The Alpha/Beta Interferon Response Controls Tissue Tropism and Pathogenicity of Poliovirus

Abstract

Poliovirus selectively replicates in neurons in the spinal cord and brainstem, although poliovirus receptor (PVR) expression is observed in both the target and nontarget tissues in humans and transgenic mice expressing human PVR (PVR-transgenic mice). We assessed the role of alpha/beta interferon (IFN) in determining tissue tropism by comparing the pathogenesis of the virulent Mahoney strain in PVR-transgenic mice and PVR-transgenic mice deficient in the alpha/beta IFN receptor gene (PVR-transgenic/Ifnar knockout mice). PVR-transgenic/Ifnar knockout mice showed increased susceptibility to poliovirus. After intravenous inoculation, severe lesions positive for the poliovirus antigen were detected in the liver, spleen, and pancreas in addition to the central nervous system. These results suggest that the alpha/beta IFN system plays an important role in determining tissue tropism by protecting nontarget tissues that are potentially susceptible to infection. We subsequently examined the expression of IFN and IFN-stimulated genes (ISGs) in the PVR-transgenic mice. In the nontarget tissues, ISGs were expressed even in the noninfected state, and the expression level increased soon after poliovirus infection. On the contrary, in the target tissues, ISG expression was low in the noninfected state and sufficient response after poliovirus infection was not observed. The results suggest that the unequal IFN response is one of the important determinants for the differential susceptibility of tissues to poliovirus. We consider that poliovirus replication was observed in the nontarget tissues of PVR-transgenic/Ifnar knockout mice because the IFN response was null in all tissues.

Spectrum of disease outcomes in mice infected with YFV-17D

“…All studies were performed in a manner designed to minimize pain and suffering, and any animals that exhibited severe disease signs were euthanized immediately in accordance with IACUC approved end points. For this study, WT mice were immune-competent C57BL/6 PVR-Tg21 mice (IFNAR +/+ ) expressing the human poliovirus receptor and immune-deficient mice were C57BL/6 PVR-Tg21 mice deficient for the IFN-a/b receptor (IFNAR 2/2 ) expressing the human poliovirus receptor (provided by S. Koike, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan) (Ida-Hosonuma et al, 2005). Mice (3-4 or 6-7 weeks old) were injected in the footpad, subcutaneously in the back scruff, intramuscularly in the left quadricep or intraperitoneally with 10 4 (Figs 1, 3, 4, 5 and 6) or 10 7 p.f.u.…”

Local Type I IFN Receptor Signaling Protects against Virus Spread within the Central Nervous System

“…Whereas lethally infected wild-type (WT) mice show productive virus infection exclusively in the CNS, in IFNAR Ϫ/Ϫ mice the virus is universally spread (20). Thus, IFNAR expression does seem to play a role in determining viral tropism (21).…”

Enterovirus 94, a proposed new serotype in human enterovirus species D

“…Moreover, Both virus and host determinants affect the tissue tropism of a virus. These determinants include receptor specificity, host-cell factors participating in translation and replication initiation (reviewed by Whitton et al, 2005) and the local cytokine (alpha/beta interferon) milieu at the site of infection (Ida-Hosonuma et al, 2005;Yoshikawa et al, 2006). The ability of EV94 to replicate in a wide variety of cell lines in vitro suggests that its receptor is expressed widely.…”