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Chiu, Isaac

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Chiu

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Isaac

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Chiu, Isaac
Author's Publications: search.filters.isAuthorOfPublication.b0989b31-7e2f-49b9-b8d2-97737d418729

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    Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion
    (Springer Science and Business Media LLC, 2023-03-01) Pinho-Ribeiro, Felipe A.; Deng, Liwen; Neel, Dylan V.; Erdogan, Ozge; Basu, Himanish; Yang, Daping; Choi, Samantha; Walker, Alec J.; Carneiro-Nascimento, Simone; He, Kathleen; Wu, Glendon; Stevens, Beth; Doran, Kelly S.; Levy, Dan; Chiu, Isaac
    The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. How pain and neuroimmune interactions impact meningeal host defense is unclear. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system (CNS), affecting over 2.5 million people a year3-5. Here we find that Nav1.8+ neuron signaling to immune cells in the meninges via the neuropeptide calcitonin gene-related peptide (CGRP) exacerbates bacterial meningitis. Nociceptor ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors via Pneumolysin to release CGRP, which acts through its receptor RAMP1 on meningeal macrophages to inhibit chemokine expression, neutrophil recruitment and antimicrobial defenses. Macrophage-specific RAMP1 deficiency or blockade of RAMP1 signaling enhanced immune responses and bacterial clearance in meninges and brain. Therefore, targeting a neuro-immune axis in the meninges can enhance host defenses and potentially produce treatments for bacterial meningitis.
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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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    Bacteria activate sensory neurons that modulate pain and inflammation
    (2013) Chiu, Isaac; Heesters, Balthasar; Ghasemlou, Nader; Von Hehn, Christian A.; Zhao, Fan; Tran, Johnathan; Wainger, Brian; Strominger, Amanda; Muralidharan, Sriya; Horswill, Alexander R.; Wardenburg, Juliane Bubeck; Hwang, Sun Wook; Carroll, Michael; Woolf, Clifford
    Summary Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviors. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils/monocytes is not necessary for Staphylococcus aureus induced pain in mice. Mechanical and thermal hyperalgesia parallels live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin alpha-hemolysin through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host-pathogen interactions.
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    Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts
    (2015) Wainger, Brian; Buttermore, Elizabeth D.; Oliveira, Julia T.; Mellin, Cassidy; Lee, Seungkyu; Saber, Wardiya Afshar; Wang, Amy; Ichida, Justin K.; Chiu, Isaac; Barrett, Lee; Huebner, Eric A.; Bilgin, Canan; Tsujimoto, Naomi; Brenneis, Christian; Kapur, Kush; Rubin, Lee; Eggan, Kevin; Woolf, Clifford
    Reprogramming somatic cells from one cell fate to another can generate specific neurons suitable for disease modeling. To maximize the utility of patient-derived neurons, they must model not only disease-relevant cell classes but also the diversity of neuronal subtypes found in vivo and the pathophysiological changes that underlie specific clinical diseases. Here, we identify five transcription factors that reprogram mouse and human fibroblasts into noxious stimulus-detecting (nociceptor) neurons that recapitulate the expression of quintessential nociceptor-specific functional receptors and channels found in adult mouse nociceptor neurons as well as native subtype diversity. Moreover, the derived nociceptor neurons exhibit TrpV1 sensitization to the inflammatory mediator prostaglandin E2 and the chemotherapeutic drug oxaliplatin, modeling the inherent mechanisms underlying inflammatory pain hypersensitivity and painful chemotherapy-induced neuropathy. Using fibroblasts from patients with familial dysautonomia (hereditary sensory and autonomic neuropathy type III), we show that the technique can reveal novel aspects of human disease phenotypes in vitro.
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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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    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
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    Anthrax Toxins Regulate Pain Signaling and Can Deliver Molecular Cargoes Into ANTXR2+ DRG Sensory Neurons
    (Springer Science and Business Media LLC, 2021-12-20) Yang, Nicole J.; Isensee, Jörg; Neel, Dylan V.; Quadros, Andreza U.; Zhang, Han-Xiong Bear; Lauzadis, Justas; Liu, Sai Man; Shiers, Stephanie; Belu, Andreea; Palan, Shilpa; Marlin, Sandra; Maignel, Jacquie; Kennedy-Curran, Angela; Tong, Victoria S.; Moayeri, Mahtab; Röderer, Pascal; Nitzsche, Anja; Lu, Mike; Pentelute, Bradley L.; Brüstle, Oliver; Tripathi, Vineeta; Foster, Keith A.; Price, Theodore J.; Collier, Robert; Leppla, Stephen H.; Puopolo, Michelino; Bean, Bruce; Cunha, Thiago M.; Hucho, Tim; Chiu, Isaac
    Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF). Intrathecal administration of edema toxin (ET); (PA + EF) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan and nerve injury. Analgesia depended on ANTXR2 expressed by Nav1.8+ or Advillin+ neurons. ET modulated protein kinase A signaling in mouse sensory and human induced pluripotent stem cell-derived sensory neurons, and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors, which may lead to the development of new pain therapeutics.