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.

Differentiation of Neurons Restricts Arbovirus Replication and Increases Expression of the Alpha Isoform of IRF-7

“…Collectively, maturation of neurons is associated with increased levels of IFN signaling pathway components (33,34). Mature neurons are able to produce an innate immune response upon virus infection (28,(30)(31)(32)(33). Increased basal levels of Irf-3 and Irf-7 expression could contribute to an enhanced host response to infection.…”

“…These studies suggest a potential role for IFN signaling in maturation-dependent neuronal restriction of neuronotropic virus replication. Neurons can induce IFN signaling upon infection (28,(30)(31)(32)(33), and IFN expression is increased during maturation of cultured neurons (34). However, autocrine IFN signaling has not been implicated in maturation-dependent control of virus replication (33).…”

Daxx Upregulation within the Cytoplasm of Reovirus-Infected Cells Is Mediated by Interferon and Contributes to Apoptosis

“…Upregulation of Daxx was previously reported in bone marrow cells following type I IFN exposure (46,47). We previously showed that interferon signaling is initiated in the reovirus-infected brain and serves to limit local viral tropism and systemic viral spread (11,40,44). Thus, we hypothesized that IFN was driving Daxx upregulation during reovirus infection.…”

“…2). However, Daxx was not upregulated in reovirus-infected brain slices prepared from IFNAR Ϫ/Ϫ donor mice, despite the fact that viral growth is enhanced in this context (40). This indicated that the type I interferon arm of innate immunity is the major mechanism underlying reovirus-induced Daxx upregulation.…”

“…Organotypic brain slice culture studies. Brain slice cultures (BSCs) were prepared from 2-to 3-day-old mice as previously described (40). Briefly, four 400-m coronal sections of the cerebrum (containing hippocampi and thalamus) were made from a single animal by using a vibrating blade microtome (VT1000S; Leica, Bannockburn, IL).…”