Tuberculosis (TB) remains a public health problem in resource-limited settings such as Mali, West Africa. In 2011, WHO estimated the prevalence, incidence and mortality from TB in Mali was 90, 62 and 9 per 100,000 population. There is considerable variability in the outcome of Mycobacterium tuberculosis complex (MTBC) infection which has been traditionally attributed to host and environmental factors. MTBC is composed of 8 subspecies. Clinical TB disease in humans is caused mainly by M tuberculosis and M africanum. Recently, we identified by spoligotyping that M africanum and M tuberculosis are the most prevalent strains in Mali as they are throughout West Africa, respectively accounting for 27.8 and 71.4% of TB cases. In humans, both species transmit equally well to household contacts, however M africanum is less likely to progress to clinical disease, less likely to be multidrug resistant, and patients with disease are more likely to be malnourished, older, or have co-infection with HIV, suggesting it has a preference for hosts with certain genetic backgrounds and/or with impaired immunity. The immune response to TB is complex and not yet characterized completely which is making it difficult to develop new vaccines and drugs. Taken altogether, the fact that M africanum has not spread beyond West Africa, that it has decreased virulence in vivo, and has predilection for immuno-compromised individuals, strongly suggests that it is a failing pathogen on a global level. A research strategy that investigates host immune responses with pathogen factors may reveal critical aspects of host immunity and mycobacterial pathogenicity.
The specific aims of this project are: 1) test a model of sympatric TB, based on associations of specific HLA alleles and bacterial strain-dependent T cell epitope sequences;2) characterize human phenotypic consequences from loss of cAMP intoxication virulence mechanism in M africanum, reductions in TNF-? and antimicrobial peptide expression;and 3) identify host transcriptomic factors that differentiate active infection with M tuberculosis from M africanum. Professor Diallo, head of the TB program in Mali, and the SEREFO Laboratory team at the University of Bamako are highly qualified to lead this proposal. SEREFO was established in 2005 by National Institutes of Allergy and Infectious Diseases (NIAID) under the direction of Dr. Cliff Lane. The program has become an NIAID International Center for the Excellence in Research (ICER) and is supported by extramural programs including the University of Maryland BMP Project, International Network for Strategic Initiatives in Global Health (INSIGHT-the START Study), the International Center for Malaria Research (ICEMRS) and the AIDS Clinical Trials Group (ACTG). The Fogarty International Center/NIH has trained many of the research staff through its AIDS International Training and Research Program (AITRP) based at Northwestern University. Other key collaborators include Johns Hopkins University, New York University, the Howard Hughes Medical Institute. The overarching intent of this project will advance the development of local scientific expertise, build local research infrastructure and increase collaborative research partnerships in Mali.

Public Health Relevance

Human tuberculosis in West Africa is caused by Mycobacterium tuberculosis and M africanum, however there is considerable variability in the outcome of clinical infection. A research strategy that investigates specific host immune responses with pathogen factors may reveal critical aspects of host immunity and mycobacterial pathogenicity which may lead to the development of better vaccines and anti- tuberculosis drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI110386-01
Application #
8664215
Study Section
Special Emphasis Panel (ZRG1-IDM-R (54))
Program Officer
Lacourciere, Karen A
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$152,391
Indirect Cost
$11,288
Name
University of Bamako
Department
Type
DUNS #
565539819
City
Bamako
State
Country
Mali
Zip Code
BP E2-528
Diarra, Bassirou; Kone, Mahamadou; Togo, Antieme Combo Georges et al. (2018) Mycobacterium africanum (Lineage 6) shows slower sputum smear conversion on tuberculosis treatment than Mycobacterium tuberculosis (Lineage 4) in Bamako, Mali. PLoS One 13:e0208603
Kone, B; Sarro, Y S; Maiga, M et al. (2018) Clinical characteristics of non-tuberculous mycobacterial pulmonary infections in Bamako, Mali. Epidemiol Infect 146:354-358
Kone, Amadou; Diarra, Bassirou; Cohen, Keira et al. (2018) Differential HLA allele frequency in Mycobacterium africanum vs Mycobacterium tuberculosis in Mali. HLA :
Manson, Abigail L; Cohen, Keira A; Abeel, Thomas et al. (2017) Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance. Nat Genet 49:395-402
Togo, Antieme Combo Georges; Kodio, Ousmane; Diarra, Bassirou et al. (2017) The most frequent Mycobacterium tuberculosis complex families in mali (2006-2016) based on spoligotyping. Int J Mycobacteriol 6:379-386
Sanogo, M; Kone, B; Diarra, B et al. (2017) Performance of microscopic observation drug susceptibility for the rapid diagnosis of tuberculosis and detection of drug resistance in Bamako, Mali. Clin Microbiol Infect 23:408.e1-408.e6
Diarra, Bassirou; Toloba, Yacouba; Konate, Bakary et al. (2017) Extensively drug resistant tuberculosis in Mali: a case report. BMC Res Notes 10:561
Diarra, B; Goita, D; Tounkara, S et al. (2016) Tuberculosis drug resistance in Bamako, Mali, from 2006 to 2014. BMC Infect Dis 16:714
Maiga, Mamoudou; Cohen, Keira; Baya, Bocar et al. (2016) Stool microbiome reveals diverse bacterial ureases as confounders of oral urea breath testing for Helicobacter pylori and Mycobacterium tuberculosis in Bamako, Mali. J Breath Res 10:036012
Koita, Ousmane A; Murphy, Robert L; Fongoro, Saharé et al. (2016) Clinical Research and the Training of Host Country Investigators: Essential Health Priorities for Disease-Endemic Regions. Am J Trop Med Hyg 94:253-7

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