Tuberculosis remains a devastating disease of mankind resulting in 3 million deaths per year. There are 10 million new cases of tuberculosis worldwide, and for the first time after a 32 year decline, the number of new cases of tuberculosis in the United States has increased for the last 3 years. In New York city alone, there was a 36% rise in the number of tuberculosis cases, predominantly in the black and hispanic populations. This rise of tuberculosis is most likely associated with the increase in AIDS patients and so is still likely to worsen. M. avium infections are a primary cause of fatality of AIDS patients. Although, M. tuberculosis, the causative agent of tuberculosis, is one of earliest described pathogens of man, analysis of this organism or any other mycobacterium by genetic means has been previously impossible. The goal of this proposal is to develop the systems and methodology, using modern recombinant DNA technology, to permit genetic analysis of the mycobacteria. By developing the first efficient transfection system and a novel E. coli-mycobacteria shuttle vector, we have introduced recombinant DNA molecules into both M. smegmatis and BCG vaccine strains for the first time. This novel vector, termed a shuttle plasmid, replicates in mycobacteria as a phage and in E. coli as a plasmid. This vector has been successfully used to introduce and stably express the first selectable marker gene for mycobacteria genetic research. We plan to use these genetic approaches to analyze the pathogenesis of mycobacteria, which could lead to new avenues for drug design. These methods will contribute to the development of BCG, currently the most widely used vaccine in the world, into a recombinant multivaccine vehicle, which would provide a novel approach to development of vaccines where T cell memory and effector responses are important.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Unknown (R22)
Project #
1R22AI026170-01A1
Application #
3565515
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1988-12-01
Project End
1993-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Tufariello, JoAnn M; Chapman, Jessica R; Kerantzas, Christopher A et al. (2016) Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence. Proc Natl Acad Sci U S A 113:E348-57
Vilchèze, Catherine; Leung, Lawrence W; Bittman, Robert et al. (2016) Synthesis and biological activity of alkynoic acids derivatives against mycobacteria. Chem Phys Lipids 194:125-38
Wong, Ka-Wing; Jacobs Jr, William R (2016) Postprimary Tuberculosis and Macrophage Necrosis: Is There a Big ConNECtion? MBio 7:e01589-15
Noy, Tahel; Vergnolle, Olivia; Hartman, Travis E et al. (2016) Central Role of Pyruvate Kinase in Carbon Co-catabolism of Mycobacterium tuberculosis. J Biol Chem 291:7060-9
Tufariello, JoAnn M; Kerantzas, Christopher A; Vilchèze, Catherine et al. (2015) The Complete Genome Sequence of the Emerging Pathogen Mycobacterium haemophilum Explains Its Unique Culture Requirements. MBio 6:e01313-15
Zolla, Valerio; Nizamutdinova, Irina Tsoy; Scharf, Brian et al. (2015) Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis, and pathogen clearance. Aging Cell 14:582-94
Packiam, Mathanraj; Weinrick, Brian; Jacobs Jr, William R et al. (2015) Structural characterization of muropeptides from Chlamydia trachomatis peptidoglycan by mass spectrometry resolves ""chlamydial anomaly"". Proc Natl Acad Sci U S A 112:11660-5
Berney, Michael; Berney-Meyer, Linda; Wong, Ka-Wing et al. (2015) Essential roles of methionine and S-adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 112:10008-13
Ojha, Anil K; Jacobs Jr, William R; Hatfull, Graham F (2015) Genetic dissection of mycobacterial biofilms. Methods Mol Biol 1285:215-26
Pope, Welkin H; Jacobs-Sera, Deborah; Russell, Daniel A et al. (2014) Genomics and proteomics of mycobacteriophage patience, an accidental tourist in the Mycobacterium neighborhood. MBio 5:e02145

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