During the first International Research Development Award, Dr. de Jong moved to the Gambia in 2003. Her intention was to identify M. tuberculosis strains particularly well suited for transmission and cavitation; however a fortuitous split between M. africanum and M. tuberculosis allowed her to compare transmission, cavitation, and other phenotypes between two phylogenetically distinct members of the M. tuberculosis complex. This analysis showed that 1) both patients infected with and contacts of M. africanum have a blunted immune responses to Early Secretory Antigen 6 (ESAT-6),which has relevance to the development ? of diagnostic tests and vaccines; 2) M. africanum is more prevalent in HIV infected people, suggesting M. africanum behaves as a more opportunistic infection, 3) M. africanum is less likely to progress to disease in household contacts during the 2 year follow-up. These observations led Dr. de Jong to hypothesize that genetic differences relative to M. tuberculosis result in M. africanum's weakened ability to progress from infection to disease, and that this is compensated by increased persistence due to evasion of the immune response. In turn, she hypothesizes that latent infection with M. africanum provides a degree of immunization against disease with M. tuberculosis. She now proposes to test these hypotheses with studies on differences in the genome and ex vivo ? transcriptome, as well as immunological studies using antigens specific to M. africanum and M. tuberculosis in TB cases and their household contacts. Moreover, she plans to characterize the immune response to M. africanum and M. tuberculosis in more detail. Looking at HIV/TB co-infection, she will correlate the CD4 counts of HIV patients in the Gambia and Guinea- Bissau before and after antitubercular therapy with the mycobacterial genotype cultured from their sputum. This will demonstrate if disease with M. africanum occurs at lower CD4 counts or if it is simply more immunosuppressive. M. africanum infection provides an important model for understanding M. tuberculosis infections. Combining information from the full sequences, the genes preferentially expressed in active infection, and the immuno-epidemiologic data will likely lead to important insights into the pathogenesis of M. tuberculosis infection with relevance to enhancing our tools for the diagnosis and control of this disease. Tuberculosis is caused by any of a group of related bacteria, one of which is very common in West-Africa. The proposed research tries to explain why this bacterium, M. africanum, is more common in HIV infected people, and why a new diagnostic test does not work as well in people with this type of tuberculosis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
2K01TW006083-05A1
Application #
7341783
Study Section
Special Emphasis Panel (ZRG1-ICP2-B (50))
Program Officer
Jessup, Christine
Project Start
2002-09-18
Project End
2010-11-30
Budget Start
2007-12-15
Budget End
2008-11-30
Support Year
5
Fiscal Year
2008
Total Cost
$119,843
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Bold, Tyler D; Davis, Daphne C; Penberthy, Kristen K et al. (2012) Impaired fitness of Mycobacterium africanum despite secretion of ESAT-6. J Infect Dis 205:984-90
de Jong, Bouke C; Adetifa, Ifedayo; Walther, Brigitte et al. (2010) Differences between tuberculosis cases infected with Mycobacterium africanum, West African type 2, relative to Euro-American Mycobacterium tuberculosis: an update. FEMS Immunol Med Microbiol 58:102-5
de Jong, Bouke C; Antonio, Martin; Gagneux, Sebastien (2010) Mycobacterium africanum--review of an important cause of human tuberculosis in West Africa. PLoS Negl Trop Dis 4:e744
de Jong, Bouke C; Hammond, Abdulrahman; Otu, Jacob K et al. (2010) Immunogenicity of antigens from the TbD1 region present in M. africanum and missing from ""modern"" M. tuberculosis: a cross- sectional study. BMC Infect Dis 10:11
de Jong, Bouke C; Antonio, Martin; Awine, Timothy et al. (2009) Use of spoligotyping and large sequence polymorphisms to study the population structure of the Mycobacterium tuberculosis complex in a cohort study of consecutive smear-positive tuberculosis cases in The Gambia. J Clin Microbiol 47:994-1001
Jeffries, David J; Abernethy, Neil; de Jong, Bouke C (2009) Supervised learning for the automated transcription of spacer classification from spoligotype films. BMC Bioinformatics 10:248
de Jong, Bouke C; Hill, Philip C; Aiken, Alex et al. (2008) Progression to active tuberculosis, but not transmission, varies by Mycobacterium tuberculosis lineage in The Gambia. J Infect Dis 198:1037-43
Seale, Anna C; de Jong, Bouke C; Zaidi, Irfan et al. (2008) Effects of cryopreservation on CD4+ CD25+ T cells of HIV-1 infected individuals. J Clin Lab Anal 22:153-8
de Jong, B C; Hill, P C; Aiken, A et al. (2007) Clinical presentation and outcome of tuberculosis patients infected by M. africanum versus M. tuberculosis. Int J Tuberc Lung Dis 11:450-6
de Jong, Bouke C; Hill, Philip C; Brookes, Roger H et al. (2006) Mycobacterium africanum elicits an attenuated T cell response to early secreted antigenic target, 6 kDa, in patients with tuberculosis and their household contacts. J Infect Dis 193:1279-86

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