Type I interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection

• Published in: Journal of neurovirology 2011-08, Vol.17 (4), p.314-326
• Main Authors: Dionne, Kalen R., Galvin, John M., Schittone, Stephanie A., Clarke, Penny, Tyler, Kenneth L.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain - drug effects; Brain - immunology; Brain - metabolism; Brain - pathology; Brain - virology; Enzyme-Linked Immunosorbent Assay; GTP-Binding Proteins - biosynthesis; GTP-Binding Proteins - immunology; Heart - drug effects; Heart - virology; Human viral diseases; Humans; Immunohistochemistry; Immunology; Immunomodulators; Infectious Diseases; Interferon Type I - genetics; Interferon Type I - immunology; Interferon Type I - metabolism; Interferon Type I - pharmacology; Interferon-alpha - biosynthesis; Interferon-alpha - immunology; Interferon-beta - biosynthesis; Interferon-beta - immunology; Kidney - drug effects; Kidney - pathology; Kidney - virology; Liver - drug effects; Liver - pathology; Liver - virology; Medical sciences; Mice; Mice, Knockout; Myxovirus Resistance Proteins; Neuroglia - drug effects; Neuroglia - immunology; Neuroglia - metabolism; Neuroglia - pathology; Neuroglia - virology; Neurology; Neurons - drug effects; Neurons - virology; Neurosciences; Orthoreovirus, Mammalian - drug effects; Orthoreovirus, Mammalian - physiology; Pharmacology. Drug treatments; Receptor, Interferon alpha-beta - deficiency; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - immunology; Reoviridae Infections - genetics; Reoviridae Infections - immunology; Reoviridae Infections - metabolism; Reoviridae Infections - mortality; Reoviridae Infections - pathology; Reoviridae Infections - virology; Reovirus; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; Spleen - drug effects; Spleen - pathology; Spleen - virology; Survival Rate; Viral diseases; Viral diseases of the nervous system; Viral Tropism - drug effects; Viral Tropism - immunology; Virology; Virus Replication - drug effects
• ISSN: 1355-0284; 1538-2443
• DOI: 10.1007/s13365-011-0038-1

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.