Infection by malaria parasites triggers dynamic immune responses leading to diverse symptoms and pathologies; however, the molecular mechanisms responsible for these reactions are largely unknown. We performed Trans-species Expression Quantitative Trait Locus analysis to identify a large number of host genes that respond to malaria parasite infections. Here we functionally characterize one of the host genes called receptor transporter protein 4 (RTP4) in responses to malaria parasite and virus infections. RTP4 is induced by type I IFN (IFN-I) and binds to the TANK-binding kinase (TBK1) complex where it negatively regulates TBK1 signaling by interfering with expression and phosphorylation of both TBK1 and IFN regulatory factor 3. Rtp4^−/− mice were generated and infected with malaria parasite Plasmodiun berghei ANKA. Significantly higher levels of IFN-I response in microglia, lower parasitemia, fewer neurologic symptoms, and better survival rates were observed in Rtp4^−/− than in wild-type mice. Similarly, RTP4 deficiency significantly reduced West Nile virus titers in the brain, but not in the heart and the spleen, of infected mice, suggesting a specific role for RTP4 in brain infection and pathology. This study reveals functions of RTP4 in IFN-I response and a potential target for therapy in diseases with neuropathology.

疟疾寄生虫感染会触发动态免疫反应，导致多种症状和病状。然而，引起这些反应的分子机制在很大程度上尚不清楚。我们进行了跨物种表达定量性状基因座分析，以鉴定对疟原虫感染有反应的大量宿主基因。在这里，我们在功能上表征了响应疟疾寄生虫和病毒感染的宿主基因之一，称为受体转运蛋白4（RTP4）。RTP4由I型IFN（IFN-I）诱导，并与TANK结合激酶（TBK1）复合物结合，在其中它通过干扰TBK1和IFN调节因子3的表达和磷酸化来负调节TBK1信号传导。Rtp4 ^-/-小鼠产生并感染了疟原虫伯氏疟原虫ANKA。与野生型小鼠相比，Rtp4 ^-/-的小胶质细胞中的IFN-I反应水平显着升高，寄生虫血症更低，神经系统症状更少，存活率更高。同样，RTP4缺乏明显降低了感染小鼠的大脑中的西尼罗河病毒滴度，但没有降低心脏和脾脏中的西尼罗河病毒滴度，表明RTP4在脑部感染和病理学中具有特定作用。这项研究揭示了RTP4在IFN-I反应中的功能以及在神经病理疾病中治疗的潜在靶标。