NK cells contribute to immunity against viral infection, but information on their role in defense against intracellular bacteria is limited. Innate defenses are important in the immune response to Mycobacterium tuberculosis because two-thirds of close contacts of tuberculosis patients remain healthy and have negative tuberculin skin tests. This suggests that innate immunity controls the infection before T cells recognize mycobacterial antigens and mount a delayed type hypersensitivity response. Understanding innate immunity to M. tuberculosis will enhance our capacity to develop vaccines that protect against tuberculosis, including the bioterrorist threat of multidrug-resistant tuberculosis. Recently, we found that NK cells use the NKp46 receptor to lyse M. tuberculosis infected monocytes. This proposal will characterize the mechanisms by which NK cells contribute to innate immunity against M. tuberculosis, through the following aims. 1) Identify novel ligands for NKp46 on M. tuberculosis-infected mononuclear phagocytes. NKp46 ligand(s) will be identified by immunoprecipitation, followed by mass spectrometry. The ligand will be cloned and expressed, allowing production of recombinant protein and antibodies. These tools will be used to confirm the interactions between NKp46 and its ligand(s) in vivo;2) characterize the mechanisms by which NK cells lyse infected mononuclear phagocytes. We will evaluate the mycobacterial factors and effector mechanisms that mediate lysis of infected cells such as Fas, perforin/granzyme and ATP-mediated lysis;3) Delineate the signaling pathways by which NKp46 mediates lysis of M. tuberculosis-Infected mononuclear phagocytes. We will use specific pathway inhibitors, measure enzyme phosphorylation and kinase activity, perform immunoprecipitation and Western blotting, and alter levels of individual signaling molecules through use of viral expression vectors expressing positive or dominant negative constructs;4) Characterize the NK cell subpopulations that mediate lysis of M. tuberculosis-infected mononuclear phagocytes. We will study NK cell subpopulations expressing specific patterns of cell surface markers and cytokines, using multiparameter cell sorting. These studies will provide fundamental information on the innate immune responses and lay the groundwork for development of vaccines that take advantage of the functional capacity of NK cells. These findings will facilitate development of immunomodulatory strategies to boost the immune response to M. tuberculosis, including multidrug-resistant tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054629-05
Application #
7538343
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Parker, Tina M
Project Start
2005-04-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2010-12-31
Support Year
5
Fiscal Year
2009
Total Cost
$255,795
Indirect Cost
Name
University of Texas Health Center at Tyler
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772337
City
Tyler
State
TX
Country
United States
Zip Code
75708
Venkatasubramanian, S; Cheekatla, S; Paidipally, P et al. (2017) IL-21-dependent expansion of memory-like NK cells enhances protective immune responses against Mycobacterium tuberculosis. Mucosal Immunol 10:1031-1042
Cheekatla, Satyanarayana Swamy; Tripathi, Deepak; Venkatasubramanian, Sambasivan et al. (2017) IL-21 Receptor Signaling Is Essential for Optimal CD4+ T Cell Function and Control of Mycobacterium tuberculosis Infection in Mice. J Immunol 199:2815-2822
Venkatasubramanian, Sambasivan; Tripathi, Deepak; Tucker, Torry et al. (2016) Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection. Eur J Immunol 46:464-79
Venkatasubramanian, Sambasivan; Dhiman, Rohan; Paidipally, Padmaja et al. (2015) A rho GDP dissociation inhibitor produced by apoptotic T-cells inhibits growth of Mycobacterium tuberculosis. PLoS Pathog 11:e1004617
Dhiman, Rohan; Venkatasubramanian, Sambasivan; Paidipally, Padmaja et al. (2014) Interleukin 22 inhibits intracellular growth of Mycobacterium tuberculosis by enhancing calgranulin A expression. J Infect Dis 209:578-87
Dhiman, Rohan; Periasamy, Sivakumar; Barnes, Peter F et al. (2012) NK1.1+ cells and IL-22 regulate vaccine-induced protective immunity against challenge with Mycobacterium tuberculosis. J Immunol 189:897-905
Periasamy, Sivakumar; Dhiman, Rohan; Barnes, Peter F et al. (2011) Programmed death 1 and cytokine inducible SH2-containing protein dependent expansion of regulatory T cells upon stimulation With Mycobacterium tuberculosis. J Infect Dis 203:1256-63
Dhiman, Rohan; Bandaru, Anuradha; Barnes, Peter F et al. (2011) c-Maf-dependent growth of Mycobacterium tuberculosis in a CD14(hi) subpopulation of monocyte-derived macrophages. J Immunol 186:1638-45
Barnes, Peter F; Samten, Buka; Shams, Homayoun et al. (2009) Progress in understanding the human immune responses to Mycobacterium tuberculosis. Tuberculosis (Edinb) 89 Suppl 1:S5-9
Paidipally, Padmaja; Periasamy, Sivakumar; Barnes, Peter F et al. (2009) NKG2D-dependent IL-17 production by human T cells in response to an intracellular pathogen. J Immunol 183:1940-5

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