Abstract
Variation within the HLA locus been shown to play an important role in the susceptibility to and outcomes of numerous infections, but its influence on immunity to P. falciparum malaria is unclear. Increasing evidence indicates that acquired immunity to P. falciparum is mediated in part by the cellular immune response, including NK cells, CD4 and CD8 T cells, and semi-invariant γδ T cells. HLA molecules expressed by these lymphocytes influence the epitopes recognized by P. falciparum-specific T cells, and class I HLA molecules also serve as ligands for inhibitory receptors including KIR. Here we assessed the relationship of HLA class I and II alleles to the risk of P. falciparum infection and symptomatic malaria in a cohort of 892 Ugandan children and adults followed prospectively via both active and passive surveillance. We identified two HLA class I alleles, HLA-B*53:01 and HLA-C*06:02, that were associated with a higher prevalence of P. falciparum infection. Notably, no class I or II HLA alleles were found to be associated with protection from P. falciparum parasitemia or symptomatic malaria. These findings suggest that class I HLA plays a role in the ability to restrict parasitemia, supporting an essential role for the cellular immune response in P. falciparum immunity. Our findings underscore the need for better tools to enable mechanistic studies of the T cell response to P. falciparum at the epitope level and suggest that further study of the role of HLA in regulating pre-erythrocytic stages of the P. falciparum life cycle is warranted.
Highlights
Plasmodium falciparum (P. falciparum) malaria remains a leading cause of morbidity and mortality in sub-Saharan Africa, in children
It is increasingly appreciated that the cellular immune response plays an important role in immunity to P. falciparum [4, 5], at the pre-erythrocytic stages of infection when the parasite resides within Human leukocyte antigens (HLA)-bearing hepatocytes and the multiplicity of infection is lowest
Blood smears were performed every 3 months to assess P. falciparum parasitemia and participants came to clinic when ill or febrile to be assessed for malaria
Summary
Plasmodium falciparum (P. falciparum) malaria remains a leading cause of morbidity and mortality in sub-Saharan Africa, in children. Prior studies have identified numerous host genetic variants that influence susceptibility to malaria [1], most of which impact the structure and function of erythrocytes. Human leukocyte antigens (HLA) play an important role in the cellular immune response to many infectious diseases, both by presenting antigen to T cells and by acting as ligands for immune receptors, including killer immunoglobulin-like receptors (KIR). It is increasingly appreciated that the cellular immune response (including CD8 and CD4 T cells, NK cells and γδ T cells) plays an important role in immunity to P. falciparum [4, 5], at the pre-erythrocytic stages of infection when the parasite resides within HLA-bearing hepatocytes and the multiplicity of infection is lowest. The influence of HLA on susceptibility to malaria has not been rigorously assessed in the context of cohort studies that incorporate careful longitudinal measurement of both P. falciparum parasitemia and clinical malaria
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