A study demonstrates that a toxin produced by the anthrax microbe can effectively suppress multiple types of pain.
Anthrax has a bad reputation. The anthrax microbe has been misused as a weapon of fear, causing deadly lung infections in humans and ugly but painless skin sores in livestock and humans.
Now, according to the findings of a new study, the nasty bacteria may also have unexpectedly good potential—one of its poisons has been shown to mute numerous forms of pain in mice.
The study found that this specific anthrax toxin alters signaling in pain-sensing neurons and, when administered in a controlled manner into neurons of the central and peripheral nervous systems, can provide relief to distressed animals.
The study, headed by Harvard Medical School researchers, was published in Nature Neuroscience on Dec. 20.
Additionally, the researchers mixed components of the anthrax toxin with several types of molecular cargo and transported them into pain-sensing neurons. By targeting pain receptors directly, the approach avoids the systemic effects of existing analgesics, such as opioids.
“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,” said research senior investigator Isaac Chiu, associate professor of immunology at Harvard Medical School.
The researchers stated that there is a continuing need to expand the present treatment arsenal for pain management. Ineffective painkillers like opioids have serious side effects like rewiring the brain’s reward system, making them more addictive, and suppressing respiration, which can be fatal.
“There’s still a great clinical need for developing non-opioid pain therapies that are not addictive but that are effective in silencing pain,” added study first author Nicole Yang.
“Our experiments show that one strategy, at least experimentally, could be to specifically target pain neurons using this bacterial toxin.”
The researchers warn that this strategy is still experimental and needs to be refined in future animal trials and eventually in humans.
Primed to connect
The Chiu lab has long studied the relationship between microorganisms and the neurological and immune systems. Other pathogenic bacteria can interact with neurons and modify signals to enhance pain, according to Chiu’s previous research. Only a few research have looked into whether certain microorganisms can reduce or block pain. Chiu and Yang set out to do this.
The current study began by examining how pain-sensing neurons vary from other neurons in the human body. They started with gene-expression data. Pain fibers had anthrax toxin receptors, whereas other types of neurons did not. The anthrax bacterium was structurally poised to engage with the pain fibers. Who knew? The latest study answers that question.
The findings show that pain is silenced when sensory neurons in the dorsal root ganglia link with two anthrax-made proteins. When one of the bacterial proteins, protective antigen (PA), attaches to the nerve cell receptors, it generates a pore that allows the other two bacterial proteins, edema factor (EF) and lethal factor (LF), to enter the nerve cell. The study also found PA and EF combined, known as edema toxin, disrupt signaling inside nerve cells, thus silencing pain.
Using the quirks of microbial evolution for new therapies
In a series of tests, the researchers discovered that the anthrax toxin affected signaling in human nerve cells in dishes, as well as in living animals. Injecting the toxin into mice’s lower spines resulted in powerful pain-blocking effects, stopping the animals from sensing high-temperature and mechanical stimulations. Importantly, the animals’ other vital signs, including as heart rate, body temperature, and motor coordination, were unaffected, indicating that this approach was highly selective and precise in targeting pain fibers and inhibiting pain without causing extensive systemic effects.
Moreover, injecting mice with anthrax toxin relieved symptoms of two other types of pain: pain caused by inflammation and pain caused by nerve cell damage, both of which are common in the aftermath of traumatic injury and certain viral infections such as herpes zoster, or shingles, as well as as a complication of diabetes and cancer treatment.
Furthermore, the researchers discovered that as the pain decreased, the treated nerve cells remained physiologically intact—a finding that suggests the pain-blocking effects were not caused by nerve cell injury but rather by altered signaling inside them.
Finally, the scientists created a carrier vehicle out of anthrax proteins that was utilized to transfer other pain-blocking chemicals into nerve cells. Botulinum toxin, a potentially fatal bacterium recognized for its capacity to alter nerve signals, was one of these chemicals. This method, too, relieved discomfort in mice. The results show that this could be a revolutionary pain-targeting delivery strategy.
“We took parts of the anthrax toxin and fused them to the protein cargo that we wanted it to deliver,” Yang added. “In the future, one could think of different kinds of proteins to deliver targeted treatments.”
The researchers warn that as the research develops, the safety of the toxin treatment must be closely evaluated, especially since the anthrax protein has been linked to compromising the integrity of the blood-brain barrier during infection.
The latest findings pose another intriguing question: why would a microbe mute pain evolutionarily?
Chiu believes that one possible explanation—albeit a highly speculative one—is that microbes have evolved ways to communicate with their hosts in order to assist their own expansion and survival. In the instance of anthrax, that adaptive mechanism could be changed signaling, which prevents the host from sensing pain and thus the presence of the germ. This theory could help explain why the anthrax bacterium sometimes causes painless black skin lesions, according to Chiu.
The new findings also suggest to new drug development possibilities beyond the typical small-molecule medicines that are currently being developed in labs.
“Bringing a bacterial therapeutic to treat pain raises the question ‘Can we mine the natural world and the microbial world for analgesics?’” said Chiu.
“Doing so can increase the range and diversity of the types of substances we look to in search for solutions.”
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