Tuberculosis (TB) chemotherapy often fails to sterilize Mycobacterium tuberculosis (Mtb) resulting in individuals at risk of relapse TB. The mechanisms that allow Mtb to survive during paucibacillary persistent TB infections are for the most part unknown. Drug treatment and silencing of in vivo essential genes can cure acute and chronic Mtb infections in mice to the extent that CFU can no longer be detected on agar plates. However, as in humans, Mtb in these mice is often not sterilized and paucibacillary persistence eventually results in relapse of TB. We propose to develop a new animal model of paucibacillary persistence and use this model to identify the processes that Mtb requires to persist following apparent eradication. The proposed experiments will increase understanding of the mechanisms leading to paucibacillary persistence and will establish a model for studying paucibacillary disease and relapse in mice.
Tuberculosis (TB) is the world's second leading cause of premature human death from an infectious disease. Work outlined in this proposal will increase our understanding of the mechanisms leading to paucibacillary persistence of M. tuberculosis and has the potential to contribute to the development of new TB drugs, and ultimately help reducing the impact of this disease on global health.
|Ocheretina, Oksana; Byrt, Erin; Mabou, Marie-Marcelle et al. (2016) False-positive rifampin resistant results with Xpert MTB/RIF version 4 assay in clinical samples with a low bacterial load. Diagn Microbiol Infect Dis 85:53-5|
|Warrier, Thulasi; Kapilashrami, Kanishk; Argyrou, Argyrides et al. (2016) N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 113:E4523-30|
|Glickman, Michael S; Schluger, Neil (2016) Adding Insult to Injury: Exacerbating TB Risk with Smoking. Cell Host Microbe 19:432-3|
|Gold, Ben; Smith, Robert; Nguyen, Quyen et al. (2016) Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis. J Med Chem 59:6027-44|
|Lupoli, Tania J; Fay, Allison; Adura, Carolina et al. (2016) Reconstitution of a Mycobacterium tuberculosis proteostasis network highlights essential cofactor interactions with chaperone DnaK. Proc Natl Acad Sci U S A 113:E7947-E7956|
|Nathan, Carl (2015) What can immunology contribute to the control of the world's leading cause of death from bacterial infection? Immunol Rev 264:2-5|
|Nathan, Carl; Barry 3rd, Clifton E (2015) TB drug development: immunology at the table. Immunol Rev 264:308-18|
|Ocheretina, Oksana; Shen, Lishuang; Escuyer, Vincent E et al. (2015) Whole Genome Sequencing Investigation of a Tuberculosis Outbreak in Port-au-Prince, Haiti Caused by a Strain with a ""Low-Level"" rpoB Mutation L511P - Insights into a Mechanism of Resistance Escalation. PLoS One 10:e0129207|
|Gold, Ben; Roberts, Julia; Ling, Yan et al. (2015) Rapid, Semiquantitative Assay To Discriminate among Compounds with Activity against Replicating or Nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother 59:6521-38|
|Severe, Linda; Fitzgerald, Daniel W; Deschamps, Marie M et al. (2014) ""I am proud of myself, just the way I am"" (Mwen fyÃ© de tÃ©t mwen, jan mwen ye ya): a qualitative study among young Haitian women seeking care for sexually transmitted infections (STIs) in Haiti. AIDS Educ Prev 26:158-69|