Cross-regulation of host STATs for the survival of Toxoplasma gondii

초록

Toxoplasma gondii is an obligate intracellular protozoan parasite and well known as an important zoonotic and opportunistic pathogen. T. gondii infects macrophages primarily and is capable of penetrating and growing within almost all nucleated host cells. By the infection, macrophages are exposed to IFN-secreted from neighboring cells of the immune network after the IL-12 stimulation from the infected macrophages, which act to kill the intracellular pathogen through STAT1 (signal transducer and activator of transcription 1). But, IFN-does not control intracellular growth of T. gondii completely, so once the cells are infected first, subsequent exposure to IFN-is unable to control the infection and the parasite grows normally. This enables to presume a certain cytokine cross-regulation or STAT cross-regulation within the infected cells. Actually, T. gondii infection autonomously phosphorylates STAT6 to translocate into the nucleus of the host cells without IL-4 stimulation and that the STAT6 activation controls the effects of IFN- to kill the intracellular parasites. Therefore, T. gondii inside the host cells overcomes the lethal trap casted by STAT1 activation from outside IFN-stimulation with STAT6 activation of host cells without exogenous IL-4, that is, the cross-regulation in STAT level rather than cytokine level. Activation of STAT6 in T. gondii-infected macrophages also enhances the expression of genes for two large clusters of serine protease inhibitors (SERPIN B3 and B4) and C-C chemokine ligands (CCL1, 2, 8, 13, and 22), the former for intracellular action of protease inhibition and the later for more Th2 environment to favor the intracellular growth and proliferation. These implicates that STAT6 is the master regulator of the host cell gene expressions to arrange the favorite place for the intracellular parasite.