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

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

Anesthesiology

Stony Brook University

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

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.

Original language	English
Pages (from-to)	168-179
Number of pages	12
Journal	Nature Neuroscience
Volume	25
Issue number	2
DOIs	https://doi.org/10.1038/s41593-021-00973-8
State	Published - Feb 2022

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Yang, N. J., Isensee, J., Neel, D. V., Quadros, A. U., Zhang, H. X. B., Lauzadis, J., Liu, S. M., Shiers, S., Belu, A., Palan, S., Marlin, S., Maignel, J., Kennedy-Curran, A., Tong, V. S., Moayeri, M., Röderer, P., Nitzsche, A., Lu, M., Pentelute, B. L., ... Chiu, I. M. (2022). Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2⁺ DRG sensory neurons. Nature Neuroscience, 25(2), 168-179. https://doi.org/10.1038/s41593-021-00973-8

@article{99fd2d2636f34dd09319045ecf53a000,

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

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.",

author = "Yang, \{Nicole J.\} and J{\"o}rg Isensee and Neel, \{Dylan V.\} and Quadros, \{Andreza U.\} and Zhang, \{Han Xiong Bear\} and Justas Lauzadis and Liu, \{Sai Man\} and Stephanie Shiers and Andreea Belu and Shilpa Palan and Sandra Marlin and Jacquie Maignel and Angela Kennedy-Curran and Tong, \{Victoria S.\} and Mahtab Moayeri and Pascal R{\"o}derer and Anja Nitzsche and Mike Lu and Pentelute, \{Bradley L.\} and Oliver Br{\"u}stle and Vineeta Tripathi and Foster, \{Keith A.\} and Price, \{Theodore J.\} and Collier, \{R. John\} and Leppla, \{Stephen H.\} and Michelino Puopolo and Bean, \{Bruce P.\} and Cunha, \{Thiago M.\} and Tim Hucho and Chiu, \{Isaac M.\}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = feb,

doi = "10.1038/s41593-021-00973-8",

language = "English",

volume = "25",

pages = "168--179",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Research",

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Yang, NJ, Isensee, J, Neel, DV, Quadros, AU, Zhang, HXB, Lauzadis, J, Liu, SM, Shiers, S, Belu, A, Palan, S, Marlin, S, Maignel, J, Kennedy-Curran, A, Tong, VS, Moayeri, M, Röderer, P, Nitzsche, A, Lu, M, Pentelute, BL, Brüstle, O, Tripathi, V, Foster, KA, Price, TJ, Collier, RJ, Leppla, SH, Puopolo, M, Bean, BP, Cunha, TM, Hucho, T & Chiu, IM 2022, 'Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2⁺ DRG sensory neurons', Nature Neuroscience, vol. 25, no. 2, pp. 168-179. https://doi.org/10.1038/s41593-021-00973-8

TY - JOUR

T1 - Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2+ DRG sensory neurons

AU - Yang, Nicole J.

AU - Isensee, Jörg

AU - Neel, Dylan V.

AU - Quadros, Andreza U.

AU - Zhang, Han Xiong Bear

AU - Lauzadis, Justas

AU - Liu, Sai Man

AU - Shiers, Stephanie

AU - Belu, Andreea

AU - Palan, Shilpa

AU - Marlin, Sandra

AU - Maignel, Jacquie

AU - Kennedy-Curran, Angela

AU - Tong, Victoria S.

AU - Moayeri, Mahtab

AU - Röderer, Pascal

AU - Nitzsche, Anja

AU - Lu, Mike

AU - Pentelute, Bradley L.

AU - Brüstle, Oliver

AU - Tripathi, Vineeta

AU - Foster, Keith A.

AU - Price, Theodore J.

AU - Collier, R. John

AU - Leppla, Stephen H.

AU - Puopolo, Michelino

AU - Bean, Bruce P.

AU - Cunha, Thiago M.

AU - Hucho, Tim

AU - Chiu, Isaac M.

PY - 2022/2

Y1 - 2022/2

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85121477572

U2 - 10.1038/s41593-021-00973-8

DO - 10.1038/s41593-021-00973-8

M3 - Article

C2 - 34931070

SN - 1097-6256

VL - 25

SP - 168

EP - 179

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 2

ER -

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

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