Abstract

Active tuberculosis causes lung cavities where TB-bacteria grow to high levels. Cavitary TB is more transmissible to others, harder to treat in the patient who has it, and more likely to lead to drug resistance. This proposal will combine an animal model in which TB cavities reproducibly develop with novel radiologic imaging technologies and traditional pharmacologic tools to determine whether the TB cavity serves as a sanctuary site where bacteria may escape high drug concentrations and develop resistance. The last part of the study will determine whether giving immunosuppressive drugs which block cavity development together with antibiotics is useful in accelerating cure in an animal model of TB.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079590-03
Application #
7917381
Study Section
Special Emphasis Panel (ZAI1-DDS-M (M1))
Program Officer
Parker, Tina M
Project Start
2008-08-07
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
3
Fiscal Year
2010
Total Cost
$645,971
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

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
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
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
Luna, Brian; Kubler, André; Larsson, Christer et al. (2015) In vivo prediction of tuberculosis-associated cavity formation in rabbits. J Infect Dis 211:481-5
Kübler, André; Luna, Brian; Larsson, Christer et al. (2015) Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. J Pathol 235:431-44
Hiruy, Hiwot; Rogers, Zoe; Mbowane, Chris et al. (2015) Subtherapeutic concentrations of first-line anti-TB drugs in South African children treated according to current guidelines: the PHATISA study. J Antimicrob Chemother 70:1115-23
Drain, Paul K; Hyle, Emily P; Noubary, Farzad et al. (2014) Diagnostic point-of-care tests in resource-limited settings. Lancet Infect Dis 14:239-49
Almeida, Deepak V; Tyagi, Sandeep; Li, Si-Yang et al. (2014) Revisiting Anti-tuberculosis Activity of Pyrazinamide in Mice. Mycobact Dis 4:145
Foster, Brent; Bagci, Ulas; Ziyue Xu et al. (2014) Segmentation of PET images for computer-aided functional quantification of tuberculosis in small animal models. IEEE Trans Biomed Eng 61:711-24

Showing the most recent 10 out of 25 publications