title: Both TRIF and IPS-1 adaptor proteins contribute to the cerebral innate immune response against herpes simplex virus 1 infection.
abstract: Toll-like receptors (TLRs) and RNA helicases (RLHs) are important cell sensors involved in the immunological control of viral infections through production of type I interferon (IFN). The impact of a deficiency in the TRIF and IPS-1 adaptor proteins, respectively, implicated in TLR3 and RLH signaling pathways, was investigated during herpes simplex virus 1 (HSV-1) encephalitis. TRIF(-/-), IPS-1(-/-), and C57BL/6 wild-type (WT) mice were infected intranasally with 7.5 × 10(5) PFU of HSV-1. Mice were monitored for neurological signs and survival over 20 days. Groups of mice were sacrificed on days 3, 5, 7, 9, and 11 postinfection for determination of brain viral replication by quantitative PCR (qPCR), plaque assay, and immunohistochemistry and for alpha/beta interferon (IFN-α/β) levels and phosphorylation of interferon regulatory factors 3 and 7 (IRF-3 and -7) in brain homogenates by enzyme-linked immunosorbent assay (ELISA) and Western blotting, respectively. TRIF(-/-) and IPS-1(-/-) mice had higher mortality rates than WT mice (P = 0.02 and P = 0.09, respectively). Viral antigens were more disseminated throughout the brain, correlating with a significant increase in brain viral load for TRIF(-/-) (days 5 to 9) and IPS-1(-/-) (days 7 and 9) mice compared to results for the WT. IFN-β production was reduced in brain homogenates of TRIF(-/-) and IPS-1(-/-) mice on day 5 compared to results for the WT, whereas IFN-α levels were increased on day 7 in TRIF(-/-) mice. Phosphorylation levels of IRF-3 and IRF-7 were decreased in TRIF(-/-) and IPS-1(-/-) mice, respectively. These data suggest that both the TRIF and IPS-1 signaling pathways are important for the control of HSV replication in the brain and survival through IFN-β production.
authors.affiliation: Research Center in Infectious Diseases, CHUQ-CHUL, and Department of Microbiology-Infectiology and Immunology, Laval University, Quebec City, QC, Canada.
authors.forename: Rafik
authors.initials: R
authors.lastname: Menasria
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boivin
authors.forename: Manon
authors.initials: M
authors.lastname: Lebel
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Piret
authors.forename: Jean
authors.initials: J
authors.lastname: Gosselin
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000276:immunology; D018792:Encephalitis, Viral / Q000276:immunology*; D006561:Herpes Simplex / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology*; D019562:Viral Load; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D034741:RNA, Small Interfering; C512612:MAVS protein, mouse; C476286:Ticam1 protein, mouse