Mycobacterium tuberculosis is remarkable in its ability to infect the human host and remain quiescent for many years only to reactivate when host defenses are suppressed. One-third of the global population is latently infected with tuberculosis, yet this clinically inactive state when bacilli are often non- cultivatable is poorly understood and inadequately characterized. Appropriate animal models that more accurately mimic human diseases are needed to test vaccine candidates, and to understand the complex relationship between mycobacteria and host. The currently available animal models in mice and guinea pigs are characterized by multibacillary disease and are distinguished by the host response. Mice mount a poor delayed type hypersensitivity response and develop chronic lung disease, eventually succumbing to a progressive granulomatous pulmonary disease with high bacillary load. Guinea pigs also have a multibacillary disease, but are exquisitely susceptible with rapid hematogenous dissemination and a strong DTH response that results in rapid lung inflammation, destruction and death. Paucibacillary latent disease can only be induced with the administration of antibiotics. In contrast, rabbits are relatively resistant to aerosol infection with M. tuberculosis and mount a granulomatous response that effectively contains the bacilli. Over the course of 6-l2 months, all culturable bacilli disappear. In addition, the histopathologic response is remarkably similar to that of humans pointing to the rabbit model of tuberculosis as a promising avenue by which to study stage-specific changes in both host and bacilli. In this application, we will aerosol infect rabbits and allow the granulomatous lung lesions to regress to latency. With the use of immunosuppressive agents such as corticosteroids, iNOS inhibitors, and specific anti-cytokine antibody, we will reactivate infection. In parallel, we will refine the in vitro granuloma assay using rabbit white blood cells to have an in vitro model with which to correlate and compare our in vivo results. Harvesting serum and rabbit tissue at various stages of infection, we will characterize the stage-specific host humoral and cell-mediated immune responses. Understanding the antibody expression profile during latent disease may lead to important diagnostics in a disease hampered by diagnostics with low sensitivity and specificity. In addition, we will analyze the transcriptional bacterial response to various disease stages using microarrays and RT-PCR with molecular beacons. Finally, we will use a transposon mutant library to identify clones that are impaired in specific stages of infection. Appropriate animal models are critical to the successful development of tuberculosis vaccines, new drugs and better diagnostic tests for tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071554-04
Application #
6892152
Study Section
Special Emphasis Panel (ZAI1-GPJ-M (J1))
Program Officer
Peavy, Hannah H
Project Start
2002-06-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$549,634
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kesavan, Anup K; Brooks, Megan; Tufariello, JoAnn et al. (2009) Tuberculosis genes expressed during persistence and reactivation in the resistant rabbit model. Tuberculosis (Edinb) 89:17-21
Manabe, Yukari C; Breen, Ronan; Perti, Tara et al. (2009) Unmasked tuberculosis and tuberculosis immune reconstitution inflammatory disease: a disease spectrum after initiation of antiretroviral therapy. J Infect Dis 199:437-44
Mendez, Susana; Hatem, Christine L; Kesavan, Anup K et al. (2008) Susceptibility to tuberculosis: composition of tuberculous granulomas in Thorbecke and outbred New Zealand White rabbits. Vet Immunol Immunopathol 122:167-74
Manabe, Yukari C; Kesavan, Anup K; Lopez-Molina, Javier et al. (2008) The aerosol rabbit model of TB latency, reactivation and immune reconstitution inflammatory syndrome. Tuberculosis (Edinb) 88:187-96
Manabe, Yukari C; Campbell, James D; Sydnor, Emily et al. (2007) Immune reconstitution inflammatory syndrome: risk factors and treatment implications. J Acquir Immune Defic Syndr 46:456-62
Helke, Kris L; Mankowski, Joseph L; Manabe, Yukari C (2006) Animal models of cavitation in pulmonary tuberculosis. Tuberculosis (Edinb) 86:337-48
Kesavan, Anup K; Mendez, Susana E; Hatem, Christine L et al. (2005) Effects of dexamethasone and transient malnutrition on rabbits infected with aerosolized Mycobacterium tuberculosis CDC1551. Infect Immun 73:7056-60
Manabe, Yukari C; Hatem, Christine L; Kesavan, Anup K et al. (2005) Both Corynebacterium diphtheriae DtxR(E175K) and Mycobacterium tuberculosis IdeR(D177K) are dominant positive repressors of IdeR-regulated genes in M. tuberculosis. Infect Immun 73:5988-94
Dorman, Susan E; Hatem, Christine L; Tyagi, Sandeep et al. (2004) Susceptibility to tuberculosis: clues from studies with inbred and outbred New Zealand White rabbits. Infect Immun 72:1700-5
Dannenberg Jr, Arthur M (2003) Macrophage turnover, division and activation within developing, peak and ""healed"" tuberculous lesions produced in rabbits by BCG. Tuberculosis (Edinb) 83:251-60

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