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代谢重编程提示通过稳定干扰素γ诱导的IRF1来稳定疫苗病毒感染结果

Tyron Chang^1,2, Jessica Alvarez^1,3, Sruthi Chappidi¹

¹Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

|October 30, 2024

概括

代谢影响干扰素刺激基因 (ISG) 蛋白质表达,葡萄糖或银河糖改变IRF1和IFITM3水平. 这种对ISG蛋白质的代谢调节提供了一个新的层,控制对病毒感染的免疫反应.

科学领域:

免疫学免疫学免疫学
细胞生物学细胞生物学
代谢过程中的代谢.

背景情况:

干扰素 (IFN) 诱导的活动,包括干扰素刺激基因 (ISG),对于免疫反应和感染结果至关重要.
在疾病中异常的ISG表达表明了除初级干扰素信号外的调节层.
代谢的差异,特别是葡萄糖与银河糖的利用,特征组织的身份和影响病毒的易感性.

研究的目的:

调查不同代谢条件 (通过葡萄糖的有氧糖解与通过银河糖的氧化酸化) 对干扰素刺激基因表达 (ISG) 的影响.
探索这些代谢状态如何调节关键ISG的蛋白质水平,如IRF1和IFITM3,以响应干扰素刺激.
确定ISG代谢调节对病毒复制的功能影响.

主要方法:

在有利于葡萄糖 (有氧糖解) 或银河糖 (氧化酸化) 的介质中培养人类,小鼠和猫细胞.
用干涉子 (IFN-α,IFN-γ) 刺激细胞并分析ISGRNA和蛋白质表达.
利用蛋白质酶抑制和IRF1淘汰 (KO) 模型来评估调控机制和病毒复制动态.
在不同的代谢和干扰素条件下感染了疫苗病毒 (a poxvirus) 的细胞,并测量了病毒标位和蛋白质表达.

主要成果:

扩展的干扰素原始化导致ISG蛋白表达的分歧:IRF1在IFN-γ/葡萄糖上调,而IFITM3在银河糖上升.
IFN-γ诱导的IRF1的葡萄糖/银糖调节在物种之间保持不变,并且取决于蛋白质酶活性.
葡萄糖/IFN-γ治疗减少了疫苗病毒的复制,这种效果取决于IRF1;这种效果在银河糖介质中丢失了.
一个影响疹病毒和天花病毒标位的晚期病毒复制阻断,但不影响蛋白质表达,与葡萄糖/银糖状况有关.

结论:

一个由葡萄糖和银河糖代谢介导的ISG蛋白IRF1的新型调节层已被确定.
免疫细胞对营养可用性的代谢感知可以通过干扰素通路中的嵌入子程序快速适应抗病毒反应.
这些发现突出了细胞代谢和天生的免疫力之间的相互作用,影响病毒控制.

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