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标题：Genetic variation that determines TAPBP expression levels associates with the course of malaria in an HLA allotype-dependent manner
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作者：Victoria Walker-Sperling ; Jean C. Digitale ; Mathias Viard 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：29
DOI：10.1073/pnas.2205498119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Peptides are selected and bound to HLA-I within the endoplasmic reticulum, aided by the molecular chaperone tapasin. HLA-I allotypes vary in their dependence on tapasin for peptide loading, and tapasin-independent allotypes present a more diverse set of peptides than tapasin-dependent allotypes. We show that imputed TAPBP messenger RNA-expression levels, along with HLA-I allotype-specific tapasin dependence level, associate with malaria outcome. High TAPBP expression significantly associated with protection amongst individuals with tapasin-dependent HLA allotypes relative to low tapasin expression. Tapasin expression had no effect on tapasin-independent allotypes, which conferred protection regardless of imputed tapasin-expression levels. Thus, intrinsically high tapasin-expression levels may compensate for the restrictive nature of HLA-I tapasin dependence in the peptide-loading process, attenuating the course of malaria. HLA class I (HLA-I) allotypes vary widely in their dependence on tapasin (TAPBP), an integral component of the peptide-loading complex, to present peptides on the cell surface. We identified two single-nucleotide polymorphisms that regulate TAPBP messenger RNA (mRNA) expression in Africans, rs111686073 ( G/ C) and rs59097151 (A/ G), located in an AP-2α transcription factor binding site and a microRNA (miR)-4486 binding site, respectively. rs111686073G and rs59097151A induced significantly higher TAPBP mRNA expression relative to the alternative alleles due to higher affinity for AP-2α and abrogation of miR-4486 binding, respectively. These variants associated with lower Plasmodium falciparum parasite prevalence and lower incidence of clinical malaria specifically among individuals carrying tapasin-dependent HLA-I allotypes, presumably by augmenting peptide loading, whereas tapasin-independent allotypes associated with relative protection, regardless of imputed TAPBP mRNA expression levels. Thus, an attenuated course of malaria may occur through enhanced breadth and/or magnitude of antigen presentation, an important consideration when evaluating vaccine efficacy.
关键词：enmalariatapasinHLA