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

结核病（TB）仍然是对公共卫生的全球威胁，仅在2018年就有近200万人死于结核病。结核病是由几种称为结核分枝杆菌复合体（MTBC）的细菌物种引起的，尽管结核分枝杆菌（Mtb）和非洲分枝杆菌（Maf）是人类的主要病原体。在MTBC菌株中，由于独特克隆的不同基因组特征，传播和引起疾病的倾向可能不同，这影响了逃避宿主免疫应答的能力。事实上，早期的研究已经证明了结核病易感性的高度遗传性。然而，鉴定TB易感基因座的努力有限，并且在很大程度上忽略了MTBC内的遗传变异性。人类和人类适应的结核分枝杆菌之间的共同进化可能促成了人类结核病的一些特征。这一概念得到了特定病原体基因型局限于不同人群的局部适应性证据的支持。例如，虽然Mtb在全球分布，但Maf仅限于西非，在那里它可以导致高达50%的人类结核病病例。到目前为止，Maf在西非的地理限制的根本原因仍然难以捉摸，并且缺乏人类结核病中宿主-病原体协同进化的正式证明。一项将探索配对的人类和MTBC基因组变异对临床相关表型的综合影响的研究对于理解疾病发病机制和宿主免疫应答至关重要，并将极大地有助于控制干预措施的设计。在这项研究中，我们的目标是通过分析来自加纳的结核病患者及其同源MTBC菌株的配对全基因组多样性数据，确定结核病中宿主-病原体协同进化的潜在基因和遗传机制。我们将调查不同的宿主遗传多态性和相关的病原体相互作用位点，并确定基因组变异和遗传关联的功能表型后果。我们的研究将为宿主-病原体共同进化的作用提供新的基因组和功能见解，以及驱动特定基因型在人群中传播的特定宿主-病原体基因组变量的相关性，并了解为什么Maf仅限于西非。这项研究产生的数据不仅有助于我们确定加纳人口中感染不同结核病谱系的风险，而且也有治疗效果不佳的风险。从长远来看，这项研究将告知政策制定者宿主导向疗法作为特定个体结核病治疗辅助手段的作用。

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.