Nature Sub-Journal: Fighting with Poison!

Click the blue word to pay attention to that our sensory neurons can perceive potentially noxious stimuli, and protect the body by activating pain perception and triggering defensive behavior
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There are differences in the response of bacteria to nociceptors: Staphylococcus aureus can directly activate nociceptors, while Mycobacterium ulcerans can inhibit the activity of nociceptors
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Anthrax toxin is the main virulence factor of Bacillus anthracis.
It is composed of protective antigen (PA), edema factor (EF) and lethal factor (LF), which can form lethal toxin (PA+LF) and edema toxin (PA+EF)
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There are two receptors for PA: ANTXR1 and ANTXR2, of which the affinity with ANTXR2 is higher
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Edema toxin is a calmodulin-dependent adenylate cyclase that acts on target cells through cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA), the latter being the main signal transduction pathway for nociceptors and pain
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On December 20, 2021, the research team of Isaac M.
Chiu of the Department of Immunology of Harvard Medical School revealed that anthrax toxin can relieve pain in mice and can be used as a drug carrier to target botulinum toxin to sensory neurons to exert analgesic effects
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The researchers found that mouse and human DRG (Dorsal Root Ganglion) tissues are enriched and express ANTXR2 through single-cell sequencing
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After intrathecal injection of lethal toxin and edema toxin, the edema toxin treatment group can increase the sensitivity of mice to mechanical stimuli and heat, and can also relieve harmful thermal and mechanical stimuli, showing obvious analgesic-like effects: In addition, Injection of edema toxin does not cause the death of DRG sensory neurons
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On the other hand, intrathecal injection of edema toxin can effectively alleviate neuropathic pain caused by nerve injury, as well as inflammatory pain caused by carrageenan, further indicating that edema toxin has analgesic potential
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The sodium channel Nav1.
8 encoding gene is Scn10a, which is specifically enriched and expressed in a voltage-gated sodium channel of sensory neurons in the dorsal root ganglion (DRG)
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After specifically knocking out Scn10a-positive DRG or ANTXR2 on peripheral somatosensory neurons, intrathecal injection of edema toxin did not cause analgesic effects
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However, knocking out ANTXR2 on endothelial cells or immune cells cannot block the analgesic effect of edema toxin
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This indicates that the pain relief behavior mediated by edema toxin depends on the receptor ANTXR2 on the nociceptor
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Surprisingly, the behavioral effects caused by the injection of edema toxins at different sites are completely different
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Injection of edema toxin into the sole of the foot induced mechanical allodynia lasting for 8 hours, and the level of cAMP at the sole of the foot increased, but the level of cAMP in the DRG or spinal cord did not change
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Correspondingly, intrathecal injection of edema toxin will only increase the level of DRG or cAMP in the spinal cord, but has no effect on the sole of the foot
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Previous studies have confirmed that the increase in cAMP levels and the activation of PKA signals cause hyperexcitability and hyperalgesia
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Researchers found that intrathecal injection of edema toxin promoted the excitability of sensory neurons, but it was not accompanied by an increase in nociceptor current or neuropeptide release
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The botulinum toxin produced by botulinum toxin blocks the fusion of synaptic vesicles with the membrane of the presynaptic terminal by cutting the components of the SNARE complex, inhibiting the release of neurotransmitters, thereby blocking synaptic transmission
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On the other hand, the protective antigen protein PA and the N-terminus of the lethal factor protein are fused into the carrier protein to deliver the target protein to the host cell through the specific binding of the receptor
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Researchers modified the above-mentioned protein delivery system, fused PA, the N-terminal of the lethal factor protein, and the light chain of botulinum toxin, which can target botulinum toxin to nociceptors and effectively relieve pain
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In summary, this article reveals that the receptor ANTXR2, which is enriched in DRG expression, mediates the analgesic effect of anthrax toxin
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Expanded the application of bacterial toxins in the development of analgesic drugs
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[References] 1.
https://doi.
org/10.
1038/s41593-021-00973-8 The pictures in the text are from the references