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

Author(s):Show less -

Yang, Nicole J. ^[1] ; Isensee, Joerg ^{[2, 3]} ; Neel, V, Dylan ; Quadros, Andreza U. ^[4] ; Zhang, Han-Xiong Bear ^[5] ; Lauzadis, Justas ^[6] ; Liu, Sai Man ^[7] ; Shiers, Stephanie ^[8] ; Belu, Andreea ^{[2, 3]} ; Palan, Shilpa ^[7] ; Marlin, Sandra ^[7] ; Maignel, Jacquie ^[9] ; Kennedy-Curran, Angela ^[10] ; Tong, Victoria S. ^[10] ; Moayeri, Mahtab ^[11] ; Roederer, Pascal ^{[12, 13, 14]} ; Nitzsche, Anja ^{[12, 13, 14]} ; Lu, Mike ^[15] ; Pentelute, Bradley L. ^{[15, 16, 17, 18]} ; Bruestle, Oliver ^{[12, 13]} ; Tripathi, Vineeta ^[7] ; Foster, Keith A. ^[7] ; Price, Theodore J. ^[8] ; Collier, R. John ^[19] ; Leppla, Stephen H. ^[11] ; Puopolo, Michelino ^[6] ; Bean, Bruce P. ^[5] ; Cunha, Thiago M. ^[4] ; Hucho, Tim ^{[2, 3]} ; Chiu, Isaac M. ^[10]

Affiliation:Show less -

^[1] Harvard Med Sch, Dept Immunol, Boston, MA 02115 - USA

^[2] Univ Cologne, Univ Hosp Cologne, Cologne - Germany

^[3] Univ Cologne, Fac Med, Dept Anesthesiol & Intens Care Med, Translat Pain Res, Cologne - Germany

^[4] Univ Sao Paulo, Ctr Res Inflammatory Dis, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil

^[5] Harvard Med Sch, Dept Neurobiol, Boston, MA 02115 - USA

^[6] Stony Brook Med, Dept Anesthesiol, Stony Brook, NY - USA

^[7] Ipsen Bioinnovat Ltd, Abingdon, Oxon - England

^[8] Univ Texas Dallas, Ctr Adv Pain Studies, Dept Neurosci, Richardson, TX 75083 - USA

^[9] Ipsen Innovat, Les Ulis - France

^[10] Neel, Dylan, V, Harvard Med Sch, Dept Immunol, Boston, MA 02115 - USA

^[11] NIAID, Lab Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 - USA

^[12] Univ Hosp Bonn, Bonn - Germany

^[13] Univ Bonn, Inst Reconstruct Neurobiol, Med Fac, Bonn - Germany

^[14] LIFE & BRAIN GmbH, Cell Unit, Bonn - Germany

^[15] MIT, Dept Chem, Cambridge, MA 02139 - USA

^[16] Broad Inst MIT & Harvard, Cambridge, MA 02142 - USA

^[17] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[18] MIT, Ctr Environm Hlth Sci, Cambridge, MA 02139 - USA

^[19] Harvard Med Sch, Dept Microbiol, Boston, MA 02115 - USA

• Document type: Journal article
• Source: NATURE NEUROSCIENCE; DEC 2021.
• Web of Science Citations: 1

Abstract

Discovering that nociceptive sensory neurons express the receptor for anthrax toxin, Yang et al. show that anthrax toxin can induce potent analgesia in mice and facilitate the delivery of potentially analgesic cargo proteins into nociceptive neurons. 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. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC