Abstract

Asymptomatic mycobacterial infections are characterized by the presence of very few bacilli which are difficult to find, may not be acid-fast, and may not be culturable. These bacilli have been proposed to persist within closed airways of the mammalian lung under what have been described as microaerophilic or anaerobic conditions. We have begun characterizing the biochemical changes which accompany the adaptation to microaerophilic survival and replication. We have shown that the mycobacterial a-crystallin protein is specifically expressed during stationary-phase and under low-oxygen conditions in virulent mycobacterial strains. This protein was overexpressed and purified and shown to have ATP-independent chaperone function and to provide protection from autolysis to aging bacteria. Targeted gene replacement was used to create a genetic knockout of the alpha crystallin protein in virulent MTB and the resulting strain shows dramatically decreased abilities in growth and replication in macrophage models of infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000783-02
Application #
6099099
Study Section
Special Emphasis Panel (LHD)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
National Institute of Allergy and Infectious Diseases
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Boshoff, Helena I M; Lun, Desmond S (2010) Systems biology approaches to understanding mycobacterial survival mechanisms. Drug Discov Today Dis Mech 7:e75-e82
Boshoff, Helena I; Tahlan, Kapil (2010) Mechanisms underlying mycobacterial infections. Drug Discov Today Dis Mech 7:e1-e3
Eum, Seok-Yong; Kong, Ji-Hye; Hong, Min-Sun et al. (2010) Neutrophils are the predominant infected phagocytic cells in the airways of patients with active pulmonary TB. Chest 137:122-8
Samuel, Linoj P; Song, Chang-Hwa; Wei, Jun et al. (2007) Expression, production and release of the Eis protein by Mycobacterium tuberculosis during infection of macrophages and its effect on cytokine secretion. Microbiology 153:529-40
Reed, Michael B; Gagneux, Sebastien; Deriemer, Kathryn et al. (2007) The W-Beijing lineage of Mycobacterium tuberculosis overproduces triglycerides and has the DosR dormancy regulon constitutively upregulated. J Bacteriol 189:2583-9
Barry, Clifton E; Crick, Dean C; McNeil, Michael R (2007) Targeting the formation of the cell wall core of M. tuberculosis. Infect Disord Drug Targets 7:182-202
Manjunatha, Ujjini H; Boshoff, Helena; Dowd, Cynthia S et al. (2006) Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 103:431-6
Azhikina, Tatyana; Gvozdevsky, Nikolay; Botvinnik, Anna et al. (2006) A genome-wide sequence-independent comparative analysis of insertion-deletion polymorphisms in multiple Mycobacterium tuberculosis strains. Res Microbiol 157:282-90
Goodwin, Michael B; Boshoff, Helena I; Barry 3rd, Clifton E et al. (2006) Quantification of small molecule organic acids from Mycobacterium tuberculosis culture supernatant using ion exclusion liquid chromatography/mass spectrometry. Rapid Commun Mass Spectrom 20:3345-50
Manjunatha, Ujjini H; Lahiri, Ramanuj; Randhawa, Baljit et al. (2006) Mycobacterium leprae is naturally resistant to PA-824. Antimicrob Agents Chemother 50:3350-4

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