Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden

Type I interferons (T1-IFN) are critical in the innate immune response, acting upon infected and uninfected cells to initiate an antiviral state by expressing genes that inhibit multiple stages of the lifecycle of many viruses. T1-IFN triggers the production of Interferon-Stimulated Genes (ISGs), activating an antiviral program that reduces virus replication. The importance of the T1-IFN response is highlighted by the evolution of viral evasion strategies to inhibit the production or action of T1-IFN in virus-infected cells. T1-IFN is produced via activation of pathogen sensors within infected cells, a process that is targeted by virus-encoded immunomodulatory molecules. This is probably best exemplified by the prototypic poxvirus, Vaccinia virus (VACV), which uses at least 6 different mechanisms to completely block the production of T1-IFN within infected cells in vitro. Yet, mice lacking aspects of T1-IFN signaling are often more susceptible to infection with many viruses, including VACV, than wild-type mice. How can these opposing findings be rationalized? The cytosolic DNA sensor cGAS has been implicated in immunity to VACV, but has yet to be linked to the production of T1-IFN in response to VACV infection. Indeed, there are two VACV-encoded proteins that effectively prevent cGAS-mediated activation of T1-IFN. We find that the majority of VACV-infected cells in vivo do not produce T1-IFN, but that a small subset of VACV-infected cells in vivo utilize cGAS to sense VACV and produce T1-IFN to protect infected mice. The protective effect of T1-IFN is not mediated via ISG-mediated control of virus replication. Rather, T1-IFN drives increased expression of CCL4, which recruits inflammatory monocytes that constrain the VACV lesion in a virus replication-independent manner by limiting spread within the tissue. Our findings have broad implications in our understanding of pathogen detection and viral evasion in vivo, and highlight a novel immune strategy to protect infected tissue. Author summary The recognition of virus infection leads to a quick and robust antiviral response mediated by type I interferons (T1-IFN). Nearly all viruses have acquired genes that block the induction or action of T1-IFN in order to attain a replicative advantage. Some viruses thwart the T1-IFN response so thoroughly, that cells infected in vitro do not produce any T1-IFN. And yet, animal models with defects in T1-IFN signaling are more sensitive to infection with these viruses than their wild-type counterparts. In this study, we find evidence to explain these otherwise contradicting findings. We show that a small population of infected cells in vivo are able to utilize a pathogen-sensing pathway that is completely blocked in vitro. T1-IFN produced by these specialized cells protects mice by recruiting inflammatory monocytes that restrict the spread of virus within infected tissue, independent of viral burden. Our findings have a direct impact on our understanding of how viruses are detected in infected tissue, and present a novel strategy of the immune system to limit pathology at peripheral sites of infection.