Department of Molecular Biology and Microbiology, Tufts Universitygrid.429997.8 School of Medicine, Boston, Massachusetts, USA.
Program in Biochemistry, Tufts Universitygrid.429997.8 Graduate School of Biomedical Sciences, Boston, Massachusetts, USA.
mBio. 2022 Dec 20;13(6):e0244622. doi: 10.1128/mbio.02446-22. Epub 2022 Oct 18.
As a result of the ongoing virus-host arms race, viruses have evolved numerous immune subversion strategies, many of which are aimed at suppressing the production of type I interferons (IFNs). Apoptotic caspases have recently emerged as important regulators of type I IFN signaling both in noninfectious contexts and during viral infection. Despite being widely considered antiviral factors since they can trigger cell death, several apoptotic caspases promote viral replication by suppressing innate immune response. Indeed, we previously discovered that the AIDS-associated oncogenic gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) exploits caspase activity to suppress the antiviral type I IFN response and promote viral replication. However, the mechanism of this novel viral immune evasion strategy is poorly understood, particularly with regard to how caspases antagonize IFN signaling during KSHV infection. Here, we show that caspase activity inhibits the DNA sensor cGAS during KSHV lytic replication to block type I IFN induction. Furthermore, we used single-cell RNA sequencing to reveal that the potent antiviral state conferred by caspase inhibition is mediated by an exceptionally small percentage of IFN-β-producing cells, thus uncovering further complexity of IFN regulation during viral infection. Collectively, these results provide insight into multiple levels of cellular type I IFN regulation that viruses co-opt for immune evasion. Unraveling these mechanisms can inform targeted therapeutic strategies for viral infections and reveal cellular mechanisms of regulating interferon signaling in the context of cancer and chronic inflammatory diseases. Type I interferons are key factors that dictate the outcome of infectious and inflammatory diseases. Thus, intricate cellular regulatory mechanisms are in place to control IFN responses. While viruses encode their own immune-regulatory proteins, they can also usurp existing cellular interferon regulatory functions. We found that caspase activity during lytic infection with the AIDS-associated oncogenic gammaherpesvirus Kaposi's sarcoma-associated herpesvirus inhibits the DNA sensor cGAS to block the antiviral type I IFN response. Moreover, single-cell RNA sequencing analyses unexpectedly revealed that an exceptionally small subset of infected cells (<5%) produce IFN, yet this is sufficient to confer a potent antiviral state. These findings reveal new aspects of type I IFN regulation and highlight caspases as a druggable target to modulate cGAS activity.
由于病毒与宿主之间的持续军备竞赛，病毒已经进化出许多免疫颠覆策略，其中许多旨在抑制 I 型干扰素（IFN）的产生。凋亡 Caspase 最近已成为非传染性环境中和病毒感染期间 I 型 IFN 信号传导的重要调节剂。尽管它们可以触发细胞死亡，被广泛认为是抗病毒因素，但几种凋亡 Caspase 通过抑制先天免疫反应来促进病毒复制。事实上，我们之前发现，艾滋病相关致癌γ疱疹病毒卡波济肉瘤相关疱疹病毒（KSHV）利用 Caspase 活性抑制抗病毒 I 型 IFN 反应并促进病毒复制。然而，这种新型病毒免疫逃避策略的机制尚不清楚，特别是 Caspase 如何在 KSHV 感染期间拮抗 IFN 信号传导。在这里，我们表明 Caspase 活性在 KSHV 裂解复制过程中抑制 DNA 传感器 cGAS 以阻断 I 型 IFN 的诱导。此外，我们使用单细胞 RNA 测序揭示了 Caspase 抑制赋予的强大抗病毒状态是由极少数产生 IFN-β的细胞介导的，从而揭示了病毒感染过程中 IFN 调节的进一步复杂性。总的来说，这些结果提供了对病毒逃避免疫所涉及的细胞 I 型 IFN 调节多个层面的深入了解。揭示这些机制可以为病毒感染的靶向治疗策略提供信息，并揭示癌症和慢性炎症性疾病背景下调节干扰素信号的细胞机制。 I 型干扰素是决定传染性和炎症性疾病结果的关键因素。因此，存在复杂的细胞调节机制来控制 IFN 反应。虽然病毒编码自己的免疫调节蛋白，但它们也可以篡夺现有的细胞干扰素调节功能。我们发现，与艾滋病相关的致癌γ疱疹病毒卡波济肉瘤相关疱疹病毒的裂解感染期间 Caspase 活性抑制 DNA 传感器 cGAS 以阻断抗病毒 I 型 IFN 反应。此外，单细胞 RNA 测序分析出人意料地表明，一小部分 (<5%) 感染细胞产生 IFN，但这足以赋予强大的抗病毒状态。这些发现揭示了 I 型 IFN 调节的新方面，并强调 Caspase 是调节 cGAS 活性的可药物靶标。
