Distinct polymorphisms in HLA-class-I molecules of HbE/B-thalassemia cohort in Eastern India influences their vulnerability to Apicomplexan infections

Although genetic disorders like HbE/{beta}-thalassemia-(HBT) are associated with detrimental health outcomes, they may be subject to positive-selection in endemic regions of parasitic infections. In sub-Saharan-Africa, individuals with HBT, dependent on regular blood-transfusions have been observed to exhibit protection against malaria, while remaining susceptible to toxoplasmosis. This observation suggests, hematological genetic-disorders may significantly influence pathogenesis of Apicomplexan infections. In HBT-patients from Eastern-India, protection against toxoplasmosis was identified in individuals carrying Human-Leukocyte-Antigen-A*33-(HLA-A*33) allele. This protective effect was found to be conserved in peripheral-blood-mononuclear-cells-(PBMCs) obtained from both HBT-patients and healthy-controls. While parasite-entry into PBMCs was permitted, intracellular proliferation was restricted, which was linked to significantly enhanced CD8-IFN-{gamma} response in A*33-positive-cells relative to susceptible-genotypes. The elevated IFN-{gamma} production was attributed to increased binding-affinity of A*33 with Toxoplasma-derived-peptides like SAG2C, leading to improved antigen-presentation. Interestingly, no protective role of A*33 was observed against Plasmodium, indicating a pathogen-specific interaction between HLA-alleles and Apicomplexan-derived-antigens. Further next-generation-sequencing of class-I and-II HLA-loci in HBT-patients revealed a potential association between HLA-C*07 and protection against Plasmodium infection. These findings provide mechanistic insights into how host genetic-factors may influence susceptibility to Apicomplexan infections and suggest that such interactions could contribute to evolutionary persistence of deleterious HBT-mutations in regions where these infections are co-prevalent. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/25332941v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@57f993org.highwire.dtl.DTLVardef@1c2534forg.highwire.dtl.DTLVardef@eb8007org.highwire.dtl.DTLVardef@1228caa_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Schematic Representation of allele-pathogen dynamics explored in this study, highlighting the selective fitness advantage conferred by specific HLA variants in the context of Toxoplasma and Plasmodium infection. C_FIG