The type I interferon response bridles rabies virus infection and reduces pathogenicity

• Published in: Journal of neurovirology Vol. 17; no. 4; pp. 353 - 367
• Main Authors: Chopy, Damien, Detje, Claudia N., Lafage, Mireille, Kalinke, Ulrich, Lafon, Monique
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.08.2011
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Female; Flow Cytometry; Humans; Immunohistochemistry; Immunology; Infectious Diseases; Injections, Intramuscular; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Interferon Type I - biosynthesis; Interferon Type I - immunology; Interferon Type I - pharmacology; Mice; Mice, Knockout; Neuroblastoma - immunology; Neuroblastoma - pathology; Neuroblastoma - virology; Neurology; Neurons - immunology; Neurons - virology; Neurosciences; Primary Cell Culture; Rabies - immunology; Rabies - mortality; Rabies - pathology; Rabies - virology; Rabies virus; Rabies virus - physiology; Real-Time Polymerase Chain Reaction; Receptor, Interferon alpha-beta - deficiency; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - immunology; Signal Transduction - immunology; Spinal Cord - immunology; Spinal Cord - virology; STAT2 Transcription Factor - genetics; STAT2 Transcription Factor - metabolism; Survival Rate; Viral Load - immunology; Virology; Nervous system; Type I interferon; NesCre; Rabies virus; mice; IFNAR
• ISSN: 1355-0284; 1538-2443
• DOI: 10.1007/s13365-011-0041-6

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.