Deletion of the K1L gene results in a vaccinia virus that is less pathogenic due to muted innate immune responses, yet still elicits protective immunity

Ariana G. Bravo Cruz, Aiguo Han, Edward J. Roy, Arielle B. Guzmán, Rita J. Miller, Elizabeth A. Driskell, William D. O'Brien, Joanna L. Shisler

Research output: Contribution to journalArticle

Abstract

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-κB antagonism. However, the effect of K1 during animal infection is poorly understood. We determined that a K1L-less vaccinia virus (vΔK1L) 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, vΔK1L replicated to levels nearly identical to those of VACV, implying that the decreased immune response to vΔK1L infection, not virus replication, dictated lesion size. Several lines of evidence support this theory. First, vΔK1L induced slightly less edema than vK1L, as revealed by histopathology and noninvasive quantitative ultrasound technology (QUS). Second, infiltrating immune cell populations were decreased in vΔK1L-infected ears. Third, cytokine and chemokine gene expression was decreased in vΔK1L-infected ears. While these results identified the biological basis for smaller lesions, they remained puzzling; because K1 antagonizes NF-κB in vitro, antiviral gene expression was expected to be higher during vΔK1L infection. Despite these diminished innate immune responses, vΔK1L vaccination induced a protective VACV-specific CD8+ T cell response and protected against a lethal VACV challenge. Thus, vΔK1L 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.

Original languageEnglish (US)
Article numbere00542-17
JournalJournal of virology
Volume91
Issue number15
DOIs
StatePublished - Aug 1 2017

    Fingerprint

Keywords

  • K1L
  • Poxvirus
  • Vaccines
  • Vaccinia virus
  • Viral pathogenesis
  • Virus-host interactions

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this