Type I Interferons Act Directly on Nociceptors to Produce Pain Sensitization: Implications for Viral Infection-Induced Pain.

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-ß) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity.

Late prenatal immune activation in mice leads to behavioral and neurochemical abnormalities relevant to the negative symptoms of schizophrenia.

Based on the human epidemiological association between prenatal infection and higher risk of schizophrenia, a number of animal models have been established to explore the long-term brain and behavioral consequences of prenatal immune challenge. Accumulating evidence suggests that the vulnerability to specific forms of schizophrenia-related abnormalities is critically influenced by the precise timing of the prenatal immunological insult. In the present study, we tested the hypothesis whether late prenatal immune challenge in mice may induce long-term behavioral and neurochemical dysfunctions primarily associated with the negative symptoms of schizophrenia. We found that prenatal exposure to the viral mimic polyriboinosinic-polyribocytidilic acid (Poly-I:C; 5 mg/kg, i.v.) on gestation day (GD) 17 led to significant deficits in social interaction, anhedonic behavior, and alterations in the locomotor and stereotyped behavioral responses to acute apomorphine (APO) treatment in both male and female offspring. In addition, male but not female offspring born to immune challenged mothers displayed behavioral/cognitive inflexibility as indexed by the presence of an abnormally enhanced latent inhibition (LI) effect. Prenatal immune activation in late gestation also led to numerous, partly sex-specific changes in basal neurotransmitter levels, including reduced dopamine (DA) and glutamate contents in the prefrontal cortex and hippocampus, as well as reduced γ-aminobutyric acid (GABA) and glycine contents in the hippocampus and prefrontal cortex, respectively. The constellation of behavioral and neurochemical abnormalities emerging after late prenatal Poly-I:C exposure in mice leads us to conclude that this immune-based experimental model provides a powerful neurodevelopmental animal model especially for (but not limited to) the negative symptoms of schizophrenia.

Neuropharmacological sequelae of persistent CNS viral infections: lessons from Borna disease virus.

Borna Disease Virus (BDV) is a neurotropic RNA virus that is worldwide in distribution, causing movement and behavior disorders in a wide range of animal species. BDV has also been reported to be associated with neuropsychiatric diseases of humans by serologic study and by recovery of nucleic acid or virus from blood or brain. Natural infections of horses and sheep produce encephalitis with erratic excited behaviors, hyperkinetic movement or gait abnormalities; naturally infected cats have ataxic "staggering disease." Experimentally infected primates develop hyperactivity, aggression, disinhibition, then apathy; prosimians (lower primates) have hyperactivity, circadian disruption, abnormal social and dominance behaviors, and postural disorders. However, the neuropharmacological determinants of BD phenotypes in laboratory and natural hosts are incompletely understood. Here we review how experimentally infected rodents have provided models for examining behavioral, pharmacologic, and biochemical responses to viral challenge, and how rodents experimentally infected as neonates or as adolescents are providing models for examining age-specific neuropharmacological adaptations to viral injury.