title: Resistance to HSV-1 infection in the epithelium resides with the novel innate sensor, IFI-16.
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.
authors.affiliation: Department of Microbiology, Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Conrady
authors.forename: M
authors.initials: M
authors.lastname: Zheng
authors.forename: K A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: D J J
authors.initials: DJ
authors.lastname: Carr
mesh_terms: D021581:Active Transport, Cell Nucleus; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D019573:Epithelium, Corneal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006566:Herpesviridae Infections / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism*; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism; D019562:Viral Load / Q000235:genetics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D053594:Myeloid Differentiation Factor 88; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051193:Toll-Like Receptors; C489664:Ifi16 protein, mouse; C494233:Irf3 protein, mouse; C476286:Ticam1 protein, mouse