背景:I型干扰素(IFN-I),由多个调节器精确控制,包括细胞因子信号抑制因子1(SOCS1),对于宿主防御病原体至关重要。然而,IFN-α/β对疟疾寄生虫感染的影响,有益或有害,仍然有争议。
目的:相互矛盾的结果被怀疑是由于寄生虫种类和宿主遗传背景的差异。迄今为止,之前没有一项研究采用两种寄生虫模型的比较方法来研究IFN-I应答的潜在机制.此外,SOCS1是否以及如何参与不同的IFN-α/β动力学尚不清楚。
方法:在这里,我们进行单细胞RNA测序分析(scRNA-seq),以剖析IFN-α/β对P.yoelii17XL(17XL)和P.bergheiANKA(PbANKA)感染的反应动力学;进行流式细胞术分析和功能耗竭,以确定IFN-I诱导的关键细胞参与者;并建立数学模型以探索由SOIFN-1动力学
结果:17XL刺激早期保护性但不足的Toll样受体7(TLR7)-干扰素调节因子7(IRF7)依赖性IFN-α/β反应,导致CD11ahiCD49dhiCD4+T细胞活化以增强抗疟疾免疫力。相反,通过toll样受体9(TLR9)-IRF7/干扰素基因刺激因子(STING)-干扰素调节因子3(IRF3)依赖性途径的晚期IFN-α/β诱导可扩展程序性细胞死亡蛋白1(PD-1)CD8T细胞,并在PbANKA感染期间损害宿主免疫力。此外,功能测定和数学建模表明,SOCS1通过负反馈和非相干前馈回路(I1-FFL)显着抑制IFN-α/β的产生。此外,各种转录因子(TF)的差异激活模式协同调节不同的IFN-I应答。
结论:本研究揭示了IFN-I在抗疟疾免疫中的双重功能:早期IFN-α/β通过促进CD11ahiCD49dhiCD4+T细胞增强针对疟原虫感染的免疫应答,而晚期IFN-α/β通过扩增PD-1+CD8+T细胞抑制这些反应。此外,SOCS1相关的网络基序和TFs激活模式都有助于确定IFN-I应答的不同动力学。因此,我们的研究结果表明,针对SOCS1或TFs调节的IFN-I动力学的治疗方法可能是预防疟疾和提高疫苗疗效的有效方法.
BACKGROUND: Type I interferon (IFN-I, IFN-α/β), precisely controlled by multiple regulators, including suppressor of cytokine signaling 1 (SOCS1), is critical for host defense against pathogens. However, the impact of IFN-α/β on malaria parasite infections, beneficial or detrimental, remains controversial.
OBJECTIVE: The contradictory results are suspected to arise from differences in parasite species and host genetic backgrounds. To date, no prior study has employed a comparative approach utilizing two parasite models to investigate the underlying mechanisms of IFN-I response. Moreover, whether and how SOCS1 involves in the distinct IFN-α/β dynamics is still unclear.
METHODS: Here we perform single-cell RNA sequencing analyses (scRNA-seq) to dissect the dynamics of IFN-α/β responses against P. yoelii 17XL (17XL) and P. berghei ANKA (PbANKA) infections; conduct flow cytometry analysis and functional depletion to identify key cellular players induced by IFN-I; and establish mathematical models to explore the mechanisms underlying the differential IFN-I dynamics regulated by SOCS1.
RESULTS: 17XL stimulates an early protective but insufficient toll-like receptor 7 (TLR7)-interferon regulatory factor 7 (IRF7)-dependent IFN-α/β response, resulting in CD11ahiCD49dhiCD4+ T cell activation to enhance anti-malarial immunity. On the contrary, a late IFN-α/β induction through toll-like receptor 9 (TLR9)-IRF7/ stimulator of interferon genes (STING)- interferon regulatory factor 3 (IRF3) dependent pathways expands programmed cell death protein 1 (PD-1)+CD8+ T cells and impairs host immunity during PbANKA infection. Furthermore, functional assay and mathematical modeling show that SOCS1 significantly suppresses IFN-α/β production via negative feedback and incoherent feed-forward loops (I1-FFL). Additionally, differential activation patterns of various transcriptional factors (TFs) synergistically regulate the distinct IFN-I responses.
CONCLUSIONS: This study reveals the dual functions of IFN-I in anti-malarial immunity: Early IFN-α/β enhances immune responses against Plasmodium infection by promoting CD11ahiCD49dhiCD4+ T cell, while late IFN-α/β suppresses these response by expanding PD-1+CD8+ T cells. Moreover, both the SOCS1-related network motifs and TFs activation patterns contribute to determine distinct dynamics of IFN-I responses. Hence, our findings suggest therapies targeting SOCS1- or TFs-regulated IFN-I dynamics could be an efficacious approach for preventing malaria and enhancing vaccine efficacy.