Early preclinical work led by researchers from Harvard Medical School has found certain elements in a toxin produced by the anthrax bacterium can silence activity in pain-signaling brain neurons. The research proposes this could be a new model for future pain therapeutics.
Anthrax toxins are composed of several molecules secreted by the anthrax bacterium. On their own each protein is non-toxic, but in combination they can be lethal. This new research first set out to understand how these anthrax toxins affect neurons in the brain.
The research first discovered specific pain-sensing neurons in the dorsal root ganglion (DRG) seem to carry receptors with a high affinity for binding to anthrax toxins. Across a series of impressive experiments the researchers demonstrated exactly how two particular anthrax proteins altered signaling inside nerve cells.
There are two kinds of anthrax toxins – edema toxin and lethal toxin. Both toxins share a key protein in common, called PA (protective antigen). PA has been likened to a Trojan horse, helping to ferry either the edema factor (EF) protein or the lethal factor (LF) protein into a cell.
The new research compellingly demonstrated how the edema toxin (composed of PA and EF) can selectively target and silence pain-signaling neurons in the dorsal root ganglion. Mouse experiments showed when these two proteins were injected into the animals’ spine they effectively homed in on certain neurons in the brain and blocked pain sensations.
“This molecular platform of using a bacterial toxin to deliver substances into neurons and modulate their function represents a new way to target pain-mediating neurons,” says Isaac Chiu, senior investigator on the research.
Because these anthrax proteins are so accurate in the neurons they specifically target, the researchers experimented with using them as a novel carrier system. In this instance botulinum toxin, known to suppress pain signaling, was hidden inside this anthrax protein delivery system. In mice this unique approach also effectively blocked pain sensations.
“We took parts of the anthrax toxin and fused them to the protein cargo that we wanted it to deliver,” explains Nicole Yang, first author on the new study. “In the future, one could think of different kinds of proteins to deliver targeted treatments.”
Of course, it is very early days for this kind of research and lots more work will be needed before a potential new therapy moves from the lab to the clinic. The researchers are confident by delivering this edema toxin to the brain through the spine, called intrathecal administration, it will avoid potential toxicity problems in the rest of the body. However, further research is obviously needed to better understand any broader effects this toxin could have on the brain directly.
So far the early signs are this toxin’s activity on the brain is highly targeted and there were no indications in the animal tests to suggest there were disruptions to other mechanisms such as motor function. The researchers intriguingly hypothesize that this incredible specificity of the toxin’s activity in the brain could be an evolutionary adaptation helping the anthrax bacterium avoid detection in organisms it infects.
A common feature of anthrax is black skin lesions that are frequently described as painless by patients. Chiu speculates this pain-blocking mechanism may explain that strange analgesic phenomenon. He also points out this research is a perfect example of how the natural world can help scientists develop new ways of treating pain.
“Bringing a bacterial therapeutic to treat pain raises the question ‘Can we mine the natural world and the microbial world for analgesics?’” adds Chiu. “Doing so can increase the range and diversity of the types of substances we look to in search for solutions.”
The new study was published in the journal Nature Neuroscience.
Source: Harvard Medical School
