title: Interferon regulatory factor 3-dependent pathways are critical for control of herpes simplex virus type 1 central nervous system infection.
abstract: The initiation of the immune response at the cellular level relies on specific recognition molecules to rapidly signal viral infection via interferon (IFN) regulatory factor 3 (IRF-3)-dependent pathways. The absence of IRF-3 would be expected to render such pathways inoperative and thereby significantly affect viral infection. Unexpectedly, a previous study found no significant change in herpes simplex virus (HSV) pathogenesis in IRF-3(-/-) mice following intravenous HSV type 1 (HSV-1) challenge (K. Honda, H. Yanai, H. Negishi, M. Asagiri, M. Sato, T. Mizutani, N. Shimada, Y. Ohba, A. Takaoka, N. Yoshida, and T. Taniguchi, Nature 434:772-777, 2005). In contrast, the present study demonstrated that IRF-3(-/-) mice are significantly more susceptible to HSV infection via the corneal and intracranial routes. Following corneal infection with 2 x 10(6) PFU of HSV-1 strain McKrae, 50% of wild-type mice survived, compared to 10% of IRF-3-deficient mice. Significantly increased viral replication and inflammatory cytokine production were observed in brain tissues of IRF-3(-/-) mice compared to control mice, with a concomitant deficit in production of both IFN-beta and IFN-alpha. These data demonstrate a critical role for IRF-3 in control of central nervous system infection following HSV-1 challenge. Furthermore, this work underscores the necessity to evaluate multiple routes of infection and animal models in order to fully determine the role of host resistance factors in pathogenesis.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Dartmouth Medical School, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Vineet D
authors.initials: VD
authors.lastname: Menachery
authors.forename: Tracy Jo
authors.initials: TJ
authors.lastname: Pasieka
authors.forename: David A
authors.initials: DA
authors.lastname: Leib
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000276:immunology; D020805:Central Nervous System Viral Diseases / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006561:Herpes Simplex / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007370:Interferon Type I / Q000096:biosynthesis; D016849:Keratitis, Herpetic / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014779:Virus Replication
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse