Resistance to HSV-1 infection in the epithelium resides with the novel innate sensor, IFI-16

Mucosal Immunol. 2012 Mar;5(2):173-83. doi: 10.1038/mi.2011.63. Epub 2012 Jan 11.

Abstract

Toll-like receptors (TLRs) are innate sentinels required for clearance of bacterial and fungal infections of the cornea, but their role in viral immunity is currently unknown. We report that TLR signaling is expendable in herpes simplex virus (HSV)-1 containment as depicted by plaque assays of knockout mice (MyD88(-/-), Trif(-/-) and MyD88(-/-) Trif(-/-) double knockout) resembling wild-type controls. To identify the key sentinel in viral recognition of the cornea, in vivo knockdown of the DNA sensor IFI-16/p204 in the corneal epithelium was performed and resulted in a loss of IFN-regulatory factor-3 (IRF-3) nuclear translocation, interferon-α production, and viral containment. The sensor seems to have a similar function in other HSV clinically relevant sites such as the vaginal mucosa in which a loss of p204/IFI-16 results in significantly more HSV-2 shedding. Thus, we have identified an IRF-3-dependent, IRF-7- and TLR-independent innate sensor responsible for HSV containment at the site of acute infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Vesicular Transport / genetics
  • Animals
  • Cell Nucleus / metabolism*
  • Epithelium, Corneal / immunology
  • Epithelium, Corneal / metabolism*
  • Epithelium, Corneal / pathology
  • Epithelium, Corneal / virology
  • Herpesviridae Infections / immunology*
  • Herpesvirus 1, Human / immunology*
  • Herpesvirus 1, Human / pathogenicity
  • Host-Pathogen Interactions
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / immunology
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon-alpha / immunology
  • Interferon-alpha / metabolism
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Toll-Like Receptors / metabolism
  • Viral Load / genetics

Substances

  • Adaptor Proteins, Vesicular Transport
  • Ifi16 protein, mouse
  • Interferon Regulatory Factor-3
  • Interferon-alpha
  • Irf3 protein, mouse
  • Myeloid Differentiation Factor 88
  • Nuclear Proteins
  • Phosphoproteins
  • TICAM-1 protein, mouse
  • Toll-Like Receptors