title: Type I interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection.
abstract: In vivo and ex vivo models of reoviral encephalitis were utilized to delineate the contribution of type I interferon (IFN) to the host's defense against local central nervous system (CNS) viral infection and systemic viral spread. Following intracranial (i.c.) inoculation with either serotype 3 (T3) or serotype 1 (T1) reovirus, increased expression of IFN-α, IFN-β, and myxovirus-resistance protein (Mx1; a prototypical IFN stimulated gene) was observed in mouse brain tissue. Type I IFN receptor deficient mice (IFNAR(-/-)) had accelerated lethality, compared to wildtype (B6wt) controls, following i.c. T1 or T3 challenge. Although viral titers in the brain and eyes of reovirus infected IFNAR(-/-) mice were significantly increased, these mice did not develop neurologic signs or brain injury. In contrast, increased reovirus titers in peripheral tissues (liver, spleen, kidney, heart, and blood) of IFNAR(-/-) mice were associated with severe intestinal and liver injury. These results suggest that reovirus-infected IFNAR(-/-) mice succumb to peripheral disease rather than encephalitis per se. To investigate the potential role of type I IFN in brain tissue, brain slice cultures (BSCs) were prepared from IFNAR(-/-) mice and B6wt controls for ex vivo T3 reovirus infection. Compared to B6wt controls, reoviral replication and virus-induced apoptosis were enhanced in IFNAR(-/-) BSCs indicating that a type I IFN response, initiated by resident CNS cells, mediates innate viral immunity within the brain. T3 reovirus tropism was extended in IFNAR(-/-) brains to include dentate neurons, ependymal cells, and meningeal cells indicating that reovirus tropism within the CNS is dependent upon type I interferon signaling.
authors.affiliation: Medical Scientist Training Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Kalen R
authors.initials: KR
authors.lastname: Dionne
authors.forename: John M
authors.initials: JM
authors.lastname: Galvin
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schittone
authors.forename: Penny
authors.initials: P
authors.lastname: Clarke
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Tyler
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000276:immunology; D006321:Heart / Q000187:drug effects / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D064547:Myxovirus Resistance Proteins; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009474:Neurons / Q000187:drug effects / Q000821:virology; D030102:Orthoreovirus, Mammalian / Q000187:drug effects* / Q000502:physiology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012088:Reoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000187:drug effects / Q000473:pathology / Q000821:virology; D015996:Survival Rate; D056189:Viral Tropism / Q000187:drug effects / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D007370:Interferon Type I; D016898:Interferon-alpha; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D019204:GTP-Binding Proteins