BACKGROUND: Tuberculosis (TB) leads to the death of 1.7 million people annually. The failure of the bacille Calmette-Guérin vaccine, synergy between AIDS and TB, and the emergence of drug resistance have worsened this situation. It is imperative to delineate the mechanisms employed by Mycobacterium tuberculosis to successfully infect and persist in mammalian lungs. METHODS: Nonhuman primates (NHPs) are arguably the best animal system to model critical aspects of human TB. We studied genes essential for growth and survival of M. tuberculosis in the lungs of NHPs experimentally exposed to aerosols of an M. tuberculosis transposon mutant library. RESULTS: Mutants in 108 M. tuberculosis genes (33.13% of all genes tested) were attenuated for in vivo growth. Comparable studies have reported the attenuation of only approximately 6% of mutants in mice. The M. tuberculosis mutants attenuated for in vivo survival in primates were involved in the transport of various biomolecules, including lipid virulence factors; biosynthesis of cell-wall arabinan and peptidoglycan; DNA repair; sterol metabolism; and mammalian cell entry. CONCLUSIONS: Our study highlights the various virulence mechanisms employed by M. tuberculosis to overcome the hostile environment encountered during infection of primates. Prophylactic approaches aimed against bacterial factors that respond to such in vivo stressors have the potential to prevent infection at an early stage, thus likely reducing the extent of transmission of M. tuberculosis.
BACKGROUND:Tuberculosis (TB) leads to the death of 1.7 million people annually. The failure of the bacille Calmette-Guérin vaccine, synergy between AIDS and TB, and the emergence of drug resistance have worsened this situation. It is imperative to delineate the mechanisms employed by Mycobacterium tuberculosis to successfully infect and persist in mammalian lungs. METHODS: Nonhuman primates (NHPs) are arguably the best animal system to model critical aspects of humanTB. We studied genes essential for growth and survival of M. tuberculosis in the lungs of NHPs experimentally exposed to aerosols of an M. tuberculosis transposon mutant library. RESULTS: Mutants in 108 M. tuberculosis genes (33.13% of all genes tested) were attenuated for in vivo growth. Comparable studies have reported the attenuation of only approximately 6% of mutants in mice. The M. tuberculosis mutants attenuated for in vivo survival in primates were involved in the transport of various biomolecules, including lipid virulence factors; biosynthesis of cell-wall arabinan and peptidoglycan; DNA repair; sterol metabolism; and mammalian cell entry. CONCLUSIONS: Our study highlights the various virulence mechanisms employed by M. tuberculosis to overcome the hostile environment encountered during infection of primates. Prophylactic approaches aimed against bacterial factors that respond to such in vivo stressors have the potential to prevent infection at an early stage, thus likely reducing the extent of transmission of M. tuberculosis.
Authors: Robert Van der Geize; Katherine Yam; Thomas Heuser; Maarten H Wilbrink; Hirofumi Hara; Matthew C Anderton; Edith Sim; Lubbert Dijkhuizen; Julian E Davies; William W Mohn; Lindsay D Eltis Journal: Proc Natl Acad Sci U S A Date: 2007-01-30 Impact factor: 11.205
Authors: Sanjay K Jain; S Moises Hernandez-Abanto; Qi-Jian Cheng; Prabhpreet Singh; Lan H Ly; Lee G Klinkenberg; Norman E Morrison; Paul J Converse; Eric Nuermberger; Jacques Grosset; David N McMurray; Petros C Karakousis; Gyanu Lamichhane; William R Bishai Journal: J Infect Dis Date: 2007-04-23 Impact factor: 5.226
Authors: Suzana Savvi; Digby F Warner; Bavesh D Kana; John D McKinney; Valerie Mizrahi; Stephanie S Dawes Journal: J Bacteriol Date: 2008-03-28 Impact factor: 3.490
Authors: Ashwani Kumar; Jose C Toledo; Rakesh P Patel; Jack R Lancaster; Adrie J C Steyn Journal: Proc Natl Acad Sci U S A Date: 2007-07-03 Impact factor: 11.205
Authors: Chad J Roy; Satheesh K Sivasubramani; Noton K Dutta; Smriti Mehra; Nadia A Golden; Stephanie Killeen; James D Talton; Badre E Hammoud; Peter J Didier; Deepak Kaushal Journal: Antimicrob Agents Chemother Date: 2011-12-05 Impact factor: 5.191
Authors: Smriti Mehra; Nadia A Golden; Kerstan Stuckey; Peter J Didier; Lara A Doyle; Kasi E Russell-Lodrigue; Chie Sugimoto; Atsuhiko Hasegawa; Satheesh K Sivasubramani; Chad J Roy; Xavier Alvarez; Marcelo J Kuroda; James L Blanchard; Andrew A Lackner; Deepak Kaushal Journal: J Infect Dis Date: 2012-03-07 Impact factor: 5.226
Authors: Alan Williams; Carolin Güthlein; Nicola Beresford; Erik C Böttger; Burkhard Springer; Elaine O Davis Journal: J Bacteriol Date: 2011-07-01 Impact factor: 3.490
Authors: Malabika Sarker; Carolyn Talcott; Peter Madrid; Sidharth Chopra; Barry A Bunin; Gyanu Lamichhane; Joel S Freundlich; Sean Ekins Journal: Pharm Res Date: 2012-04-04 Impact factor: 4.200
Authors: Smriti Mehra; Xavier Alvarez; Peter J Didier; Lara A Doyle; James L Blanchard; Andrew A Lackner; Deepak Kaushal Journal: J Infect Dis Date: 2012-12-18 Impact factor: 5.226