Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>One of the first signs of viral infection is body-wide aches and pain. While 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 are 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-β) 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 interferons 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.</jats:p><jats:sec><jats:title>SIGNIFICANCE STATEMENT</jats:title><jats:p>It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 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) that 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</jats:p></jats:sec>

Acute activation of bronchopulmonary vagal nociceptors by type I interferons

“…The data are also largely in keeping with the findings of a recent study of single-cell RNAseq analysis of 88 airway specific vagal sensory neurons (Mazzone et al 2020). Previous studies have shown that both type 1 and type 2 IFN receptors are also expressed in sensory neurons in the dorsal root ganglion and play a role in sensitizing nociceptors (Barragan-Iglesias et al 2020). Moreover, these receptors appear to be transported towards the central and peripheral terminals (Neumann et al 1997;Vikman et al 1998;Liu et al 2016).…”

“…Previous studies have shown that both type 1 and type 2 IFN receptors are also expressed in sensory neurons in the dorsal root ganglion and play a role in sensitizing nociceptors (Barragan‐Iglesias et al . 2020). Moreover, these receptors appear to be transported towards the central and peripheral terminals (Neumann et al .…”

Central Nervous System Targets and Routes for SARS-CoV-2: Current Views and New Hypotheses

“… 105 The painful peripheral neuropathies observed in some COVID-19 patients could be associated with interferon-1-induced hyperexcitability of DRG neurons resulting from viral infection. 108 A similar exacerbated immune response may also account for the peripheral vascular inflammatory reactions observed in the multisystem Kawasaki-like syndrome that affects some COVID-19 patients, 109 , 110 particularly children. Dermatological manifestations of COVID-19 such as maculopapular exanthem present in ∼36% of patients 111 could also progress from the DRG neuron to the skin in an anterograde fashion, as schematically shown in the bottom right portion of Figure 2 (red arrow).…”

PML-Dependent Memory of Type I Interferon Treatment Results in a Restricted Form of HSV Latency

“…Peripheral neurons are capable of responding to type I IFN signaling, given the robust induction in ISG expression and formation of PML-NBs following treatment with IFNα, and this is supported by a number of previous studies (Yordy et al, 2012, Katzenell and Leib, 2016, Song et al, 2016, Barragan-Iglesias et al, 2020. Importantly, however, peripheral neurons produce little to no type I interferons upon HSV infection (Yordy et al, 2012, Rosato andLeib, 2014), indicating that IFN production arises from other surrounding infected cells.…”