Differential Innate Immune Signaling in Macrophages by Wild-Type Vaccinia Mature Virus and a Mutant Virus with a Deletion of the A26 Protein.

ABSTRACT: The Western Reserve (WR) strain of mature vaccinia virus contains an A26 envelope protein that mediates virus binding to cell surface laminin and subsequent endocytic entry into HeLa cells. Removal of the A26 protein from the WR strain mature virus generates a mutant, WR?A26, that enters HeLa cells through plasma membrane fusion. Here, we infected murine bone marrow-derived macrophages (BMDM) with wild-type strain WR and the WR?A26 mutant and analyzed viral gene expression and cellular innate immune signaling. In contrast to previous studies, in which both HeLa cells infected with WR and HeLa cells infected with WR?A26 expressed abundant viral late proteins, we found that WR expressed much less viral late protein than WR?A26 in BMDM. Microarray analysis of the cellular transcripts in BMDM induced by virus infection revealed that WR preferentially activated type 1 interferon receptor (IFNAR)-dependent signaling but WR?A26 did not. We consistently detected a higher level of soluble beta interferon secretion and phosphorylation of the STAT1 protein in BMDM infected with WR than in BMDM infected with WR?A26. When IFNAR-knockout BMDM were infected with WR, late viral protein expression increased, confirming that IFNAR-dependent signaling was differentially induced by WR and, in turn, restricted viral late gene expression. Finally, wild-type C57BL/6 mice were more susceptible to mortality from WR?A26 infection than to that from WR infection, whereas IFNAR-knockout mice were equally susceptible to WR and WR?A26 infection, demonstrating that the ability of WR?A26 to evade IFNAR signaling has an important influence on viral pathogenesis in vivoIMPORTANCE The vaccinia virus A26 protein was previously shown to mediate virus attachment and to regulate viral endocytosis. Here, we show that infection with strain WR induces a robust innate immune response that activates type 1 interferon receptor (IFNAR)-dependent cellular genes in BMDM, whereas infection with the WR?A26 mutant does not. We further demonstrated that the differential activation of IFNAR-dependent cellular signaling between WR and WR?A26 not only is important for differential host restriction in BMDM but also is important for viral virulence in vivo Our study reveals a new property of WR?A26, which is in regulating host antiviral innate immunity in vitro and in vivo.

SUBMITTER: Kasani SK 

PROVIDER: S-EPMC5571262 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature