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

Abstract

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.

γδ T cells mediate a requisite portion of a wound healing response triggered by cutaneous poxvirus infection

“…However, in the absence of  T cells, VACV infection induced a marked increase in tissue pathology over that observed in a WT situation. Neither tissue resident nor recruited  T cells appear to modulate any of the tissue protective functions (e.g., recruitment of myeloid cell populations, production of reactive oxygen species or Type I interferon) we have previously described as important during cutaneous VACV infection [11][12][13]. However, while investigating the mechanisms by which  T cells impact local tissue pathology we discovered induction of a unique wound healing signature induced early after VACV infection.…”

“…Mice infected in the ears with VACV develop visible lesions that undergo necrosis and the necrotic tissue is then lost [3,4]. We have previously described a role for two recruited populations of monocytes, production of reactive oxygen species and local Type I IFN production in control of the severity of pathology observed following dermal VACV infection [11][12][13]. However, none of the factors mentioned above are involved in control of local VACV replication or spread from the original site of infection.…”

“…It is possible that, rather than controlling immunopathology,  T cells coordinate the changes in the immune response that lead to resolution of inflammation and subsequent reduction of local tissue pathology. We have previously described a role for two recruited populations of monocytes in control of the severity of pathology observed following dermal VACV infection but these populations of monocytes do not have a large effect upon local VACV replication [11][12][13].…”

“…The CD11b + Ly6C + Ly6G + myeloid cells are monocytic in nature and limit local tissue damage via production of reactive oxygen species [11]. In contrast, the classical CD11b + Ly6C + Ly6Gmonocytes are attracted to the site of infection by Type I IFN-stimulated production of CCL4, and also moderate tissue damage, possibly by becoming infected and soaking up excess virions [13]. Since  T cells are found in the VACV lesion ( Fig.…”

“…After systemic infection,  T cells exhibit cytolytic control over the replication and spread of VACV infection [7][8][9][10], but our previous work has identified key differences in how the immune system responds to control viruses after systemic infection versus the more relevant peripheral cutaneous infection. In particular, we have identified both cellular and molecular mechanisms that are induced following cutaneous VACV infection which act to control the extent of local pathology measured by lesion size and tissue loss, but which do not have large effects upon local VACV replication [11][12][13]. Therefore, we sought to examine the role of skin resident and skin recruited  T cells after cutaneous VACV infection.…”