弓形虫毒力分子与其地域分布、基因型、宿主免疫应答以及感染的结局密切相关：宿主感染早期ROP16I/III诱导巨噬细胞(Mφ)向M2极化，虫体快速增殖和播散；而GRA15II使Mφ向M1极化，虫体被杀灭或抑制，宿主进入慢性隐性感染状态。课题组前期发现我国流行的弓形虫Chinese1强毒株（Wh3）和弱毒株（Wh6）中上述两个效应分子具有相同的基因型和表型特征，提示存在着尚未认知的Mφ极化诱导因子。我们发现TgMIF在II型和Wh6弱毒株高表达，并可活化ERK/MAPK和NF-κB通路，诱导Mφ向M1极化，提示TgMIF是又一个重要的效应分子，但机制不明。本研究构建Tgmif敲除虫株和TgMIF慢病毒，体内外研究TgMIF对Mφ极化的影响；采用抑制剂、过表达或shRNA在ERK/MAPK/NF-κB信号途径免疫应答轴中发现关键作用因子，为阐明我国流行的Wh6弱毒株成囊及隐性感染提供一种新机制。

Toxoplasma gondii is a foodborne parasitic protozoon that can infect virtually all warm-blooded animals, including humans. Different strains of Toxoplasma have evolved specific effector molecules to modulate the immune responses of different hosts. The Toxoplasma rhoptry kinase ROP16 carried by type I and III strains, which activates STAT6, drives macrophages to alternative activatied cells (M2); this leads to less inflammation and enhanced parasite survival, but also to a higher mortality rate of hosts. The Toxoplasma dense granule protein GRA15 carried by II strain, which activates NF-κB, drives macrophages toward classical activatied cells (M1); this leads to effective control of acute infection and results in the chronic stage of infection. Our previous study found that these above two effectors in strains with genotype Chinese 1 (the virulent Wh3 strain and the less virulent Wh6 strain) prevalent in China have the same genotype and phenotypic characteristics, suggesting that there are other unknown effector molecules required for macrophage polarization. Our preliminary data indicated that TgMIF, a Toxoplasma ortholog of Macrophage migration Inhibitory Factor, was highly expressed in type II and Chinese 1 Wh6 strains, and activated ERK/MAPK and NF- κ B pathways, inducing macrophages to polarize toward M1. Our results strongly suggested that TgMIF might be another important effector molecule inducing macrophage polarization, but the mechanism of regulating immune response is unclear. The present study will analyze the polarization of macrophages infected with Tgmif knockout transgenic strains, such as ME49mif-/- and Wh6mif-/- strains. In addition, we will uncover the signal pathway and illuminate the mechanism by using recombinant TgMIF viruses and these Tgmif knockout transgenic strains. Using shRNA, over-expression and inhibitors of signal pathway, we will define the related key molecules in ERK/MAPK/NF-κB axis targeted by TgMIF. So far, no relevant approach has been seen. The results will provide a deep insight into the pathogenesis of Toxoplasma genotype Chinese 1(Wh6 strain) prevalent in China and provide important clues to their widespread success in establishing chronic infection.