1. DTBEInvestigation of drug resistance and host-pathogen interactions of Mycobacterium tuberculosis
J. E. Posey Mycobacterium tuberculosis, the causative agent of TB, is responsible for approximately two million deaths each year, and more than one third of the world’s population is infected with M. tuberculosis.With the emergence of multi drug (MDR) and recently extensively drug (XDR) resistant strains of M. tuberculosis, the development of a better vaccine and identification of new targets for developments of new antimycobacterial drugs is crucial.Our laboratory identifies and investigates novel mechanisms of of resistance to second line drugs such as kanamycin, capreomycin and fluoroquinolones.One technique used to detect these novel resistance mechanisms is whole genome sequencing.Once a new mechanism is characterized, we can then design molecular tests to quickly identify drug resistant strains of M. tuberculosis.We also use the latest genetic tools available to study the host-pathogen interaction and the immune response to M. tuberculosis to aid in the design of better vaccines to prevent the disease.We are currently characterizing a specific 26 kb deletion in a sublineage of M. tuberculosis that seems to cause more severe cavitary disease than strains that harbor these genes.We are performing functional genetic studies to determine the role of these genes in the pathogenesis of the bacteria. References Ramirez MV, Cowart K, Campbell P, Morlock GP, Sikes D, Winchell J, Posey JE.2010.Rapid detection of multidrug resistant tuberculosis using real-time PCR and high resolution melt analysis.J Clin. Microbiol.48(11): Zaunbrecher MA, Sikes D, Metchock B, Shinnick TM, Posey JE.2009.Overexpression of a chromosomally encoded aminoglycoside acetyltransferase confers kanamycin resistance in Mycobacterium tuberculosis.Proc. Natl. Acad. Sci. USA. 106(47):20004-9
Starks AM, Gumusboga A, Plikaytis BB, Shinnick TM, Posey JE.2009.Mutations at embB codon 306 are an important molecular indicator of ethambutol resistance in Mycobacterium tuberculosis.Antimicrob. Agents Chemother.53(3): 1061-1066. Posey JE, Shinnick TM, and Quinn FD.2005.Characterization of the Twin Arginine Translocase (TAT) System in Mycobacterium smegmatis.J. Bacteriol.188(4):1332-1340.
2. DTBE Immunology and Cell biology of Mycobacterium tuberculosis Infections and Development of New Generation Vaccines
S. B. Sable Development and evaluation of new generation prophylactic, post-exposure and therapeutic vaccines is urgently needed for the effective control of global tuberculosis pandemic. The current and proposed focus areas of immunology activity include:1. Development of new generation mucosal vaccine against tuberculosis; 2. Evaluation of quality and magnitude of local T-cell response and identification of correlates of protection in the lungs; and 3. Protective efficacy of BCG and second generation vaccines against different M. tuberculosis families/clades prevalent in different parts of the world. References
Sable SB, Plikaytis BB, Shinnick TM. Tuberculosis Subunit Vaccine Development: Impact of Physicochemical Properties of Mycobacterial Test Antigens. Vaccine. 2007 Feb 19; 25(9):1553-66. Sable SB, Kalra M, Verma I, Khuller GK. Tuberculosis subunit vaccine design and the conflict of antigenicity and immunogenicity. Clin. Immunol. 2007 Mar; 122(3):239-51.