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Abstract
SummaryIn sterile neuroinflammation, a pathological role is proposed for microglia, whereas in viral encephalitis, their function is not entirely clear. Many viruses exploit the odorant system and enter the CNS via the olfactory bulb (OB). Upon intranasal vesicular stomatitis virus instillation, we show an accumulation of activated microglia and monocytes in the OB. Depletion of microglia during encephalitis results in enhanced virus spread and increased lethality. Activation, proliferation, and accumulation of microglia are regulated by type I IFN receptor signaling of neurons and astrocytes, but not of microglia. Morphological analysis of myeloid cells shows that type I IFN receptor signaling of neurons has a stronger impact on the activation of myeloid cells than of astrocytes. Thus, in the infected CNS, the cross talk among neurons, astrocytes, and microglia is critical for full microglia activation and protection from lethal encephalitis.
Highlights
Acute viral infections of the CNS are rare, but can be devastating
Protective IFN-b is induced locally within the olfactory bulb (OB), primarily in astrocytes and to a lesser extent in neurons (Detje et al, 2015; Pfefferkorn et al, 2015), and the virus is efficiently arrested in a type I interferon receptor (IFNAR)-dependent manner so that the host is protected from lethal encephalitis (Detje et al, 2009)
We found that vesicular stomatitis virus (VSV) infection via the olfactory route induces accumulation of activated microglia and monocytes in the OB via local proliferation and infiltration
Summary
Acute viral infections of the CNS are rare, but can be devastating. Rabies is a prototypic acute neurotropic zoonotic infection causing many deaths worldwide (John et al, 2015). Other zoonotic pathogens that cause encephalitis include Japanese encephalitis virus (JEV), Dengue virus (DenV), and West Nile virus (WNV) and are often associated with pathologies such as high morbidity, mortality, and post-recovery neurocognitive deficits (John et al, 2015; Sadek et al, 2010). These pathogens are shown to enter the CNS through the olfactory bulb (OB) (Kalinke et al, 2011; Koyuncu et al, 2013; van Riel et al, 2015). In addition to the induction of interferon-b (IFN-b), CNS infection via the olfactory route results in recruitment of myeloid cells such as microglia (Getts et al, 2008), and peripheral immune cells such as dendritic cells (DCs) (D’Agostino et al, 2012), T cells, monocytes, and others (Steel et al, 2009) into the CNS
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