Immune Regulation In Toxoplasmosis And Other Opportunist

Niaid Extramural Activities

Investigators

Linked publications & trials

Abstract

Dendritic cell (DC) production of IL-12 is thought to be a major initiation step in host resistance to Toxoplasma gondii. We had previously shown that T. gondii stimulated IL-12 production depends on the transcription factor ICSBP and in separate work that DC belonging to the CD8 alpha + subset are the major source of the cytokine in spleen following injection of a parasite extract (STAg). This year we discovered that a key reason why ICSBP deficient mice fail to mount IL-12 responses is that they have a defect that prevents the development of CD8 alpha + DC. In work published in January we reported that the eicosinoid LXA4 down-regulates STAg induced IL-12 production by DC. Using 5-LO deficient mice that fail to generate the mediator, we have now shown that LXA4 is a critical regulator of both IL-12 production and immunopathology during natural infection with T.gondii. Our previous work established that the chemokine receptor CCR5 is necessary for high level IL-12 induction by T.gondii and thereby partially controls resistance to infection. This year we discovered that MyD88, an important adaptor molecule for toll-like receptors (TLR) also plays a major role in both the IL-12 response of DC to STAg as well as control of infection and appears to work co-operatively with CCR5 in mediating these effects. A key implication of this work is that TLR are critical elements in the recognition of T. gondii by the innate immune system. In a parallel study, MyD88 was also shown to play an important function in parasite induction of Th1 cells, a role even more crucial than that played by IL-12 itself . Thus, while IL-12 deficient mice exposed to T.gondii still develop a small number of IFN-gamma producing T cells (see last year's report),similarly exposed MyD88 deficient mice not only fail to develop any Th1 cells but default completely to a Th2 pattern. In a related collaborative project with other LPD labs, we have been examining the response of human DC and macrophages to T. gondii as well as other intracellular and extracellular pathogens by means of microarray analysis. In the course of doing this work, we have devised a new algorithm for examining functional relationships between genes expressed in such experiments. The procedure involves the analysis of term occurrence frequencies in Medline abstracts corresponding to each gene expressed and then cross-comparing these frequencies between all of the genes induced in a set. The data mining method not only can reveal previously unrecognized functional relationships between different genes but also by association can suggest possible activities for new genes whose function has not been clearly established.