Researchers Use Botox to Block Flesh-Eating Group A Strep Infections

Streptococcus pyogenes bacteria are best known for causing strep throat, scarlet fever, and impetigo, but they can also cause necrotizing fasciitis, a flesh-eating disease. Now, in a new study, Harvard Medical School researchers have made a discovery about how this bacterium invades the body, giving new insight into stopping these life-threatening infections.

The Centers for Disease Control and Prevention estimates that the United States sees 11,000 to 13,000 cases of invasive group A Streptococcus, or group A strep, each year. This includes cases of cellulitis with blood infection, pneumonia, and necrotizing fasciitis, which lead to 1,100 to 1,600 annual deaths in the country. Necrotizing fasciitis is a rare but very serious skin infection that can spread quickly through the body and kill soft tissue, becoming deadly in a very short period of time without an early and accurate diagnosis, prompt antibiotic treatment, and surgery. A number of bacteria can cause these skin infections, including group A strep, Klebsiella, Clostridium, Escherichia coli, Staphylococcus aureus, and Aeromonas hydrophila. Early symptoms of necrotizing fasciitis include localized pain, fever, chills, fatigue, and vomiting. Most individuals who get these infections have health conditions that lower their body’s ability to fight infection, such as diabetes, kidney disease, or cancer, and more than 1 in 4 cases are deadly.

Group A strep bacteria produce a toxin called streptococcal pyrogenic exotoxin B (SpeB), which can infect and kill the connective tissue that surrounds muscles, nerves, fat, and blood vessels. Previous studies have found targeting the peptide signal these bacteria secrete to produce the toxin may be an effective strategy for fighting group A strep infections. In a new study funded by grants from the National Institutes of Health and published in the journal Cell, Harvard Medical School researchers investigated the intense pain experienced by individuals with necrotizing fasciitis, which usually occurs before any visual signs of infection. They found that S. pyogenes target neurons and produce a toxin called streptolysin S (SLS), which activates certain pain-related neurons, leading to extreme pain. The toxin also disrupts communication between the nervous system and the immune system, essentially lowering the body’s immune response and ability to kill the bacteria.

In the study, the researchers injected mice with bacterial strains from patients with invasive strep infections. They found that mice infected with bacteria genetically modified to lack SLS did not show signs of pain or develop invasive infections. When infected with bacteria re-engineered to produce the toxin, the mice developed full-blown disease. Researchers then administered a neutralizing antibody to inactive SLS, and the mice displayed fewer signs of pain. In addition, the researchers tested the use of botulinum neurotoxin A — better known as the cosmetic product Botox – to block nerve signals. The botulinum controlled the spread of infection, and mice injected with the nerve block a week before being infected with S. pyogenes developed only minimal wounds.

“Necrotizing fasciitis is a devastating condition that remains extremely challenging to treat and has a mortality rate that’s unacceptably high,” said the study’s senior investigator Isaac Chiu, PhD, in a recent statement. “Our findings reveal a surprising new role of neurons in the development of this disease and point to promising countermeasures that warrant further exploration.”

In an interview with Contagion^®, Dr. Chiu pointed out that since the study only looked at mice, similar research needs to be conducted on larger animals and human patients. Botulinum neurotoxin A is produced by the bacterium Clostridium botulinum, so it’s use in “interbacterial warfare” is part of a growing body of research into new ways of fighting bacterial pathogens.

“If you think about it, almost every antibiotic we have is from different species that were fighting each other,” said Dr. Chiu, noting that this new study sheds light on how neurons regulate the immune system and infections, and how that can guide research into novel treatments. “That’s the hope, that with Botox we can halt really invasive infections like necrotizing fasciitis.”

Feature Picture Source: CDC / Richard R. Facklam, PhD. Picture Caption: Magnified 100x, this 1977 photograph depicted a Petri dish filled with trypticase soy agar medium containing 5% defibrinated sheep's blood, i.e., blood agar plate (BAP). After having been inoculated by streaking the surface of the BAP with Group A Streptococcus pyogenes (GAS) bacteria, the dish was incubated in a carbon dioxide enriched atmosphere at 35oC for 24 hours. The culture grew bacterial surface colonies. The characteristic color changes, i.e., a colorless region surrounding each colony in which the red blood cells in the blood agar medium had been destroyed, or "hemolyzed", indicated that these bacteria were indeed beta-hemolytic in nature.