Abstract

This application proposes the functional characterization of mycobacterial sigma factors which the PI believes will be vital in facilitating regulated, rapid responses to the changing environments experienced by the bacilli during the course of their life cycle. The application is a continuation of an R29 award during which the PI identified sigma F (sigF) as an important regulator of loci implicated in stress and infection maintenance. Scanning of the MycD database reveals 13 putative sigma factors of which 10 are of the extracytoplasmic function group which in other systems have been shown to regulate cell wall synthesis pathways and protein secretion. The PI proposes to extend his studies by knocking out all of these sigma factors in both MTB and MAC. The knockouts will be characterized for both in vitro and in vivo phenotypes and the identity of sigma factor-dependent genes will be determined by microarray studies conducted on the knockout strains.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036973-07
Application #
6169974
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Sizemore, Christine F
Project Start
1994-09-30
Project End
2004-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
7
Fiscal Year
2000
Total Cost
$275,569
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Ihms, Elizabeth A; Urbanowski, Michael E; Bishai, William R (2018) Diverse Cavity Types and Evidence that Mechanical Action on the Necrotic Granuloma Drives Tuberculous Cavitation. Am J Pathol 188:1666-1675
Amaral, Eduardo P; Riteau, Nicolas; Moayeri, Mahtab et al. (2018) Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages. Front Immunol 9:1427
Dey, Ruchi Jain; Dey, Bappaditya; Zheng, Yue et al. (2017) Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase. Nat Chem Biol 13:210-217
Gupta, Shashank; Winglee, Kathryn; Gallo, Richard et al. (2017) Bacterial subversion of cAMP signalling inhibits cathelicidin expression, which is required for innate resistance to Mycobacterium tuberculosis. J Pathol 242:52-61
Maiga, Mamoudou; Cohen, Keira; Baya, Bocar et al. (2016) Stool microbiome reveals diverse bacterial ureases as confounders of oral urea breath testing for Helicobacter pylori and Mycobacterium tuberculosis in Bamako, Mali. J Breath Res 10:036012
Ahidjo, Bintou A; Maiga, Mariama C; Ihms, Elizabeth A et al. (2016) The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis. JCI Insight 1:e86017
Kubler, Andre; Larsson, Christer; Luna, Brian et al. (2016) Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis. J Infect Dis 213:618-27
Rogers, Zoe; Hiruy, Hiwot; Pasipanodya, Jotam G et al. (2016) The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism. EBioMedicine 11:118-126
Winglee, Kathryn; Manson McGuire, Abigail; Maiga, Mamoudou et al. (2016) Whole Genome Sequencing of Mycobacterium africanum Strains from Mali Provides Insights into the Mechanisms of Geographic Restriction. PLoS Negl Trop Dis 10:e0004332
Gupta, Shashank; Tyagi, Sandeep; Bishai, William R (2015) Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model. Antimicrob Agents Chemother 59:673-6

Showing the most recent 10 out of 52 publications