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

J Neurovirol. 2011 Aug;17(4):314-26. doi: 10.1007/s13365-011-0038-1. Epub 2011 Jun 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • 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
  • Humans
  • Immunohistochemistry
  • 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
  • Mice
  • Mice, Knockout
  • Myxovirus Resistance Proteins
  • Neuroglia / drug effects
  • Neuroglia / immunology*
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neuroglia / virology
  • Neurons / drug effects
  • Neurons / virology
  • Orthoreovirus, Mammalian / drug effects*
  • Orthoreovirus, Mammalian / physiology
  • 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
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Spleen / drug effects
  • Spleen / pathology
  • Spleen / virology
  • Survival Rate
  • Viral Tropism / drug effects
  • Viral Tropism / immunology
  • Virus Replication / drug effects*

Substances

  • Interferon Type I
  • Interferon-alpha
  • Mx1 protein, mouse
  • Myxovirus Resistance Proteins
  • Receptor, Interferon alpha-beta
  • Interferon-beta
  • GTP-Binding Proteins