Although genetic disorders like HbE/β-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-γ⁺ response in A*33-positive-cells relative to susceptible-genotypes. The elevated IFN-γ 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.

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.

The authors have declared no competing interest.

This study did not receive any funding

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The purpose of the study was explained to participants and written informed consent was obtained prior to the study. The ethical approval for the study was obtained from the Ethics Committee of both the Indian Institute of Technology, Kharagpur, India as well as Nil Ratan Sarkar Medical College and Hospital, Kolkata, India prior to collection. (Approval Nos. IIT/SRIC/DR/2019 dated 06.11.2019, IIT/SRIC/DEAN/2022 dated 12.08.2022; No/NMC/3483 dated 12.07.2019; IIT/SRIC/SAO/2017 dated 11.12.2017; No/NMC/4154 dated 03.08.2016).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present work are contained in the manuscript