Analysis of caspase-mediated suppression of the cGAS/STING pathway in Kaposi’s sarcoma-associated herpesvirus lytic infection reveals a dramatic cellular heterogeneity in type I interferon responses

Abstract

AbstractAs 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)1. This focus on IFN evasion highlights the essential role of these cytokines in controlling viral infections. Apoptotic caspases have recently emerged as important regulators of type I IFN signaling in both non-infectious contexts and during viral infection2–5. Despite being widely considered anti-viral factors since they can trigger cell death, several apoptotic caspases promote viral replication by suppressing innate immune responses2–5. Indeed, we previously discovered that the AIDS-associated oncogenic gammaherpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV) exploits caspase-8 activity to suppress the antiviral type I IFN response and promote viral replication5. However, the mechanism of this novel viral immune evasion strategy is poorly understood, particularly how caspase-8 antagonizes IFN signaling during KSHV infection. Here we show that caspase activity inhibits the DNA sensor cGAS6 during KSHV lytic replication to block type I IFN induction. Furthermore, we use single-cell RNA-sequencing to reveal that the potent antiviral state conferred upon 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.