Species-specific disruption of STING-dependent antiviral cellular defenses by the Zika virus NS2B3 protease

Abstract

The limited host tropism of numerous viruses causing disease in humans remains incompletely understood. One example is Zika virus (ZIKV), an RNA virus that has reemerged in recent years. Here, we demonstrate that ZIKV efficiently infects fibroblasts from humans, great apes, New and Old World monkeys, but not rodents. ZIKV infection in human-but not murine-cells impairs responses to agonists of the cGMP-AMP synthase/stimulator of IFN genes (cGAS/STING) signaling pathway, suggesting that viral mechanisms to evade antiviral defenses are less effective in rodent cells. Indeed, human, but not mouse, STING is subject to cleavage by proteases encoded by ZIKV, dengue virus, West Nile virus, and Japanese encephalitis virus, but not that of yellow fever virus. The protease cleavage site, located between positions 78/79 of human STING, is only partially conserved in nonhuman primates and rodents, rendering these orthologs resistant to degradation. Genetic disruption of STING increases the susceptibility of mouse-but not human-cells to ZIKV. Accordingly, expression of only mouse, not human, STING in murine STING knockout cells rescues the ZIKV suppression phenotype. STING-deficient mice, however, did not exhibit increased susceptibility, suggesting that other redundant antiviral pathways control ZIKV infection in vivo. Collectively, our data demonstrate that numerous RNA viruses evade cGAS/STING-dependent signaling and affirm the importance of this pathway in shaping the host range of ZIKV. Furthermore, our results explain-at least in part-the decreased permissivity of rodent cells to ZIKV, which could aid in the development of mice model with inheritable susceptibility to ZIKV and other flaviviruses.

Zika virus infection in Collaborative Cross mice

“…Thus, Stat2 −/− mice succumb to ZIKV infection, but transgenic mice expressing human STAT2 only exhibit disease in the context of ZIKV strains with additional mouse-adaptive mutations (4, 44). In addition, the ZIKV NS2B-NS3 protease targets human but not murine STING, resulting in sustained IFN production and diminished viral replication in mouse cells (3). However, mice lacking STING were not more susceptible to ZIKV than wild-type mice (2, 3), implying that STING is a contributing but not dominant factor restricting ZIKV infection in mice.…”

“…Mice would be an attractive system for such studies due their low cost and genetic tractability and mice have proven to be a valuable system for studying other flaviviruses, such as West Nile virus (WNV). However, studies of ZIKV in mice are confounded because mouse type I interferon (IFN-αβ) signaling restricts ZIKV replication (2), in part due to the inability of ZIKV to antagonize murine STAT2 and STING (3-6). This results in diminished ZIKV replication in immune competent mice and has led most groups to use IFN-deficient mouse models including mice lacking the type I and/or type II IFN receptors (e.g., Ifnar1 −/− or Ifnar1 −/− Ifngr1 −/− double knockout), mice with defects in IFN induction or signaling (e.g., Irf3 −/− Irf5 −/− Irf7 −/− or Stat2 −/− ), or mice treated with IFNAR1-blocking antibody (7).…”

Endoplasmic reticulum: a focal point of Zika virus infection

“…Beside regulating eIF2α phosphorylation and hijacking key SG proteins, RNA viruses were reportedly capable of interfering SGs assembly through cleaving and redistributing SGs nucleating factors [74]. It was previously reported that ZIKV NS2B-NS3 protease could cleave host antiviral factors to impair intrinsic host defense; intriguingly, ZIKV did not mediate the cleavage of SG factors even though SGs assembly was affected by ZIKV NS3 and NS2B-NS3 protease [77][78][79][80][81]. Nonetheless, ZIKV infection was found to facilitate the redistribution of TIAR to viral replication sites, which correlates to viral replication output [77,78,81].…”

Conserved strategies for pathogen evasion of cGAS–STING immunity

“…Several viruses employ strategies to degrade STING to prevent its activation by 2 0 3 0 -cGAMP (Figure 4). Similar to degradation of cGAS, DENV and other related flaviviruses proteolytically cleave STING using the viral protease complex NS2B3, blocking induction of signaling [45,46 ]. In addition, the HCMV IE86 protein promotes STING degradation in the proteasome, restricting activation of downstream signaling [47].…”