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May 11, 2018

Flesh-Eating Bacteria Contained by Botox and Peptide Antagonist

Source: Erica Alana Alexandre for Chiu Lab, Harvard Medical School

  • Bacterial infections are generally a mild annoyance to the average person, often ranging from mild malaise to high fever. Yet, in rare cases, garden-variety bacterial infections, such as those that lead to strep throat, can go extremely awry and lead to massive tissue damage. For instance, the bacterium, known as Streptococcus pyogenes, is also the leading cause of serious flesh-eating disease, known as necrotizing fasciitis, which occurs in as many as 1200 people each year in the United States and in 200,000 people worldwide. Although rare, the infection, which burrows deep under the skin and eats into connective tissue and muscle, is notoriously hard to diagnose and treat promptly and can rapidly become fatal.      

    Now, new research from investigators at Harvard Medical School provides intriguing insight into the tactics used by S. pyogenes and points to several new ways to contain it. Findings from the new study—published recently in Cell, in an article entitled “Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection”—reveal that to ensure its survival, the microbe hijacks neurons and exploits the normal communication that occurs between the nervous and immune systems during injury or infection.

    "Necrotizing fasciitis is a devastating condition that remains extremely challenging to treat and has a mortality rate that's unacceptably high," explained senior study investigator Isaac Chiu, Ph.D., assistant professor of microbiology and immunobiology at Harvard Medical School. "Our findings reveal a surprising new role of neurons in the development of this disease and point to promising countermeasures that warrant further exploration."

  • Harvard Medical School researchers have uncovered the tactics used by a flesh-eating bacterium to dodge destruction by the immune system . [Kate Bredbenner/SimpleBiologist, for Harvard Medical School]

     

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

    "We hope our findings can lead to new treatments for a condition that remains rare but can inflict significant damage and even death," noted lead study investigator Felipe Pinho-Ribeiro, Ph.D., a postdoctoral researcher in Dr. Chiu’s laboratory.

    When the body is injured, the nervous system springs into action. Nerve cells 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 to keep away. This "stay away" signal plays an important protective role. In the setting of tissue injury or trauma, an overactive immune system can inflict serious collateral damage on the healthy tissue when it deploys an army of disease-fighting cells. To prevent this sort of immune mayhem, neurons can send a chemical missive telling the immune system to keep its attack dogs in check.

    "We believe this is the body's way of ensuring the delicate balance between alerting the body of brewing trouble while at the same time keeping overzealous immune cells at bay," Dr. Pinho-Ribeiro stated.

  • Click Image To Enlarge +
    Source: Pinho-Ribeiro, Felipe A. et al., Cell, 2018

    The current study first set out to create a high-fidelity animal model of human disease. To do so, the Harvard researchers 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—already known to kill red blood cells when secreted by the strep bacterium—as the key catalyst triggering pain and the ensuing immune-silencing cascade inside neurons. Indeed, mice infected with bacteria that were genetically modified to lack the toxin showed no signs of pain with infection, nor did they develop invasive disease. When reinfected with mutant germs re-engineered 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, indeed, a key driver of pain.

    Further experiments 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 calcitonin gene-related peptide (CGRP), 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.

    "Effectively, this neuronal signal silences the alarm system that normally calls on the body's infection fighters to curb infection," Dr. Chiu remarked.

    To confirm neurons as the actual site of all action, the researchers used chemical and genetic methods to silence pain fibers in a subgroup of mice. When infected with the disease-causing bacterium, these animals controlled their infections better than mice with intact neurons.

    Next, 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. The 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

    "Our findings provide a striking example of how closely intertwined the nervous and immune systems are and how intricate their interaction can be in the setting of infection," Dr. Chiu concluded. "Our study also underscores the therapeutic potential of modulating one system to affect the other as a way to treat infection."

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