The currently emerging tuberculosis epidemic, when viewed in the context of parallel problems such as emerging drug resistance, and the high susceptibility of HIV-positive individuals, is a great cause for concern. Moreover, at the basic scientific level much is still unknown about the host-parasite relationship, including what specific antigens are recognized to initially trigger host immunity, and the mechanisms underlying the clearly complex T cell-mediated cellular response to Mycobacterium tuberculosis infection. Accordingly, in this competing continuation application, we propose to continue to perform basic research in the mouse infection model in these areas; specifically, the spectrum of antigen recognition by defined T cell subsets, including how this changes during the course of the infection, and continued work into precisely defining the role of such T cell subsets, including the kinetics of their emergence and loss, and their relative contributions to the expression of specific resistance. For the first, we will use methods standardized over the past several years within the Mycobacteria Research Laboratories, CSU, to produce highly purified subcellular fractions of native mycobacterial protein antigens, and then use these fractions in in vitro assays to measure the cytokine response of purified T cell subsets harvested from mice infected with virulent M.tuberculosis. For the second, we will continue previous work under this Program aimed at defining the precise nature of the T cell response, including the expression of protective immunity, DTH, and memory immunity, and the relative contributions of CD4, CD8, and gamma delta T cell subsets to these parameters. In addition, we will investigate the roles of chemokines and cytokines in the regulation of immunity to the infection, using modern RT-PCR technology and the realistic low dose aerosol lung infection model. Finally, the roles of specific cell subsets and cytokines will also be approached using a variety of gene disrupted mouse models, already established as breeding colonies in our laboratory. We anticipate these proposed experiments will provide useful new information regarding the relative roles of T cell subsets in acquired immunity to the infection, the spectrum of T cell subset cytokine production, the antigenic targets of this production, and how these parameters change as the course of the infection progresses from a state of active to quiescent disease. As previously in this Program, the proposed work will draw upon the broad expertise of various members of the Mycobacteria Research Laboratories, CSU, as well as a number of highly qualified consultants/collaborators.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040488-04
Application #
2882215
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Ginsberg, Ann M
Project Start
1996-03-01
Project End
2001-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Ordway, Diane J; Orme, Ian M (2011) Animal models of mycobacteria infection. Curr Protoc Immunol Chapter 19:Unit19.5
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Ordway, Diane; Harton, Marisa; Henao-Tamayo, Marcela et al. (2006) Enhanced macrophage activity in granulomatous lesions of immune mice challenged with Mycobacterium tuberculosis. J Immunol 176:4931-9
Kipnis, Andre; Irwin, Scott; Izzo, Angelo A et al. (2005) Memory T lymphocytes generated by Mycobacterium bovis BCG vaccination reside within a CD4 CD44lo CD62 Ligandhi population. Infect Immun 73:7759-64
Irwin, Scott M; Izzo, Angelo A; Dow, Steven W et al. (2005) Tracking antigen-specific CD8 T lymphocytes in the lungs of mice vaccinated with the Mtb72F polyprotein. Infect Immun 73:5809-16

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