The bacterium that is the main cause of necrotizing fasciitis, or flesh-eating disease, causes widespread, deadly infection by getting the nervous system to stop the immune system from attacking it.
A team that was led by scientists from Harvard Medical School in Boston, MA, made the surprising discovery while studying the disease-promoting tactics of Streptococcus pyogenes in mice with necrotizing fasciitis.
You can read about the study in a paper shortly to be published in the journal Cell, where the researchers also suggest two potential treatments.
Should they succeed in animal and human trials, the treatments could be of immense value in containing "highly invasive bacterial infections."
"Necrotizing fasciitis," explains senior study author Isaac M. Chiu, who is an assistant professor of microbiology and immunobiology at Harvard Medical School, "is a devastating condition that remains extremely challenging to treat and has a mortality rate that's unacceptably high."
The flesh-eating disease is caused by serious bacterial infection of subcutaneous tissue, the tissue that lies just below the skin, and the fascia, the tissue that covers the organs that lie inside the body.
The disease is very rare; each year, it affects approximately 200,000 people worldwide, which includes around 1,200 individuals in the United States.
The infection — which can be caused by several types of bacteria — is not easy to diagnose, and it can develop suddenly and spread rapidly. If not treated promptly, it can result in "multiple organ failure and death," which occurs in around 30 percent of cases.
Following an injury, the nervous system sends one signal to the brain and another to the immune system. The first signal triggers pain sensations, and the second tells the immune system to hold back.
Scientists suggest that neurons, or nerve cells, have this ability to instruct the immune system to hold back in order to prevent "over-deployment" of immune cells that might cause "collateral" damage to healthy tissue.
Prof. Chiu became interested in how this nervous system and immune system interaction might work in flesh-eating disease when he discovered that affected patients often experienced an excessive level of pain that occurred before symptoms developed.
Could it be that the bacterium was somehow exploiting this natural dual response to injury to repress the immune system for its own advantage?
Bacterial toxin triggers immune silencing
To investigate this further, he and his colleagues developed a mouse model of flesh-eating disease by injecting the animals with the bacterium S. pyogenes sampled from infected human patients.
Using the mouse model, they discovered that a toxin produced by the bacterium — known as streptolysin S — was a trigger for pain and the subsequent silencing of the immune system.
In further tests, they injected mice with bacteria that had been genetically engineered so that they could not produce the toxin. Though they became infected, the mice did not show the usual pain and neither did the infection become invasive.
The researchers confirmed the role of streptolysin S by "re-engineering" the toxin-producing ability back into the modified bacteria and then introducing them into the same mice. The infection developed into "full-blown" flesh-eating disease.
The team then gave the mice an antibody that blocked the toxin. The mice's pain symptoms were much reduced, confirming that bacterial streptolysin S was the trigger.
Underlying molecular mechanisms
The researchers carried out further experiments in which they explored the underlying molecular mechanisms of the interaction between the nervous system and the immune system.
In these, they discovered that streptolysin S triggers neurons to send a pain signal to the brain. This also triggers another signal to the immune system that causes it to secrete a neurotransmitter, or chemical messenger, called calcitonin gene-related peptide (CGRP), which then holds back the immune response.
They also found that CGRP does this by both halting the despatch of neutrophils and by blocking their ability to kill bacteria at the wound site.
"Effectively," notes Prof. Chiu, "this neuronal signal silences the alarm system that normally calls on the body's infection fighters to curb infection."
He goes on to explain that such a response is appropriate when a wound is clean and not infected — you don't want the immune system coming in and inflaming healthy tissue in an attempt to deal with an infection that is not there.
But, the strep bacterium takes advantage of this and invokes the same strategy when the wound is infected, allowing the disease to develop unhindered.
Patients in the early stage of necrotizing fasciitis often feel an enormous amount of pain but do not show the symptoms that one might expect to accompany it — such as redness, swelling, and inflammation.
Prof. Chiu and colleagues suggest, however, that this is what you would expect if, for some reason, the neutrophils that bring on the inflammation and get rid of the bacteria were not summoned.
Two possible ways to halt the disease
The scientists then ran another set of experiments, wherein they introduced the bacteria into two groups of mice: one in which they had stopped the ability of the nerve fibers to carry pain signals, and another in which they had not.
These demonstrated that blocking the pain nerves improved the body's control of the infection.
Various experiments in which mice were injected with botulinum neurotoxin A — a nerve-blocker that is present in facial anti-wrinkling cosmetic treatments — showed that such an approach may work as a treatment for flesh-eating disease.
Injections of the nerve blocker even 2 days after the mice were first infected and already had wounds stopped the disease causing more tissue damage.
The researchers also tested another possible way of tackling the disease. They showed that CGRP-blockers removed the brakes on the immune system by stopping the nerve cells from sending the halt signals. They also stopped necrotizing fasciitis from spreading in mice.
"Our findings reveal a surprising new role of neurons in the development of this disease and point to promising countermeasures that warrant further exploration."
Prof. Isaac M. Chiu