Host- Pathogen Co-Evolution in Tuberculosis: The Case of Mycobacterium Africanum

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Tuberculosis (TB) remains a global threat to public health, with close to 2 million people dying from TB in 2018 alone. TB is caused by several bacterial species referred to as Mycobacterium tuberculosis complex (MTBC), although Mycobacterium tuberculosis (Mtb) and Mycobacterium africanum (Maf) are the main causative agents in humans. Among the MTBC strains, the propensity to transmit and cause disease may vary due to different genomic characteristics of unique clones, which influence the ability to evade the host immune response. Indeed, early studies have demonstrated a high degree of heritability in TB susceptibility. However, efforts for identification of TB susceptibility loci have been limited, and largely irgnored genetic variability within MTBC. Co-evolution between humans and the human-adapted MTBC is likely to have contributed to some of the characteristics of TB in humans. This notion is supported by evidence for local adaptation of specific pathogen genotypes restricted to distinct human populations. For instance, while Mtb is globally distributed, Maf is restricted to West-Africa, where it can cause up to 50% of the human TB cases. So far, the reason underlying the geographical restriction of Maf to West Africa remains elusive and a formal demonstration of host-pathogen co-evolution in human TB is lacking. A study that will explore the combined effects of paired human and MTBC genomic variation on clinically relevant phenotypes is crucial for understanding disease pathogenesis and host immune response, and will contribute greatly to the design of control interventions. In this study, we aim to identify potential genes and genetic mechanism underlying host-pathogen co-evolution in TB by analysing paired genome-wide diversity data from TB patients and their cognate MTBC strains from Ghana. We will investigate distinct host genetic polymorphisms and associated pathogen interacting loci, and determine the functional phenotypic consequence of genomic variation and genetic associations. Our study will provide new genomic and functional insights into the role of host-pathogen co-evolution, and the relevance of specific host-pathogen genomic variables that are driving the transmission of specific genotypes in the population and understand why Maf is restricted to West-Africa. The data generated from this study would not only help us identify Ghanaian populations at risk of being infected with distinct TB lineages but also at risk of poor treatment outcome. This study will, in the long run, inform policy makers on the role of host directed therapies as an adjunct to TB treatment in specific individuals.