The herpesviral antagonist m152 reveals differential activation of STING ‐dependent IRF and NF ‐κB signaling and STING 's dual role during MCMV infection

Abstract

Cytomegaloviruses (CMVs) are master manipulators of the host immune response. Here, we reveal that the murine CMV (MCMV) protein m152 specifically targets the type I interferon (IFN) response by binding to stimulator of interferon genes (STING), thereby delaying its trafficking to the Golgi compartment from where STING initiates type I IFN signaling. Infection with an MCMV lacking m152 induced elevated type I IFN responses and this leads to reduced viral transcript levels both in vitro and in vivo. This effect is ameliorated in the absence of STING. Interestingly, while m152 inhibits STING‐mediated IRF signaling, it did not affect STING‐mediated NF‐κB signaling. Analysis of how m152 targets STING translocation reveals that STING activates NF‐κB signaling already from the ER prior to its trafficking to the Golgi. Strikingly, this response is important to promote early MCMV replication. Our results show that MCMV has evolved a mechanism to specifically antagonize the STING‐mediated antiviral IFN response, while preserving its pro‐viral NF‐κB response, providing an advantage in the establishment of an infection.

STING induces early IFN-β in the liver and constrains myeloid cell-mediated dissemination of murine cytomegalovirus

“…1a, b). This observation was surprising, because in a previous in vivo study STING was reported to be involved in MCMV sensing and IFN-I induction 27,28 and mice devoid of cGAS or STING showed enhanced sensitivity to the infection with other DNA viruses, such as HSV-1 and vaccinia virus (VACV) 22,24 (Supplementary Fig. 1c, d).…”

“…TLR signaling plays an important role in the control of systemic MCMV infection 15 , whereas more recently it was discovered that STING signaling is needed to induce early systemic and splenic IFN-β responses 27,28 . To analyze the relevance of the cGAS/STING axis for protection against MCMV, TLR ( Myd88 −/− Trif −/− mice ) , RLR ( Mavs −/− mice), cGAS ( Cgas −/− mice), and STING ( Tmem173 −/− mice) signaling deficient mice were infected with 5 × 10 5 plaque forming units (pfu) of MCMV Δ m157 .…”

“…Furthermore, upon MCMV infection of BMDC or bone marrow-derived macrophages IFN-I responses are induced in a TLR/RLR-independent and STING-dependent manner 12,26 . Recently, it was suggested that STING signaling contributes to the early systemic and splenic IFN-β production after MCMV infection 27,28 . However, how STING signaling influences the pathogenesis of MCMV in vivo still remains elusive.…”

Cytomegaloviruses and Macrophages—Friends and Foes From Early on?

“…In vitro data generated in MACs further suggest that they induce NK-cell recruitment and IFN-γ production via inflammasome activation during the early response (Figure 1). On the other hand, MCMV and HCMV have evolved numerous strategies to evade the IFN I response (59)(60)(61)(62). As an example, the MCMV protein M35 antagonizes IFN I induction downstream of STING and TLRs and thus ensures MCMV replication in MACs (46) ( Table 1).…”

Impact of Natural Occurring ERAP1 Single Nucleotide Polymorphisms within miRNA-Binding Sites on HCMV Infection

“…Human cytomegalovirus (HCMV) is a β-herpesvirus that persists mostly asymptomatically in infected healthy human hosts throughout their life [1], with spontaneous phases of reactivation, lytic replication, and diffusion [2]. HCMV causes several clinical syndromes in people with impaired immunity, especially in individuals subject to organ transplant, HIV-infected patients, and immunologically immature fetus [3].…”