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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Weill Medical College of Cornell University
New York
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Namasivayam, Sivaranjani; Maiga, Mamoudou; Yuan, Wuxing et al. (2017) Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy. Microbiome 5:71
Botella, Laure; Vaubourgeix, Julien; Livny, Jonathan et al. (2017) Depleting Mycobacterium tuberculosis of the transcription termination factor Rho causes pervasive transcription and rapid death. Nat Commun 8:14731
Salerno Jr, Stephen; Mehrmohamadi, Mahya; Liberti, Maria V et al. (2017) RRmix: A method for simultaneous batch effect correction and analysis of metabolomics data in the absence of internal standards. PLoS One 12:e0179530
Hartman, Travis E; Wang, Zhe; Jansen, Robert S et al. (2017) Metabolic Perspectives on Persistence. Microbiol Spectr 5:
Saito, Kohta; Warrier, Thulasi; Somersan-Karakaya, Selin et al. (2017) Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations. Proc Natl Acad Sci U S A 114:E4832-E4840
Eoh, Hyungjin; Wang, Zhe; Layre, Emilie et al. (2017) Metabolic anticipation in Mycobacterium tuberculosis. Nat Microbiol 2:17084
Wipperman, Matthew F; Fitzgerald, Daniel W; Juste, Marc Antoine Jean et al. (2017) Antibiotic treatment for Tuberculosis induces a profound dysbiosis of the microbiome that persists long after therapy is completed. Sci Rep 7:10767
Jansen, Robert S; Rhee, Kyu Y (2017) Emerging Approaches to Tuberculosis Drug Development: At Home in the Metabolome. Trends Pharmacol Sci 38:393-405
Nathan, Carl (2017) Kunkel Lecture: Fundamental immunodeficiency and its correction. J Exp Med 214:2175-2191
Hsu, Hao-Chi; Singh, Pradeep K; Fan, Hao et al. (2017) Structural Basis for the Species-Selective Binding of N,C-Capped Dipeptides to the Mycobacterium tuberculosis Proteasome. Biochemistry 56:324-333

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