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Dual nature of type I interferon responses and feedback regulations by SOCS1 dictate malaria mortality
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-08-22 , DOI: 10.1016/j.jare.2024.08.027
Jiansen Lu 1 , Zhiqiang Hu 2 , Huaji Jiang 1 , Zebin Wen 3 , Hongyu Li 1 , Jian Li 4 , Ke Zeng 1 , Yingchao Xie 1 , Huadan Chen 1 , Xin-Zhuan Su 5 , Chunmei Cai 6 , Xiao Yu 7
Affiliation  

Introduction

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.

Objectives

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.

Conclusion

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.


中文翻译:


SOCS1 的 I 型干扰素反应和反馈调节的双重性质决定了疟疾死亡率


 介绍


I 型干扰素 (IFN-I, IFN-α/β) 由多种调节因子精确控制,包括细胞因子信号转导抑制因子 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,无论是有益的还是有害的,仍然存在争议。

 目标


这些相互矛盾的结果被怀疑是由于寄生虫物种和宿主遗传背景的差异引起的。迄今为止,先前的研究没有采用利用两种寄生虫模型的比较方法来研究 IFN-I 反应的潜在机制。此外,SOCS1 是否以及如何参与不同的 IFN-α/β 动力学仍不清楚。

 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. yoelii 17XL (17XL) 和 P. berghei ANKA (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 SOCS1 调节的差异 IFN-I 动力学的潜在机制。

 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/干扰素基因刺激剂 (STING)-干扰素调节因子 3 (IRF3) 依赖性途径诱导晚期 IFN-α/β 扩增程序性细胞死亡蛋白 1 (PD-1)+CD8+ T 细胞,并在 PbANKA 感染期间损害宿主免疫。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环 (I1-FFL) 显着抑制 IFN-α/β 的产生。此外,各种转录因子 (TFs) 的差异激活模式协同调节不同的 IFN-I 反应。

 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 细胞来增强对疟原虫感染的免疫反应,而晚期 IFN-α/β 通过扩增 PD-1+CD8+ T 细胞来抑制这些反应。此外,SOCS1 相关的网络基序和 TFs 激活模式都有助于确定 IFN-I 反应的不同动力学。因此,我们的研究结果表明,针对 SOCS1 或 TFs 调节的 IFN-I 动力学的疗法可能是预防疟疾和提高疫苗功效的有效方法。
更新日期:2024-08-22
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