- 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 "flesheating
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.
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- 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."
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- 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.
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- 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.
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- "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.
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- 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.
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- 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.
"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.
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- "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."
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- 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.
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- 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.
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- 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.
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- http://www.biocompare.com
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