IFN-β Deficiency Results in Fatal or Demyelinating Disease in C57BL/6 Mice Infected With Theiler’s Murine Encephalomyelitis Viruses

Abstract

Type I Interferons (IFN-I) are important inducers of the antiviral immune response and immune modulators. IFN-β is the most highly expressed IFN-I in the central nervous system (CNS). The infection of SJL mice with the BeAn or the DA strain of Theiler’s murine encephalomyelitis virus (TMEV) results in a progressive demyelinating disease. C57BL/6 mice are usually resistant to TMEV-induced demyelination and eliminate these strains from the CNS within several weeks. Using C57BL/6 IFN-β knockout (IFN-β-/-) mice infected with TMEV, we evaluated the role of IFN-β in neuroinfection. Despite the resistance of C57BL/6 wild type (WT) mice to TMEV infection, DA-infected IFN-β-/- mice had to be killed at 7 to 8 days post infection (dpi) due to severe clinical disease. In contrast, BeAn-infected IFN-β-/- mice survived until 98 dpi. Nevertheless at 14 dpi, BeAn-infected IFN-β-/- mice showed a stronger encephalitis and astrogliosis, higher viral load as well as higher mRNA levels of Isg15, Eif2ak2 (PKR), Tnfa, Il1b, Il10, Il12 and Ifng in the cerebrum than BeAn-infected WT mice. Moreover, the majority of IFN-β-/- mice did not clear the virus from the CNS and developed mild demyelination in the spinal cord at 98 dpi, whereas virus and lesions were absent in the spinal cord of WT mice. Persistently infected IFN-β-/- mice also had higher Isg15, Eif2ak1, Tnfa, Il1a, Il1b and Ifng mRNA levels in the spinal cord at 98 dpi than their virus-negative counterparts indicating an activation of IFN-I signaling and ongoing inflammation. Most importantly, BeAn-infected NesCre+/- IFN-βfl/fl mice, which do not express IFN-β in neurons, astrocytes and oligodendrocytes, only developed mild brain lesions similar to WT mice. Consequently, IFN-β produced by neuroectodermal cells does not seem to play a critical role in the resistance of C57BL/6 mice against fatal and demyelinating disease induced by TMEV strains.

IFNAR signaling of neuroectodermal cells is essential for the survival of C57BL/6 mice infected with Theiler’s murine encephalomyelitis virus

“…Functional categories of these genes included the terms antigen processing and presentation, response to cytokine, and response to interferon (IFN)-β. In accordance with this, TMEV-infected IFN-β −/− C57BL/6 mice show an impaired virus elimination capacity and 70% of these mice develop mild demyelination [ 7 ]. IFNs are cytokines that belong to the first line of antiviral response of the innate immune system [ 8 , 9 ].…”

“…The number of perivascular mononuclear cells was quantified in the cerebrum of complete and cell-type specific IFNAR-deficient mice using a semiquantitative scoring system (0: no infiltrates; 1: one layer of infiltrates; 2: 2–3 layers of infiltrates; 3: > 3 layers of infiltrates). Eight areas (meninges, cortex cerebri, subcortical white matter, hippocampus, thalamus/hypothalamus, third ventricle, lateral ventricles and basal ganglia) were investigated separately in both hemispheres (16 values per animal) and the mean calculated for each mouse [ 7 ]. Moreover, hippocampal cell loss was semiquantitatively quantified (0: no neuronal loss; 1: loss of < 25% of neurons; 2: loss of 25–50% of neurons; 3: loss of > 50% of neurons).…”

“…The percentage of CD3 + , CD45R + and Iba-1 + -positive cells in the perivascular area (Virchow–Robin space) of four vessels present on all three immunostained slides (cut at the level of the hippocampus) was determined. These four vessels were randomly selected, but only vessels with higher numbers of perivascular cells were selected in order to maximize the number of cells evaluated [ 7 ]. The number of GFAP + cells, MAC3 + cells, and TMEM119 + cells within the hippocampus was also evaluated semiquantitatively (0: no increase in cell number; 1: mildly increased cell number; 2: moderately increased cell number; 3: severely increased cell number) [ 51 ].…”

“…The amount of infectious virus in the samples of frozen cerebral tissue of complete and cell-type specific IFNAR-deficient mice was quantified using a plaque assay as described [ 7 ].…”

“…Interestingly, myeloid cells such as microglia seem to have minor contribution to IFN-I production during neuroinfection [ 29 , 30 ]. Nevertheless, IFN-β produced by other cells than astrocytes seems to be sufficient to maintain the resistance of C57BL/6 mice against TMEV-IDD [ 7 ].…”