한빛사논문
- 조회1,109
Nicole J. Yang1, Jörg Isensee2, Dylan V. Neel1, Andreza U. Quadros3, Han-Xiong Bear Zhang4, Justas Lauzadis5, Sai Man Liu 6, Stephanie Shiers7, Andreea Belu2, Shilpa Palan6, Sandra Marlin6, Jacquie Maignel8, Angela Kennedy-Curran 1, Victoria S. Tong1, Mahtab Moayeri9, Pascal Röderer10,11, Anja Nitzsche10,11, Mike Lu12, Bradley L. Pentelute12,13,14,15, Oliver Brüstle10, Vineeta Tripathi6, Keith A. Foster6, Theodore J. Price 7, R. John Collier16, Stephen H. Leppla9, Michelino Puopolo5, Bruce P. Bean4, Thiago M. Cunha3, Tim Hucho2 and Isaac M. Chiu 1,*
1Department of Immunology, Harvard Medical School, Boston, MA, USA. 2Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. 3Center for Research in Inflammatory Diseases, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil. 4Department of Neurobiology, Harvard Medical School, Boston, MA, USA. 5Department of Anesthesiology, Stony Brook Medicine, Stony Brook, NY, USA. 6Ipsen Bioinnovation Ltd, Abingdon, UK. 7Department of Neuroscience, Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, USA. 8Ipsen Innovation, Les Ulis, France. 9Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 10Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany. 11Cellomics Unit, LIFE & BRAIN GmbH, Bonn, Germany. 12Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. 13The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. 14Broad Institute of MIT and Harvard, Cambridge, MA, USA. 15Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. 16Department of Microbiology, Harvard Medical School, Boston, MA, USA.
*Correspondence to Isaac M. Chiu.
Abstract
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 or 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.
논문정보
- Research article
- 2021년 12월 (BRIC 등록일 2021-12-27)
- 국외 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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