Immune Regulation In Toxoplasmosis &Opportunistic Infec

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Abstract

Dendritic cell (DC) production of IL-12 is thought to be a major inititiation step in host resistance to Toxoplasma gondii. We had previously shown in an in vivo model that injection of a parasite extract (STAg) results in a burst of IL-12 synthesis followed by a week long perid of unresponsiveness ("paralysis") to STAg re-stimulation. We have now investigated the mechanism underlying paralysis and shown it to be associated with the down-regulation on DC of the chemokine receptor CCR5, previously demonstrated to be necessary for high level IL-12 induction. We went on to show that this CCR5 down-modulation is likely to be due to the induction in the host of the pharmacologic mediator lipoxin A-4 (LXA4) since this molecule is elevated in tissues following STAg injection and inhibits STAg induced IL-12 production by DC in vitro. Moreover, mice deficient in an enzyme (5-LO) important for the generation of LXA4 fail to undergo paralysis when injected with STAg. The above findings, in addition to providing a mechanism for T.gondii induced paralysis, demonstrate a new pathway for the regulation of IL-12 synthesis by DC that could be potentially manipulated to prevent inflammatory disease dependent on that cytokine. One of the mechanisms by which IL-12 is thought to mediate resistance to intracellular infections is by driving the development of IFN-gamma producing Th1 cells. This year we performed experiments indicating that this signal is not obligatory for Th1 differentiation. IL-12 deficient mice given attenuated T. gondii or Mycobacterium avium infections still developed a Th1 dominated CD4+ response profile and in fact displayed resistance to infection when the down-regulatory cytokine IL-10 was also absent. Based on this work we propose that the major function of IL-12 in host resistance is not to determine Th1 (vs Th2) differentiation but to maintain IFN-gamma production in these cells once they have differentiated. In related work we continued our investigation of the role of the 47kDa family of IFN inducible GTPases in host resistance to intracellular infection. We had previously shown that one of these genes IGTP plays a critical and selective role in control of acute T. gondii infection. Examining gene knock-outs for two other members of this family, LRG-47 and IRG-47,we found that LRG-47-deficient mice display decreased resistance to both acute T. gondii and L. monocytogenes infections, while maintaining normal resistance to murine cytomegalovirus (MCMV). Conversely, IRG-47-deficient mice displayed only partially decreased resistance to T. gondii during the chronic phase of infection, and completely normal resistance to L. monocytogenes and MCMV. These findings suggest that the 47kDa family of IFN inducible GTPases may have evolved and diversified to provide specialized IFN-gamma host defense functions against distinct pathogens.