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Investigation of responses to Mycobacterium tuberculosis complex lineages by different African host population: Implications for host-directed therapies

Award Number: K43TW011125
ORGANIZATION: FOGARTY INTERNATIONAL CENTER
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$31,218 )
2025	2022	MEDICAL RESEARCH COUNCIL UNIT THE GAMBIA AT THE LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE	ATLANTIC BOULEVARD	BANJUL				GMB	International Research and Research Training	000	5	10/1/2024	NON-COMPETING CONTINUATION	-$31,218
														Subtotal = -$31,218

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	MEDICAL RESEARCH COUNCIL UNIT THE GAMBIA AT THE LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE	ATLANTIC BOULEVARD	BANJUL				GMB	International Research and Research Training	000	5	1/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $110,841 )
2022	2022	MEDICAL RESEARCH COUNCIL LABORATORIES	MRC UNIT THE GAMBIA AT LSHTM	BANJUL				GMB	International Research and Research Training	000	5	4/12/2022	NON-COMPETING CONTINUATION	$110,841
														Subtotal = $110,841

Issue Date FY: 2021 ( Subtotal = $111,545 )
2021	2021	MEDICAL RESEARCH COUNCIL LABO RATORIES	ATLANTIC ROAD	FAJARA				GMB	International Research and Research Training	000	4	6/28/2021	NON-COMPETING CONTINUATION	$111,545
														Subtotal = $111,545

Issue Date FY: 2020 ( Subtotal = $107,334 )
2020	2020	MEDICAL RESEARCH COUNCIL LABO RATORIES	ATLANTIC ROAD	FAJARA				GMB	International Research and Research Training	000	3	4/30/2020	NON-COMPETING CONTINUATION	$107,334
														Subtotal = $107,334

Issue Date FY: 2019 ( Subtotal = $103,398 )
2019	2019	MEDICAL RESEARCH COUNCIL LABO RATORIES	ATLANTIC ROAD	FAJARA				GMB	International Research and Research Training	001	2	4/29/2019	NON-COMPETING CONTINUATION	$103,398
2019	2018	MEDICAL RESEARCH COUNCIL LABO RATORIES	ATLANTIC ROAD	FAJARA				GMB	International Research and Research Training	000	1	11/21/2018	NEW	$0
														Subtotal = $103,398

Issue Date FY: 2018 ( Subtotal = $106,087 )
2018	2018	MEDICAL RESEARCH COUNCIL LABO RATORIES	ATLANTIC ROAD	FAJARA				GMB	International Research and Research Training	000	1	9/20/2018	NEW	$106,087
														Subtotal = $106,087

Grand Total All Awards = $507,987

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Investigation of responses to Mycobacterium tuberculosis complex lineages by different African host population: Implications for host-directed therapies

Award Number: K43TW011125

ORGANIZATION: FOGARTY INTERNATIONAL CENTER

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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