Exploring the tuberculosis epidemic in Tanzania by combining human and bacterial genomics

Tuberculosis (TB) is an ancient disease that has been affecting humans for millennia. Even though effective treatment is available, TB remains a global health problem causing 1.3 million human deaths annually. TB in humans is mainly caused by members of the Mycobacterium tuberculosis complex (MTBC). The host and bacterial genetic backgrounds as well as the environment determine the outcome of TB infection and disease. Although several risk factors have been identified among each of these, their combined effect and interaction remain understudied.
In this thesis, we explored the relationship between the MTBC and human genetic diversity as well as its combined effects on TB disease. For this, we studied the TB epidemic in Dar es Salaam, Tanzania on a global scale and combined human and MTBC genomic data with detailed clinical and sociodemographic information.
Taking advantage of the wealth of MTBC and human genomes that are publically available, we also collected a global dataset of animal-adapted MTBC genomes and provided a flexible and adaptable nomenclature for the MTBC members that cause TB in livestock and zoonotic TB in humans (Chapter 3). The same approach was used in order to build reference sets for the different human-adapted MTBC lineages. These reference sets allowed us to put the MTBC genomes isolated from the Tanzanian TB patients into a global context. We found that the TB epidemic in Tanzania is driven by MTBC genotypes that were introduced within the last 320 years, suggesting that the original MTBC phylogenetic diversity was replaced during the last few centuries (Chapter 4). On the host side, we compiled several sets of human genomes comprising representatives from a variety of human populations. By combining those with the genomes of the Tanzanian TB patients, we assessed the ancestry of the latter. We found that there was little human gene flow from outside of Africa but found differences in ancestry between members of different Tanzanian tribes that were furthermore correlated with the geographical origin of the tribe (Chapter 6).
Finally, we combined the human and MTBC genomic data. We investigated the four most successful MTBC genotypes circulating in Dar es Salaam and found two human single nucleotide polymorphisms (SNPs) associated with the most recently introduced MTBC genotype (Chapter 5). Comparing the genomes of the Tanzanian TB patients to several sub-Saharan African populations, revealed that the former were mainly composed of different Bantu ancestries reflecting the effects of the Bantu migration. We then tested whether the human ancestry and the MTBC genotype had an influence on TB disease severity in Tanzania and found that Western Bantu ancestry was protective against severe lung damage in TB patients infected with the most successful MTBC genotype circulating in Dar es Salaam (Chapter 7).
In conclusion, in this thesis we demonstrate the usefulness of assessing genomic data in a global context and the importance of studying infectious diseases by considering the genomic diversity of both the host and the pathogen as well as their possible interactions.