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Roberson, David

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Roberson

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Roberson, David
Author's Publications: search.filters.isAuthorOfPublication.44f3cfe2-b68d-483b-8aa9-db35a2aba4cf

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    Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314
    (Nature Publishing Group UK, 2018) Blake, Kimbria J.; Baral, Pankaj; Voisin, Tiphaine; Lubkin, Ashira; Pinho-Ribeiro, Felipe Almeida; Adams, Kelsey; Roberson, David; Ma, Yuxin C.; Otto, Michael; Woolf, Clifford; Torres, Victor J.; Chiu, Isaac
    The hallmark of many bacterial infections is pain. The underlying mechanisms of pain during live pathogen invasion are not well understood. Here, we elucidate key molecular mechanisms of pain produced during live methicillin-resistant Staphylococcus aureus (MRSA) infection. We show that spontaneous pain is dependent on the virulence determinant agr and bacterial pore-forming toxins (PFTs). The cation channel, TRPV1, mediated heat hyperalgesia as a distinct pain modality. Three classes of PFTs—alpha-hemolysin (Hla), phenol-soluble modulins (PSMs), and the leukocidin HlgAB—directly induced neuronal firing and produced spontaneous pain. From these mechanisms, we hypothesized that pores formed in neurons would allow entry of the membrane-impermeable sodium channel blocker QX-314 into nociceptors to silence pain during infection. QX-314 induced immediate and long-lasting blockade of pain caused by MRSA infection, significantly more than lidocaine or ibuprofen, two widely used clinical analgesic treatments.
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    Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons
    (2013) Roberson, David; Gudes, Sagi; Sprague, Jared; Patoski, Haley A. W.; Robson, Victoria K.; Blasl, Felix; Duan, Bo; Oh, Seog Bae; Bean, Bruce; Ma, Qiufu; Binshtok, Alexander M.; Woolf, Clifford
    The peripheral terminals of primary sensory neurons detect histamine and non-histamine itch-provoking ligands through molecularly distinct transduction mechanisms. It remains unclear, however, whether these distinct pruritogens activate the same or different afferent fibers. We utilized a strategy of reversibly silencing specific subsets of murine pruritogen-sensitive sensory axons by targeted delivery of a charged sodium-channel blocker and found that functional blockade of histamine itch did not affect the itch evoked by chloroquine or SLIGRL-NH2, and vice versa. Notably, blocking itch-generating fibers did not reduce pain-associated behavior. However, silencing TRPV1+ or TRPA1+ neurons allowed AITC or capsaicin respectively to evoke itch, implying that certain peripheral afferents may normally indirectly inhibit algogens from eliciting itch. These findings support the presence of functionally distinct sets of itch-generating neurons and suggest that targeted silencing of activated sensory fibers may represent a clinically useful anti-pruritic therapeutic approach for histaminergic and non-histaminergic pruritus.
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    Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation
    (Elsevier BV, 2015) Talbot, Sebastien; Abdulnour, Raja-Elie; Burkett, Patrick; Lee, Seungkyu; Cronin, Shane J.F.; Pascal, Maud A.; Laedermann, Cedric; Foster, Simmie; Tran, Johnathan V.; Lai, Nicole; Chiu, Isaac; Ghasemlou, Nader; DiBiase, Matthew; Roberson, David; Von Hehn, Christian; Agac, Busranour; Haworth, Oliver; Seki, Hiroyuki; Penninger, Josef M.; Kuchroo, Vijay; Bean, Bruce; Levy, Bruce; Woolf, Clifford
    Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8+ sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large pore ion channels to specifically block nociceptors, substantially reduced ovalbumin or house dust mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4+ and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma.
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    Analysis of Voluntary Behavior to Interrogate Neural Function
    (2016-02-11) Roberson, David; Born, Richard; Rogulja, Dragana; Boyden, Ed
    Mice and rats are critical to our understanding of human biology. They share most of our genome, are susceptible to most of the same diseases and usually benefit from clinical therapeutics, if only at very high doses. Equally important has been the development of new rodent research tools that allow us to manipulate their genome, to induce new likenesses and illuminate our similarities. However, there remain substantial obstacles to modeling clinically relevant human somatosensory experiences, such as chronic pain, in rodents. Conventional rodent pain assays require robust stimuli to generate brief behavioral readouts and they are able to detect the effects of analgesics only at levels well beyond clinically effective human doses. New technologies are needed that are sensitive to low intensity nociceptive stimuli and are able to detect the effects of analgesic drugs at clinically relevant doses. It is possible to tell when someone is in pain simply by his or her body language; but rodents and other prey animals do not as readily show behaviors that betray the presence of pain or injury. We propose that ancestral selection pressures have favored propagation of prey that mask outward signs of injury or disease from the predator, and that behavioral indicators of ongoing pain or itch in rodents should therefore be most evident when the appearance of predation risk is minimized and/or from a viewpoint not naturally seen by predators. Based on this hypothesis, we developed new devices and techniques for observation and analysis of voluntary rodent behavior, with careful consideration of their ecological position as nocturnal prey animals. Here, we demonstrate the capability of one of these new technologies to detect the prolonged effects of low intensity nociceptive stimuli in freely behaving mice and rats and to show that clinically relevant analgesic doses can extinguish pain related behaviors in rodents. Applying the same hypothesis to the study of pruriception (itch), we built another device that optimizes quantification of rodent scratching behavior. We demonstrate its utility by using it to reveal new insights into the cellular basis of pain and itch sensation and advance novel therapeutics for human injury and disease.
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    Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity
    (eLife Sciences Publications, Ltd, 2014) Chiu, Isaac; Barrett, Lee; Williams, Erika; Strochlic, David E.; Lee, Seungkyu; Weyer, Andy D; Lou, Shan; Bryman, Greg; Roberson, David; Ghasemlou, Nader; Piccoli, Cara; Ahat, Ezgi; Wang, Victor; Cobos, Enrique J; Stucky, Cheryl L; Ma, Qiufu; Liberles, Stephen; Woolf, Clifford
    The somatosensory nervous system is critical for the organism's ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non-overlapping classes of neurons: 1) IB4+SNS-Cre/TdTomato+, 2) IB4−SNS-Cre/TdTomato+, and 3) Parv-Cre/TdTomato+ cells, encompassing the majority of nociceptive, pruriceptive, and proprioceptive neurons. These neurons displayed distinct expression patterns of ion channels, transcription factors, and GPCRs. Highly parallel qRT-PCR analysis of 334 single neurons selected by membership of the three populations demonstrated further diversity, with unbiased clustering analysis identifying six distinct subgroups. These data significantly increase our knowledge of the molecular identities of known DRG populations and uncover potentially novel subsets, revealing the complexity and diversity of those neurons underlying somatosensation. DOI: http://dx.doi.org/10.7554/eLife.04660.001