Human genetics of leishmania infections

Abstract

Identifying genetic risk factors for parasitic infections such as the leishmaniases could provide important leads for improved therapies and vaccines. Until recently most genetic studies of human leishmaniasis were underpowered and/or not replicated. Here, we focus on recent genome-wide association studies of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL). For VL, analysis across 2287 cases and 2692 controls from three cohorts identified a single major peak of genome-wide significance (P combined = 2.76 × 10-17) at HLA-DRB1-HLA-DQA1. HLA-DRB1*1501 and DRB1*1404/DRB1*1301 were the most significant protective versus risk alleles, respectively, with specific residues at amino acid positions 11 and 13 unique to protective alleles. Epitope-binding studies showed higher frequency of basic AAs in DRB1*1404-/*1301-specific epitopes compared to hydrophobic and polar AAs in DRB1*1501-specific epitopes at anchor residues P4 and P6 which interact with residues at DRB1 positions 11 and 13. For CL, genome-wide significance was not achieved in combined analysis of 2066 cases and 2046 controls across 2 cohorts. Rather, multiple top hits at P < 5 × 10-5 were observed, amongst which IFNG-AS1 was of specific interest as a non-coding anti-sense RNA known to influence responses to pathogens by increasing IFN-γ secretion. Association at LAMP3 encoding dendritic cell lysosomal associated membrane protein 3 was also interesting. LAMP3 increases markedly upon activation of dendritic cells, localizing to the MHC Class II compartment immediately prior to translocation of Class II to the cell surface. Together these GWAS results provide firm confirmation for the importance of antigen presentation and the regulation of IFNγ in determining the outcome of Leishmania infections.

Precision Medicine in Control of Visceral Leishmaniasis Caused by L. donovani

“…This was found in a study that assessed three independent cohorts in L. donovani in India and L. infantum/chagasi in Brazil; a similar genome-wide significance was not demonstrated in similar studies in cutaneous leishmaniasis (CL) ( Fakiola et al., 2013 ). In VL, these studies highlighted the importance of antigen presenting cell function and regulation of IFN-y in host-parasite interaction ( Fakiola et al., 2013 ; Blackwell et al., 2020 ). Interestingly, development of PKDL was linked to the decreased function of the interferon-gamma receptor 1 gene ( IFNGR1 ), that was not found in VL.…”

Identification of vaccine targets &amp; design of vaccine against SARS-CoV-2 coronavirus using computational and deep learning-based approaches.

“…Studies indicate that HLA variations are associated with susceptibility or resistance to malaria, tuberculosis, leprosy, HIV, and hepatitis virus persistence (90). A report also suggests that human coronavirus OC43 interacts with HLA class I molecules at the cell surface to establish infection (91).…”

HLA-DRB1 Alleles Associated with Lower Leishmaniasis Susceptibility Share Common Amino Acid Polymorphisms and Epitope Binding Repertoires

“…Several major histocompatibility complex (MHC) class I and class II genes of the human leukocyte antigen (HLA) gene cluster have been identified as genetic susceptibility factors for leishmaniasis, with variants affecting disease outcome both positively and negatively [ 11 , 12 ]. The HLA gene complex is located within the human chromosome 6p21 region and is highly polymorphic [ 13 ].…”