Associations Between Human Leukocyte Antigen Class I Variants and the Mycobacterium tuberculosis Subtypes Causing Disease

The human leukocyte antigen (HLA) class I molecules are involved in various biological processes and play an essential role in immunity [1]. These molecules act as multisite receptors; including peptides for antigen presentation, αβ T-cell receptors, and CD8 for cytotoxic T-cell response stimulation. The HLAs represent an unsurpassed example of polymorphism with thousands of SNPs identified to date [2]. This extreme diversity is believed to have occurred by selection events, allowing for the identification of peptide antigens from various pathogens and stimulation of an effective immune response by upregulation of the Th1 pathway [3]. HLA data for various populations demonstrate significant differences in allele frequencies between different geographical populations, with some HLA alleles completely absent from certain populations [4, 5]. The HLA genes were the first to be associated with susceptibility to tuberculosis, and many different HLA alleles have been associated in different populations [6]. The present-day population structure of several pathogens, including Mycobacterium leprae and Mycobacterium tuberculosis, can be attributed to ancient human migrations [7, 8]. Such long-standing host–pathogen interactions could lead to adaptive genetic changes in both the host and pathogen populations [9]. Evidence of this can be seen from studies that have shown that M. tuberculosis lineages have adapted to specific human populations [9–11] and the selection of strains from a distinct sublineage by a human population in a defined geographical setting [12]. In cosmopolitan settings, the association between particular M. tuberculosis complex (MTBC) lineages and their human hosts have remained even though some degree of intermingling of the different human populations has occurred [9–11]. Mycobacterium tuberculosis strains of the Beijing lineage are probably the most well characterized and are associated with increased virulence and transmission [13]. They are the most dominant strain lineage globally and have been reported in many Asian countries, and are emerging as the dominant strain in several other countries, including South Africa [14], Argentina, Cuba, Malawi, Vietnam, countries of the former Soviet Union, and parts of Western Europe [15]. Different M. tuberculosis strains induce different patterns of host immune response [16] as well as resulting in different disease phenotypes [17]. Beijing strains are also thought to be able to evade the protective effect of the BCG vaccine [18] and have evolved properties that allow them to cause disease more frequently than non-Beijing strains [19]. This could be due to their ability to modulate the host immunity toward a Th2 instead of a Th1 response or their inhibition of TNF-α release as demonstrated in activated THP-1 macrophages [20]. Within the Cape Town metropolis in South Africa, disease caused by the Beijing strains was found to be rising exponentially over a decade whereas disease caused by non-Beijing strains has remained constant [14]. Furthermore, Hanekom et al showed that the Beijing sublineage 7 strains were able to transmit and cause disease more frequently than strains from sublineages 2–6 in urban and rural populations of the Western Cape [12]. It appears that this is due to an evolutionary selection in local populations for this sublineage instead of a founder effect. In this study, we investigate the relationship between HLA class I molecules and disease by specific M. tuberculosis lineages, specifically those lineages occurring in the Western Cape, South Africa. We show that HLA class I variants are associated with several strains in our study cohort and that taking host and pathogen genetic factors into consideration is necessary for further understanding of the tuberculosis disease burden.