Nouri Hamid Reza, Schaunaman Niccolette, Kraft Monica, Numata Mari, Vercelli Donata, Chu Hong Wei
Department of Medicine, National Jewish Health, Denver, CO, United States.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
J Immunol. 2025 Jul 1;214(7):1741-1753. doi: 10.1093/jimmun/vkaf058.
Toll-interacting protein (Tollip) is an intracellular adaptor protein with diverse functions including regulation of autophagy of mitochondria-mitophagy. Tollip deficiency promotes viral infection, but whether mitophagy is involved remains unclear. We sought to determine if mitophagy and associated signaling such as mitochondrial DNA (mtDNA) release and activation of stimulator of interferon genes (STING) contribute to worsened viral infection due to Tollip deficiency. Wild-type and Tollip knockout (KO) C57/BL6 mice were intranasally infected with influenza A virus (IAV), and then treated with or without a STING agonist 2'3'cGAMP for 4 d. PINK1 (an initiator of mitophagy) KO mouse tracheal epithelial cells (mTECs) or PINK1 KO mice were infected with IAV to reveal the role of mitophagy in viral infection. In IAV-infected mice, Tollip deficiency enhanced lung mitophagy (more PINK1 and BNIP3L, but less p62), and decreased release of mtDNA. Furthermore, Tollip deficiency suppressed STING activation and the antiviral response (eg IFN-β and MX1), and increased viral load. In IAV-infected Tollip KO mice, 2'3'cGAMP activated STING and increased antiviral response coupled with less virus. PINK1-deficient mice increased lung release of mtDNA and augmented STING activation and antiviral responses. PINK1 deficiency in mTECs increased STING activation and significantly decreased the viral load. Our findings suggest that enhanced mitophagy due to Tollip deficiency reduces mtDNA release and STING activation during viral infection, resulting in decreased antiviral responses. Reduction of mitophagy and/or STING activation may open novel avenues for therapeutic intervention in human subjects with Tollip deficiency and viral infection.
Toll相互作用蛋白（Tollip）是一种细胞内衔接蛋白，具有多种功能，包括调节线粒体自噬（即线粒体吞噬）。Tollip缺乏会促进病毒感染，但线粒体吞噬是否参与其中仍不清楚。我们试图确定线粒体吞噬以及相关信号传导，如线粒体DNA（mtDNA）释放和干扰素基因刺激物（STING）的激活，是否会导致由于Tollip缺乏而使病毒感染恶化。将野生型和Tollip基因敲除（KO）的C57/BL6小鼠经鼻感染甲型流感病毒（IAV），然后用或不用STING激动剂2'3'cGAMP处理4天。用IAV感染粉色1（PINK1，线粒体吞噬的启动子）基因敲除的小鼠气管上皮细胞（mTECs）或PINK1基因敲除小鼠，以揭示线粒体吞噬在病毒感染中的作用。在IAV感染的小鼠中，Tollip缺乏增强了肺线粒体吞噬（更多的PINK1和BNIP3L，但p62较少），并减少了mtDNA的释放。此外，Tollip缺乏抑制了STING的激活和抗病毒反应（如IFN-β和MX1），并增加了病毒载量。在IAV感染的Tollip基因敲除小鼠中，2'3'cGAMP激活了STING并增加了抗病毒反应，同时病毒减少。PINK1缺陷小鼠增加了肺mtDNA的释放，并增强了STING的激活和抗病毒反应。mTECs中PINK1缺陷增加了STING的激活，并显著降低了病毒载量。我们的研究结果表明，Tollip缺乏导致的线粒体吞噬增强会减少病毒感染期间的mtDNA释放和STING激活，从而导致抗病毒反应降低。减少线粒体吞噬和/或STING激活可能为治疗Tollip缺乏和病毒感染的人类受试者开辟新的治疗途径。
