Deletion of the Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity.

All viruses strategically alter the antiviral immune response to their benefit. The vaccinia virus (VACV) K1 protein has multiple immunomodulatory effects in tissue culture models of infection, including NF-kappa B antagonism. However, the effect of K1 during animal infection is poorly understood. We determined that a K1L-less vaccinia virus (v Delta K1L) was less pathogenic than wild-type VACV in intranasal and intradermal models of infection. Decreased pathogenicity was correlated with diminished virus replication in intranasally infected mice. However, in intradermally inoculated ears, v Delta K1L replicated to levels nearly identical to those of VACV, implying that the decreased immune response to v Delta K1L infection, not virus replication, dictated lesion size. Several lines of evidence support this theory. First, v Delta K1L induced slightly less edema than vK1L, as revealed by histopathology and noninvasive quantitative ultrasound technology (QUS). Second, infiltrating immune cell populations were decreased in v Delta K1L-infected ears. Third, cytokine and chemokine gene expression was decreased in v Delta K1L-infected ears. While these results identified the biological basis for smaller lesions, they remained puzzling; because K1 antagonizes NF-kappa B in vitro, antiviral gene expression was expected to be higher during v Delta K1L infection. Despite these diminished innate immune responses, v Delta K1L vaccination induced a protective VACV-specific CD8(+) T cell response and protected against a lethal VACV challenge. Thus, v Delta K1L is the first vaccinia virus construct reported that caused a muted innate immune gene expression profile and decreased immune cell infiltration in an intradermal model of infection yet still elicited protective immunity. IMPORTANCE The vaccinia virus (VACV) K1 protein inhibits NF-kappa B activation among its other antagonistic functions. A virus lacking K1 (v Delta K1L) was predicted to be less pathogenic because it would trigger a more robust antiviral immune response than VACV. Indeed, v Delta K1L was less pathogenic in intradermally infected mouse ear pinnae. However, v Delta K1L infection unexpectedly elicited dramatically reduced infiltration of innate immune cells into ears. This was likely due to decreased expression of cytokine and chemokine genes in v Delta K1L-infected ears. As such, our finding contradicted observations from cell culture systems. Interestingly, v Delta K1L conferred protective immunity against lethal VACV challenge. This suggests that the muted immune response triggered during V Delta K1L infection remained sufficient to mount an effective protective response. Our results highlight the complexity and unpredictable nature of virus-host interactions, a relationship that must be understood to better comprehend virus pathogenesis or to manipulate viruses for use as vaccines.