Immune responses in mice lacking STAT-1 in microglia

Toxoplasma gondii is a ubiquitous intracellular protozoan parasite that establishes a life-long chronic infection largely restricted to the central nervous system (CNS). Constant immune pressure, notably IFN-γ-STAT1 signaling, is required for preventing fatal pathology during T. gondii infection. Here, we report that abrogation of STAT1 signaling in microglia, the resident immune cells of the CNS, is sufficient to induce a loss of parasite control in the CNS and susceptibility to toxoplasmic encephalitis during the early stages of chronic infection. Using a microglia-specific genetic labeling and targeting system that discriminates microglia from blood-derived myeloid cells that infiltrate the brain during infection, we find that, contrary to previous in vitro reports, microglia do not express inducible nitric-oxide synthase (iNOS) during T. gondii infection in vivo. Instead, transcriptomic analyses of microglia reveal that STAT1 regulates both (i) a transcriptional shift from homeostat...刚地弓形虫（Toxoplasma gondii）是一种广泛分布的细胞内原生动物寄生虫，可建立几乎终身的慢性感染，且感染范围主要局限于中枢神经系统（CNS）。持续的免疫压力，尤其是干扰素γ（IFN-γ）-信号转导与转录激活因子1（STAT1）信号通路，是防止刚地弓形虫感染期间出现致命病理的必要条件。本研究发现，在中枢神经系统驻留免疫细胞——小胶质细胞中阻断STAT1信号通路，足以在慢性感染早期阶段引发中枢神经系统内寄生虫增殖失控，并使宿主易患弓形虫脑炎。本研究利用可区分感染期间浸润大脑的血液来源髓系细胞与小胶质细胞的小胶质细胞特异性遗传标记与靶向系统，发现与此前体外研究报道相悖的是：体内感染刚地弓形虫时，小胶质细胞并不会表达诱导型一氧化氮合酶（iNOS）。进一步的小胶质细胞转录组学分析显示，STAT1可调控两类转录变化：其一为从稳态向...