Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2 + DRG sensory neurons.

Autor: Yang NJ; Department of Immunology, Harvard Medical School, Boston, MA, USA., Isensee J; Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Neel DV; Department of Immunology, Harvard Medical School, Boston, MA, USA., Quadros AU; Center for Research in Inflammatory Diseases, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Zhang HB; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Lauzadis J; Department of Anesthesiology, Stony Brook Medicine, Stony Brook, NY, USA., Liu SM; Ipsen Bioinnovation Ltd, Abingdon, UK., Shiers S; Department of Neuroscience, Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, USA., Belu A; Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Palan S; Ipsen Bioinnovation Ltd, Abingdon, UK., Marlin S; Ipsen Bioinnovation Ltd, Abingdon, UK., Maignel J; Ipsen Innovation, Les Ulis, France., Kennedy-Curran A; Department of Immunology, Harvard Medical School, Boston, MA, USA., Tong VS; Department of Immunology, Harvard Medical School, Boston, MA, USA., Moayeri M; Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Röderer P; Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany.; Cellomics Unit, LIFE & BRAIN GmbH, Bonn, Germany., Nitzsche A; Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany.; Cellomics Unit, LIFE & BRAIN GmbH, Bonn, Germany., Lu M; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA., Pentelute BL; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.; The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA., Brüstle O; Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany., Tripathi V; Ipsen Bioinnovation Ltd, Abingdon, UK., Foster KA; Ipsen Bioinnovation Ltd, Abingdon, UK., Price TJ; Department of Neuroscience, Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, USA., Collier RJ; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Leppla SH; Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Puopolo M; Department of Anesthesiology, Stony Brook Medicine, Stony Brook, NY, USA., Bean BP; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Cunha TM; Center for Research in Inflammatory Diseases, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Hucho T; Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Chiu IM; Department of Immunology, Harvard Medical School, Boston, MA, USA. Isaac_Chiu@hms.harvard.edu.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2022 Feb; Vol. 25 (2), pp. 168-179. Date of Electronic Publication: 2021 Dec 20.
DOI: 10.1038/s41593-021-00973-8
Abstrakt: 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 Na v 1.8 + 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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