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Unusual Patient Cases Help UCSD Researchers Link Toxin 
To Development of “Flesh-Eating” Bacterial Infections   

Three unusual patient cases of severe streptococcal (strep) infection have provided clues that allowed researchers at the University of California, San Diego (UCSD) School of Medicine to prove that a potent bacterial toxin plays an important role in producing necrotizing fasciitis (NF), the rapid infection of soft tissue referred to as “flesh‑eating disease”.  The findings are published in the January 12, 2002 issue of the journal The Lancet.

The toxin, called streptolysin S (SLS), is produced by group A Streptococcus  (GAS), a bacteria associated with mild infections such as strep throat and severe infections including NF and toxic shock syndrome.  SLS is one of the most potent toxins known, able to kill a wide variety of human cell types in laboratory testing. 

Physicians had speculated for years that SLS could play a role in the tissue destruction seen in severe human GAS infections, but proof was lacking since SLS had never been fully purified nor was there an understanding of the mechanism by which the bacteria produce the toxin.   

According to senior author Victor Nizet, M.D., UCSD assistant professor of pediatrics in the Division of Infectious Diseases and an attending physician at Children’s Hospital, San Diego, “we hope that our research can lead to the development of safe drugs that are able to neutralize the toxic actions of SLS and prove beneficial in the treatment of patients suffering from NF and other severe strep infections.”

Working closely with investigators at Mt. Sinai Hospital in Toronto and the Centers for Disease Control in Atlanta, the UCSD team recently identified the genetic basis for SLS production by GAS.  A group of nine linked genes was involved in SLS production, and a mutation in any one of the genes rendered GAS unable to make the toxin. (Infection and Immunity, 2000).  These discoveries made possible a more precise approach to study of the SLS toxin and its properties.

The clue that SLS may be pivotal in producing the tissue injury of NF came from three San Diego patients who developed this life-threatening infection.   The patients were unusual because the form of strep that caused their flesh-eating infections was not GAS, but group G Streptococcus (GGS), a species which rarely produces serious disease and typically lives harmoniously on skin or the mucous membranes of the upper respiratory tract. 

However, the clinical presentation of the GGS-infected patients and pathology studies performed on biopsies of their necrotic (dead) tissue were indistinguishable from those observed with GAS-infected patients.  The GGS bacteria isolated from the patients also bore a strong resemblance to GAS in the microbiology laboratory, as both were able to destroy red blood cells, a property known as hemolysis that is associated in GAS with production of the SLS toxin.

“We hypothesized that the GGS isolates produced a toxin similar to SLS of GAS and that this toxin could contribute to the severe tissue destruction in patients with NF,” Nizet said.

In the work reported in The Lancet, the UCSD-led team used molecular techniques to discover that the GGS bacteria isolated from the patients possessed a set of nine genes nearly identical to those responsible for SLS production in GAS.

To test the role of SLS in NF infections, the researchers produced mutant versions of both GAS and GGS that did not contain SLS.  They injected the skin of two groups of mice with normal, SLS-producing GAS or GGS, and two additional groups with the mutant, SLS-negative versions of the bacteria.  The mice infected with normal GAS or GGS developed an inflammatory lesion with high bacterial counts and diffuse tissue death.  In contrast, the mice injected with SLS-negative GAS or GGS did not develop lesions, had lower bacterial counts, and minimal degrees of tissue injury.  

As reported in the journal The Lancet, the mice (A) injected with group G strep containing SLS had ulcer formation with necrotic tissue destruction, vascular thrombosis, and evidence of tissue inflammation.  The mice injected with SLS-negative strep (B) had only minimal inflammatory changes.

“These studies thereby showed that SLS is an essential virulence factor required for both species of bacteria to cause NF,” Nizet noted.

However, GGS is not as formidable a pathogen as GAS, since serious GGS infections remain quite rare.

“GAS can cause serious infections even in patients who are previously healthy,” Nizet said.  “However, the rare cases of serious GGS infection have all been reported in patients with underlying medical conditions.  The implication here is that SLS is not the only factor involved in production of invasive strep infections and that GAS possesses more virulence factors than GGS.” 

The severity of the GGS infection in the three patients was probably triggered by their underlying medical conditions, which included diabetes, cancer, alcoholism and liver disease, Nizet added.

Co-first authors of the paper in The Lancet were Deepali Humar, M.D., infectious diseases fellow, UCSD Department of Medicine, and Vivekananda Datta, M.D., Ph.D. candidate in molecular pathology, UCSD Department of Pediatrics.  Additional authors were Darrin J. Bast, Ph.D., postdoctoral fellow, and Joyce C.S. De Azavedo, Ph.D., assistant professor, Toronto Medical Laboratories and the Department of Microbiology, Mount Sinai Hospital and University of Toronto; and Bernard Beall, Ph.D., research scientist, Centers for Disease Control and Prevention, National Center for Infectious Diseases.

The work was funded by the National Institutes of Health and a Charles E. Culpeper Foundation Biomedical Project Initiative Grant from the Rockefeller Brothers Fund.