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. Project Description Page 6
