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.