Population Protein Family Protein Microchips Protein translocation Proteins Proteomics Research Role Rural Severity of illness Sickle Hemoglobin Surface Surface Antigens Syndrome Techniques Tissues Transcript Vaccines Variant Virulence acquired immunity activated protein C receptor antigen binding experience hemoglobin AA insight malaria infection member novel peer protein expression proteogenomics receptor trait transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY In 2015, malaria killed 292,000 children under five years of age in sub-Saharan Africa. Hemoglobinopathies provide protection against malarial disease and reflect the powerful selective force of malaria on the human genome. In rural Mali, hemoglobin C trait provides protection against severe malaria and uncomplicated malaria illness. The precise mechanisms that protect children with hemoglobin C trait against malaria illness is unclear, but appear to be linked to Plasmodium falciparum malaria parasite variant antigens on the surface of infected erythrocytes that play a critical role in mediating disease severity. These variant surface antigens bind to host receptors in the endothelial membrane, facilitating tissue sequestration and avoidance of splenic clearance. The natural acquisition of immunity to P. falciparum malaria in infants and young children likely depends on the development of protective antibody responses against these variant surface antigens. Hemoglobin C trait decreases the quantity of these antigens on the surface of infected erythrocytes and alters their display. We have found that Malian children with hemoglobin C trait have reduced serorecognition of variant surface antigens compared to wild type children, suggesting that abnormally expressed variant surface antigens limit the antibody response. We hypothesize that a primary protective mechanism against malaria in children with Hemoglobin C trait is abnormal expression of a subset of parasite variant surface antigens. Identifying these abnormally expressed variant surface antigens may yield a subset of malaria proteins critical to disease pathogenesis. Using novel transcriptomic and proteogenomic techniques, we aim to identify the transcripts (Aim 1) and expressed variant surface antigens (Aim 2) in infections in children with hemoglobin AC, AA, and AS in a recent longitudinal study of malaria incidence in rural Mali. We will identify transcription and expression differences in variant surface antigens between these groups with respect to clinical and asymptomatic malaria episodes. We will then measure how seroreactivity changes to these variant surface antigens following a symptomatic versus an asymptomatic infection in these groups (Aim 3) with a custom protein microarray so that we can link disease vulnerability with variant surface antigen expression. The contributions of our research will be to identify variant surface antigen transcripts in symptomatic and asymptomatic infections of Malian children with hemoglobin AC, AA, and AS; variant surface antigens present on the surface of infected erythrocytes in these infections; and differences in seroreactivity to variant surface antigens. Our approach will determine if the effects of hemoglobin C trait occur during transcription or protein expression and translocation to the erythrocyte surface. Our ultimate goal is to identify a subset of variant surface antigen epitopes for a malaria vaccine to protect against clinical disease. Upon completion, we will be prepared to precisely map and define epitopes underlying natural protection to clinical malaria for the variant surface antigens identified as critical to disease pathogenesis and hemoglobin C trait protection.

项目总结