Malaria Immunology Laboratory, QIMR Berghofer Institute, Brisbane, Australia.
Eur J Immunol. 2015 Jan;45(1):130-41. doi: 10.1002/eji.201444824. Epub 2014 Nov 13.
Type I IFN signaling suppresses splenic T helper 1 (Th1) responses during blood-stage Plasmodium berghei ANKA (PbA) infection in mice, and is crucial for mediating tissue accumulation of parasites and fatal cerebral symptoms via mechanisms that remain to be fully characterized. Interferon regulatory factor 7 (IRF7) is considered to be a master regulator of type I IFN responses. Here, we assessed IRF7 for its roles during lethal PbA infection and nonlethal Plasmodium chabaudi chabaudi AS (PcAS) infection as two distinct models of blood-stage malaria. We found that IRF7 was not essential for tissue accumulation of parasites, cerebral symptoms, or brain pathology. Using timed administration of anti-IFNAR1 mAb, we show that late IFNAR1 signaling promotes fatal disease via IRF7-independent mechanisms. Despite this, IRF7 significantly impaired early splenic Th1 responses and limited control of parasitemia during PbA infection. Finally, IRF7 also suppressed antiparasitic immunity and Th1 responses during nonlethal PcAS infection. Together, our data support a model in which IRF7 suppresses antiparasitic immunity in the spleen, while IFNAR1-mediated, but IRF7-independent, signaling contributes to pathology in the brain during experimental blood-stage malaria.
I 型干扰素信号在小鼠血期 Plasmodium berghei ANKA (PbA) 感染期间抑制脾辅助性 T 细胞 1 (Th1) 反应，对于通过仍需充分表征的机制介导寄生虫在组织中的积累和致命性脑症状至关重要。干扰素调节因子 7 (IRF7) 被认为是 I 型干扰素反应的主要调节因子。在这里，我们评估了 IRF7 在致死性 PbA 感染和非致死性 Plasmodium chabaudi chabaudi AS (PcAS) 感染期间的作用，这两种感染是两种不同的血期疟疾模型。我们发现 IRF7 对于寄生虫在组织中的积累、脑症状或脑部病理没有必要。通过定时给予抗 IFNAR1 mAb，我们表明晚期 IFNAR1 信号通过 IRF7 非依赖性机制促进致命疾病。尽管如此，IRF7 显著抑制了 PbA 感染期间的早期脾 Th1 反应和寄生虫血症的控制。最后，IRF7 也抑制了非致死性 PcAS 感染期间的抗寄生虫免疫和 Th1 反应。总之，我们的数据支持这样一种模型，即 IRF7 抑制脾中的抗寄生虫免疫，而 IFNAR1 介导的、但 IRF7 非依赖性的信号传导导致实验性血期疟疾中的脑部病理。
