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

Nicole J Yang; Jörg Isensee; Dylan V Neel; Andreza U Quadros; Han-Xiong Bear Zhang; Justas Lauzadis; Sai Man Liu; Stephanie Shiers; Andreea Belu; Shilpa Palan; Sandra Marlin; Jacquie Maignel; Angela Kennedy-Curran; Victoria S Tong; Mahtab Moayeri; Pascal Röderer; Anja Nitzsche; Mike Lu; Bradley L Pentelute; Oliver Brüstle; Vineeta Tripathi; Keith A Foster; Theodore J Price; R John Collier; Stephen H Leppla; Michelino Puopolo; Bruce P Bean; Thiago M Cunha; Tim Hucho; Isaac M Chiu

doi:10.1038/s41593-021-00973-8

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

Nat Neurosci. 2022 Feb;25(2):168-179. doi: 10.1038/s41593-021-00973-8. Epub 2021 Dec 20.

Authors

Nicole J Yang¹, Jörg Isensee², Dylan V Neel¹, Andreza U Quadros³, Han-Xiong Bear Zhang⁴, Justas Lauzadis⁵, Sai Man Liu⁶, Stephanie Shiers⁷, Andreea Belu², Shilpa Palan⁶, Sandra Marlin⁶, Jacquie Maignel⁸, Angela Kennedy-Curran¹, Victoria S Tong¹, Mahtab Moayeri⁹, Pascal Röderer^{10

11}, Anja Nitzsche^{10

11}, Mike Lu¹², Bradley L Pentelute^{12

13

14

15}, Oliver Brüstle¹⁰, Vineeta Tripathi⁶, Keith A Foster⁶, Theodore J Price⁷, R John Collier¹⁶, Stephen H Leppla⁹, Michelino Puopolo⁵, Bruce P Bean⁴, Thiago M Cunha³, Tim Hucho², Isaac M Chiu¹⁷

Affiliations

¹ Department of Immunology, Harvard Medical School, Boston, MA, USA.
² Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³ Center for Research in Inflammatory Diseases, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
⁴ Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
⁵ Department of Anesthesiology, Stony Brook Medicine, Stony Brook, NY, USA.
⁶ Ipsen Bioinnovation Ltd, Abingdon, UK.
⁷ Department of Neuroscience, Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, USA.
⁸ Ipsen Innovation, Les Ulis, France.
⁹ Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
¹⁰ Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany.
¹¹ Cellomics Unit, LIFE & BRAIN GmbH, Bonn, Germany.
¹² Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹³ The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁶ Department of Microbiology, Harvard Medical School, Boston, MA, USA.
¹⁷ Department of Immunology, Harvard Medical School, Boston, MA, USA. Isaac_Chiu@hms.harvard.edu.

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 Na_v1.8⁺ 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.

Publication types

Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anthrax* / microbiology
Anthrax* / therapy
Bacillus anthracis* / metabolism
Bacterial Toxins* / metabolism
Ganglia, Spinal / metabolism
Humans
Induced Pluripotent Stem Cells* / metabolism
Mice
Nociceptors / metabolism
Pain
Receptors, Peptide / metabolism

Substances

ANTXR2 protein, human
Bacterial Toxins
Receptors, Peptide

Abstract

Publication types

MeSH terms

Substances

Grants and funding