The purpose of this request for competing continuation funding is to continue our work on dissecting and defining the fundamental nature of the host immune response in the lung after exposure of mice to a realistic low dose aerosol infection with Mycobacterium tuberculosis. While our past work has contributed significantly to the definition of the acquired response, it is now clear that early resistance in the lung to infection is regulated by potentially redundant layers of very poorly understood innate immune mechanisms in addition to the better-characterized TH1 protective response. In the next funding period we propose a series of experiments to define these early mechanisms more clearly using a variety of approaches including flow cytometry, high speed fluorescence-activated cell sorting, histology, and immunohistochemistry. In our first Aim we will continue to try to identify sources of IFN-gamma that appear very early during the course of the infection, concentrating on the role of NK/NKT cell subsets and their potential restriction by Class-Ib MHC encoded molecules. In a second Aim, we propose to continue studies that are constructed to define the basic requirements needed to adequately and efficiently focus lymphocytes into the infected lungs, using a combination of flow cytometric analysis and sorting followed by adoptive transfer of tagged specific T cell subsets and subsequent tracking. Finally, we propose a fresh look at the memory T cell response in tuberculosis, specifically concentrating on parameters such as longevity, turnover, and potential cell surface marker reversion, primarily defined by flow cytometry. The proposed work will draw upon the broad expertise of various members of the Mycobacteria Research Laboratories at Colorado State University, as well as several eminent consultants and advisers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI040488-06A2
Application #
6541350
Study Section
Special Emphasis Panel (ZRG1-BM-1 (04))
Program Officer
Sizemore, Christine F
Project Start
1996-03-01
Project End
2007-05-31
Budget Start
2002-08-01
Budget End
2003-05-31
Support Year
6
Fiscal Year
2002
Total Cost
$280,604
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
Henao-Tamayo, Marcela I; Ordway, Diane J; Irwin, Scott M et al. (2010) Phenotypic definition of effector and memory T-lymphocyte subsets in mice chronically infected with Mycobacterium tuberculosis. Clin Vaccine Immunol 17:618-25
Ordway, Diane; Henao-Tamayo, Marcela; Harton, Marisa et al. (2007) The hypervirulent Mycobacterium tuberculosis strain HN878 induces a potent TH1 response followed by rapid down-regulation. J Immunol 179:522-31
Woolhiser, Lisa; Tamayo, Marcela Henao; Wang, Baolin et al. (2007) In vivo adaptation of the Wayne model of latent tuberculosis. Infect Immun 75:2621-5
Park, Jae Seuk; Tamayo, Marcela Henao; Gonzalez-Juarrero, Mercedes et al. (2006) Virulent clinical isolates of Mycobacterium tuberculosis grow rapidly and induce cellular necrosis but minimal apoptosis in murine macrophages. J Leukoc Biol 79:80-6
Sambandamurthy, Vasan K; Derrick, Steven C; Hsu, Tsungda et al. (2006) Mycobacterium tuberculosis DeltaRD1 DeltapanCD: a safe and limited replicating mutant strain that protects immunocompetent and immunocompromised mice against experimental tuberculosis. Vaccine 24:6309-20
Junqueira-Kipnis, Ana Paula; Basaraba, Randall J; Gruppo, Veronica et al. (2006) Mycobacteria lacking the RD1 region do not induce necrosis in the lungs of mice lacking interferon-gamma. Immunology 119:224-31
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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