Tuberculosis (TB) has evolved with human populations such that the clades of Mycobacterium tuberculosis complex (MTBC) are closely associated with human migratory pathways out of the rift valley. TB and the human response to bacteria are thus closely aligned but may have differed under evironmental specific selective pressures. Such differences have important implications for the treatement of TB, not only for the use of antibiotics, where ethnicity is a contributor to antibiotic metabolism, but also with the development of novel immunotherapeutics, otherswise called host-directed therapeutics (HDTs). Here we propose to determine whether ethnicity, particularly amongst West African and South African poulations contributes to host immune responses to endemic MTBC lineages. Moreover, we will correlate response to these lineages with efficacy of HDTs. In this study we will use as a test case Gleevec (Imatinib), which targets the Abl tyrosine kinases, stimulates lysosomes production and augments myeloid response to TB. Imatinib is currenlty being tested in Atlanta and South Africa againist active pulmonary TB. My goal for this 5-years K43 award is to gain critical skills in transcriptomics bioinformatics and experience in HDT clinical trials to develop both my independence and a project suitable for future funding to assess the capacity of HDTs to act broadly across MTBC clades and population of different ethnicity. Such studies will be vital to establishing the general efficacy of new HDTs across human populations, and to determining the types of immune responses that are broadly efficacious and durable. MTBC genetic diversity mirrors Africa's great human genetic and environmental diversity. For instance, in West Africa, M. africanum (Maf)-lineage-6 causes about 40% and M. tuberculosis (Mtb)-lineage-4 60% of all TB. Conversely, in South Africa 65% of TB is caused by Mtb-lineage-4 and about 35% is attributed to Mtb-lineage-2, recently imported to the region. These heterogeneities affect MTBC infection and treatment outcomes, and should be particularly considered in novel HDT approaches. I will address this from three complementary angles. First, by determining the differential gene expression pathways elicited by sympatric versus allopatric MTBC lineages. Secondly, harness the top express genes to predict the responses to novel HDTs molecules. Thirdly, investigate in-vitro how Gambian and South African monocytes inhibit the growth of allopatric compared to sympatric MTBC lineages in the absence or presence of candidate HDTs molecules and measure the cellular and inflammatory response differences. The K43 will equip me with further skills in Transcriptomics, Bioinformatics, integrated data analysis approaches as well as research leadership to rationally design HDTs trials for different African populations and effectively collaborate with infectious disease medical experts throughout my career. My mentorship team comprises established researchers in TB clinical trials and genomic analysis experts (The Gambia and South Africa mentors) and TB HDT development (US mentor). I will leverage my time between the field research in The Gambia and South Africa and will take advantage of multiple grant-writing workshops available at Emory University to be in an excellent position to submit an R01 application in the fifth year to continue developing HDTs for infectious disease in Africa.
The overall aim of this project is to inform the development of host-directed therapeutics for tuberculosis in Africa where there is epidemiological evidence of differences in disease pattern, bacterial strains and human genetic diversity affecting the outcome of treatment. The results generated from the two African TB-endemic regions will improve our understanding of how new immunomodulatory molecules will work and propose novel host targets for HDT accounting for existing human and bacterial population diversity. This project will provide advanced training to equip Dr. Leopold Tientcheu with skills and competencies in clinical trial designed, transcriptomics and bioinformatics critical to develop HDT for infectious diseases in diverse African population.
