Scientists find flesh-eating germ's trick, suggesting antidotes

Source: Xinhua| 2018-05-11 00:20:19|Editor: yan
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WASHINGTON, May 10 (Xinhua) -- American scientists identified how a flesh-eating germ wreaked massive tissue damages, pointing to new ways to contain it.

A study published on Thursday in the journal Cell revealed that the bacterium, known as Streptococcus pyogenes, leading cause of the fatal disease necrotizing fasciitis, hijacked neurons and exploited the normal communication that occurred between the nervous and immune systems during injury or infection.

The study also suggested two distinct approaches involving nerve modulation to avert disease and treat these infections in mice. If replicated successfully in larger animals and in humans, these treatments could be used to block the germ's dangerous moves, prevent widespread infections and halt disease progression, according to the researchers.

Flesh-eating infections usually start with intense localized pain that is swiftly followed by the rapid death of connective and muscle tissue, rendering prompt treatment a challenge, claiming the lives of as many as three in 10 people who get the disease.

Those who survive typically need radical, sometimes disfiguring, surgery to excise diseased muscle and connective tissue. In some cases, the disease causes such extensive damage that it may lead to limb amputation.

HIJACKING TRICK

When the body is injured, the nervous system would send two separate memos. One of them goes to the brain, telling it that something is wrong, triggering the sensation of pain.

The other goes to the immune system, telling it stay away, preventing an overactive immune system can inflict serious collateral damage on healthy tissue when it deploys an army of disease-fighting cells.

It is precisely this normal part of the crosstalk between the two systems that the germ behind flesh-eating disease exploits to avoid immune destruction, the researchers have found.

The study's senior investigator Isaac Chiu, assistant professor of microbiology and immunobiology at Harvard Medical School, and his colleagues injected mice with bacterial strains that came from patients with invasive strep infections, including necrotizing fasciitis.

An initial set of experiments identified the bacterial toxin streptolysin S as the key catalyst triggering pain and the ensuing immune-silencing cascade inside neurons.

Mice infected with bacteria genetically modified to lack the toxin showed no signs of pain with infection, nor did they develop invasive disease.

But when re-infected with mutant germs reengineered to make the toxin, the animals developed full-blown disease. When researchers gave mice a neutralizing antibody that inactivated streptolysin S, the animals showed fewer symptoms suggestive of pain, indicating this toxin is a key driver of pain.

Chiu's study showed that once in contact with neurons, streptolysin S prompts them to dispatch a pain signal to the brain alerting it that something is wrong, while at the same time inducing them to release a nerve chemical, the neurotransmitter CGRP (calcitonin gene-related peptide), to keep the immune system at bay.

Experiments showed that CGRP actively interferes with the body's immune defenses in two ways.

First, it impedes the body's ability to summon disease-fighting immune cells called neutrophils to the site of infection.

Second, it inhibits any neutrophils that manage to make their way to the epicenter of infection from releasing an enzyme that secretes a bleach-like, germ-killing substance.

In the case of clean, uninfected wounds, this is precisely the right response needed to prevent tissue-damaging inflammation caused by an overactive immune system, Chiu said.

However, when infected with the germ, it allows the strep bacterium to continue unhindered on its tissue-damaging march.

The absence of inflammation-inducing neutrophils at the site infection may explain why, in the early stages of necrotizing fasciitis, patients tend to experience intense pain but without the heavy swelling, redness and overall inflammation that develop when bacteria-gobbling neutrophils rush to the wound.

TWO ANTIDOTES

The scientists injected a group of mice with the nerve-blocking substance botulinum neurotoxin A, the active ingredient in cosmetic products that temporarily remove facial wrinkles.

A week after getting the nerve-block injections, animals were infected with the disease-causing bacterium.

Compared with mice that didn't get nerve-block injections, pretreated mice developed only minimal wounds that never progressed to full-blown disease.

In another experiment, researchers administered botulinum injections not before but immediately after infection. Again, the nerve-block injections controlled the spread of infection, resulting only in small localized lesions.

A third group of mice got the nerve-block injections with some delay, two days after infection and once they had already developed a wound. The injection essentially stopped infection in its tracks and averted further damage to muscle and soft tissue.

In a final set of experiments, the researchers blocked CGRP's immune-suppressing activity by treating mice either with an injectable or ingestible form of the CGRP-blocking molecules.

This treatment rendered immune cells deaf to the "stop" signal sent by the neurons and successfully prevented the spread of necrotizing fasciitis in mice infected with the disease-causing bacterium.

Botulinum injections are already approved by the Food and Drug Administration (FDA) for a variety of cosmetic and therapeutic uses, including the treatment of migraine. CGRP blockers are nearing FDA approval as migraine treatment.

The results indicate that both the injectable nerve-block approach and antibody or other drug-based treatments against CGRP hold therapeutic promise for necrotizing fasciitis, the team said.

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