title: The type I interferon response bridles rabies virus infection and reduces pathogenicity.
abstract: Rabies virus (RABV) is a neurotropic virus transmitted by the bite of an infected animal that triggers a fatal encephalomyelitis. During its migration in the nervous system (NS), RABV triggers an innate immune response, including a type I IFN response well known to limit viral infections. We showed that although the neuroinvasive RABV strain CVS-NIV dampens type I IFN signaling by inhibiting IRF3 phosphorylation and STAT2 translocation, an early and transient type I IFN response is still triggered in the infected neuronal cells and NS. This urged us to investigate the role of type I IFN on RABV infection. We showed that primary mouse neurons (DRGs) of type I IFN(α/β) receptor deficient mice (IFNAR(-/-) mice) were more susceptible to RABV than DRGs of WT mice. In addition, exogenous type I IFN is partially efficient in preventing and slowing down infection in human neuroblastoma cells. Intra-muscular inoculation of type I IFNAR deficient mice [IFNAR(-/-) mice and NesCre ((+/-)) IFNAR ((flox/flox)) mice lacking IFNAR in neural cells of neuroectodermal origin only] with RABV reveals that the type I IFN response limits RABV dissemination in the inoculated muscle, slows down invasion of the spinal cord, and delays mortality. Thus, the type I IFN which is still produced in the NS during RABV infection is efficient enough to reduce neuroinvasiveness and pathogenicity and partially protect the host from fatal infection.
authors.affiliation: Département de Virologie Institut Pasteur, Unité de Neuroimmunologie Virale, 75015, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Chopy
authors.forename: Claudia N
authors.initials: CN
authors.lastname: Detje
authors.forename: Mireille
authors.initials: M
authors.lastname: Lafage
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Monique
authors.initials: M
authors.lastname: Lafon
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009447:Neuroblastoma / Q000276:immunology / Q000473:pathology / Q000821:virology; D009474:Neurons / Q000276:immunology* / Q000821:virology; D061251:Primary Cell Culture; D011818:Rabies / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000821:virology; D011820:Rabies virus / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013116:Spinal Cord / Q000276:immunology* / Q000821:virology; D015996:Survival Rate; D019562:Viral Load / Q000276:immunology
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D050795:STAT2 Transcription Factor; C494085:Stat2 protein, mouse; D053633:Receptor, Interferon alpha-beta