Tuberculosis (TB) is one of the top infectious causes of death, and a leading cause of death in people with HIV/AIDS, in the world at large. Given these facts, the lack of an effective preventive vaccine, and rising drug resistance, there is a clear need for a better mechanistic understanding of the immunopathogenesis of TB. While protection against the development of active disease is dependent on a competent immune system, immune responses fail to eliminate Mycobacterium tuberculosis (MTb) even in immunocompetent hosts. The vigor of host immune responses are critical determinants of whether an infection persists or is cleared. It has become clear that control of the vigor of immune responses is dependent on counter-regulatory mechanisms. While such mechanisms have been shown to be critical for the maintenance of persistent infection with several pathogens, studies in MTb infection have not provided compelling evidence of a central role for counter-regulatory pathways commonly implicated in modulating immune responses to pathogens. We have shown that the 5-lipoxygenase (LO)-derived anti-inflammatory lipid mediator, lipoxin (LX)A4 plays a biologically important role in restraining protective immune responses to MTb. Our similar findings in mouse models of Toxoplasma gondii infection allowed for initial mechanistic characterization of LXA4 mediated counter-regulation. Such studies have shown that LXs induce expression of the counter-regulatory molecule SOCS-2, and that this intracellular protein mediates the anti-inflammatory actions of LXs in vivo. Novel preliminary data indicate that LX-induced SOCS-2 mediates proteosomal degradation of TRAF-6, a key signal transduction molecule important for both innate and adaptive immune responses. These data suggest the inter-related hypotheses that underlie this proposal, that: (a) LXs play a biologically important role in restraining effective immune responses to MTb;and (b) LX-mediated counter-regulatory activity in TB occurs through SOCS-2-mediated proteosomal degradation of TRAF-6. To test these hypotheses we aim to: (1) Define the role of the 5-LO/lipoxin anti-inflammatory pathway in modulating resistance to MTb;(2) Define the therapeutic potential of modulating LX during MTb infection;and (3) Define the mechanistic role of SOCS-2 in modulating protective immunity during MTb infection.

Public Health Relevance

. Tuberculosis is one the top 3 infectious causes of death in the world at large. Approximately 30% of the world's population is infected with Mycobacterium tuberculosis. Among infected individuals, protection against the development of active tuberculosis is highly dependent on a competent immune system. The production of pro- inflammatory mediators is essential for such protective response. We recently reported that a new class of anti-inflammatory mediators, called lipoxins are produced during experimental tuberculosis in mice and inhibit protective immunity against the bacteria. In the present proposal we aim to understand the cellular and molecular interactions that lead to lipoxin production and their effects on inhibiting the immune system. We also aim here to introduce a possible therapeutic alternative based on pharmacologic inhibition of lipoxin generation. The results to be obtained from this proposal will greatly enhance our knowledge on the cellular and molecular basis from which pathogens evade immune response and persist within hosts as well as provide a novel potential form of treatment against chronic infectious diseases, such as tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI075038-05
Application #
8215622
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Parker, Tina M
Project Start
2008-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$344,148
Indirect Cost
$114,716
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Shryock, Nathaniel; McBerry, Cortez; Salazar Gonzalez, Rosa Maria et al. (2013) Lipoxin Aýýý and 15-epi-lipoxin Aýýý protect against experimental cerebral malaria by inhibiting IL-12/IFN-ýý in the brain. PLoS One 8:e61882
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