Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314

Blake, Kimbria J.; Baral, Pankaj; Voisin, Tiphaine; Lubkin, Ashira; Pinho‐Ribeiro, Felipe A.; Adams, Kelsey; Roberson, David P.; Yuxin, C.; Otto, Michael; Woolf, Clifford J.; Torres, Victor J.; Chiu, Isaac M.

doi:10.1038/s41467-017-02448-6

Cited by 133 publications

(102 citation statements)

References 59 publications

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“…Bacteria can act directly on nociceptors via N-formylated peptides that are agonists of G protein-coupled formyl peptide receptors (Chiu et al, 2013; Pinho-Ribeiro et al, 2017) that are expressed in mouse and human DRG neurons (Ray et al, 2018). Bacteria also release α-hemolysin which directly excites nociceptors to cause pain (Chiu et al, 2013; Blake et al, 2018). While nociceptors can detect bacterial invasion, rapidly sending an alert signal to the brain, they can also play more nuanced roles in bacterial host defense.…”

Section: Discussionmentioning

confidence: 99%

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

Barragán-Iglesias¹,

Franco-Enzástiga

Jeevakumar³

et al. 2019

Preprint

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ABSTRACTOne 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.SIGNIFICANCE STATEMENTIt 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

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Section: Discussionmentioning

confidence: 99%

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

Barragán-Iglesias¹,

Franco-Enzástiga

Jeevakumar³

et al. 2019

Preprint

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“…Data from patients with clinically‐established asthma show significant levels of neuropeptides in bronchoalveolar lavage fluids and lungs are very densely innervated by sensory neurons expressing both TRPV1 and TRPA1. Importantly, the fact that pharmacological silencing of pain fibers (using treatment with QX‐314, a permanently charged quaternary derivative of lidocaine) could reduce pathological features in a mouse model of lung allergic inflammation might potentially open new therapeutic perspectives in the treatment and/or prevention of human asthma by dampening pain fibers activation and muting associated pro‐inflammatory neuro‐immune cross‐talks.…”

Section: Neural Regulation Of Innate Lymphoid Cells In Inflammationmentioning

confidence: 99%

Peripheral neurons: Master regulators of skin and mucosal immune response

et al. 2019

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The body is innervated by a meshwork of heterogeneous peripheral neurons (including sensory neurons) which project virtually to all the organs. Peripheral neurons have been studied extensively in the context of their primary function of initiation of voluntary and involuntary movement, transmission of sensations and induction of appropriate behavioral response such as withdrawal to avoid tissue injury or scratching to remove irritating molecules. More recently, breakthrough articles have shown that, on top of their primary function of signal transmission to the spinal cord and brain, peripheral neurons (including afferent neurons) could directly sense environmental alarms and consequently regulate the development of various type of immune responses through the release of neuropeptides or growth factors. In this review, we discuss recent advances in the neural regulation of the immune response, both in physiological and pathological contexts bytaking into account the type of organs (lungs, skin and gut), subtypes of peripheral neurons (sympathetic, nociceptive and intrinsic gut neurons) or immune cells and strains of pathogens studied. We also highlight future challenges in the field and potential therapeutic innovations targeting neuro-immune interactions.Keywords: inflammation r neuro-immune interactions r neuropeptide r sensory neuron r tissue homeostasis C

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“…Staphylococcus, which was classi ed as a rare and non-core microbe, was identi ed as the key microbe (rank 1) in the SNI group. Staphylococcus are infamous for their in ammatory effects on hosts; for example, Staphylococcus aureus can cause abscesses, cellulitis, osteomyelitis (Blake et al, 2018;Lowy, 1998), and dermatitis (Nakamura et al, 2013); both S. aureus and S. epidermidis can cause septic arthritis (Indelli et al, 2002;Kim and Joo, 2012); and S. saprophyticus can cause pyelonephritis (Chen, 2014;Hur et al, 2016). S. haemolyticus, S. intermedius, S. lugdunensis, S. schleiferi, and S. warneri, however, are infrequent pathogens (Foster, 1996).…”

Section: Discussionmentioning

confidence: 99%

A network approach to investigating the key microbes and stability of gut microbial communities in a mouse neuropathic pain model

Brandon-Mong

Shaw

Chen

et al. 2020

Preprint

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Background Neuropathic pain is an abnormally increased sensitivity to pain, especially from mechanical or thermal stimuli. To date, the current pharmacological treatments for neuropathic pain are still unsatisfactory. The gut microbiota reportedly plays important roles in inducing neuropathic pain, so probiotics have also been used to treat it. However, the underlying questions around the interactions in and stability of the gut microbiota in a spared nerve injury-induced neuropathic pain model and the key microbes (i.e., the microbes that play critical roles) involved have not been answered. Results Here we show that spared nerve injury-induced neuropathic pain alters gut microbial diversity in mice. We successfully constructed reliable microbial interaction networks using the Metagenomic Microbial Interaction Simulator (MetaMIS) and analyzed these networks based on 177,147 simulations. Interestingly, at a higher resolution, our results showed that spared nerve injury-induced neuropathic pain altered both the stability of the microbial community and the key microbes in a gut micro-ecosystem. Oscillospira, which was classified as a low-abundance and core microbe, was identified as the key microbe in the Sham group, whereas Staphylococcus, classified as a rare and non-core microbe, was identified as the key microbe in the spared nerve injury-induced neuropathic pain group. Conclusions In summary, our results provide novel experimental evidence that spared nerve injury-induced neuropathic pain reshapes gut microbial diversity, and alters the stability and key microbes in the gut.

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Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314

Cited by 133 publications

References 59 publications

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

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

Peripheral neurons: Master regulators of skin and mucosal immune response

A network approach to investigating the key microbes and stability of gut microbial communities in a mouse neuropathic pain model

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