TBGENAfrica: An integrated approach to unraveling susceptibility to tuberculosis in Africa

Project Leads

The Problem

Africa has the highest level of genetic diversity amongst all human populations. It also has the highest level of genetic diversity amongst populations of the pathogen that causes tuberculosis. Phylogenetic analysis shows that Mycobacterium tuberculosis (MTB) emerged with modern humans in Africa ~70 thousand years ago, and has spread and diversified in close association with humans during their migration out of Africa. The project proposes that the long history of co-evolution of host and pathogen genomes contributes to the diverse outcome following MTB infection, as reflected in the variable percentage of individuals progressing to active tuberculosis and varying efficiencies of ongoing transmission.

Building on established links with leading institutions in Europe and the US, the project networks three African Institutions with ambition to develop their mycobacterial and human genetic research capacity to study human health and heredity in East Africa, focusing on host-pathogen genotype interactions
in tuberculosis. The scientific goal is to identify molecular targets that will rationalise the development of new drugs and vaccines to control a global epidemic, which disproportionately affects vulnerable East African populations.

Project Strategy

1. To map the genetic and geographic structure of human-adapted Mycobacterium tuberculosis (MTB) populations across Central and Eastern regions of Africa.
2. To test the hypothesis that the geographic and genetic structure of human-adapted MTB overlaps with the geographic and genetic structure of human populations.
3. To determine whether novel host-pathogen genome combinations are associated with distinct clinical outcomes.
4. To test whether HIV immune suppression abrogates association between host-pathogen genome combinations and clinical outcome.
5. To dissect the molecular determinants of MTB drug resistance in under-studied African populations.
6. To extend African capacity in genomics and bioinformatics research

Potential Impact

Explain what can be learned and the impact of (potential or current) findings from this project. Can also highlight

1. Novel findings on TB Host/pathogen genomics
   • Specific genetic variants that associate with TB will be identified in both host and pathogen in both East and West African countries, and African researchers are leading funding applications to extend these findings.
   • Human genome variation and African population structure will be better characterized
2. Increased capacity in genomics and bioinformatics research:
   • A sustainable multi-disciplinary network has been developed to support ongoing genetic/genomic research on TB and other endemic diseases, both communicable and non-communicable.
   • Seven PDRFs, eight PhD students and four Masters students are trained across disciplines and supportedto next career stages
   • Four research assistants/laboratory technicians, four nurses and five data assistants trained to undertakeand support research projects
3. Increased knowledge in ELSI associated with genetic susceptibility to TB among communities:
   • Results will be disseminated widely to the scientific community through conference presentations, open-access publications in peer-reviewed journals and accessible genome databases; to stakeholders (e.g.Ministries of Health, TB control programmes) through workshops and to communities through meetings,workshops, radio and other means