The research, reported in the February 21, 2006 issue of the journal Current Biology, focuses on the major human pathogen group A Streptococcus. Among the most important of all bacterial pathogens, strep is responsible for a wide range of diseases – from simple throat and skin infections to life-threatening conditions such as necrotizing fasciitis ("flesh-eating disease") and toxic shock syndrome.
"These findings suggest a novel approach to treating serious Strep infections, such as flesh-eating disease, by assisting our body's own defense system," said senior author Victor Nizet, M.D., UCSD associate professor of pediatrics and an infectious diseases physician at Children's Hospital, San Diego.
The UCSD investigators examined the interaction of Strep bacteria with neutrophils, specialized white blood cells that play a front line role in human's immune defense against pathogenic microbes. Recent research by European investigators had shown that neutrophils are particularly effective defenders because they release "nets" composed of DNA and toxic compounds to entrap and kill invading bacteria. In the current study, the UCSD scientists proved that disease-causing Strep release an enzyme that degrades these DNA nets, thereby allowing the organism to escape the neutrophil net and spread in body tissues.
The UCSD team used a molecular genetic approach for their studies, knocking out the gene encoding the DNA-degrading enzyme from a pathogenic Strep strain that was originally isolated from a patient suffering from necrotizing fasciitis.
"Deprived of this single enzyme, the mutant Strep strain was easily killed by human neutrophils", said lead author John Buchanan, Ph.D., research scientist in the UCSD department of pediatrics. "In addition, the mutant Strep bacteria no longer produced a spreading infection when injected into the skin of experimental mice."
The critical role of the DNA-degrading Strep enzyme was confirmed by cloning the corresponding gene into a normally non-pathogenic bacterial strain. Addition of the single gene allowed these bacteria to degrade DNA, escape neutrophil killing, and produce a spreading ulcer in the mouse infection model. Special fluorescent microscopy techniques were used to observe how the Strep enzyme dissolved the DNA nets and allowed bacteria to float away from the neutrophils.
"The experiments explain how this DNA-degrading enzyme contributes to the severe infections produced by certain strains of Strep bacteria, while simultaneously confirming just how important neutrophil DNA nets are to our normal immune defense," said Buchanan.
Recognizing the critical role played by the DNA-degrading enzyme in progression of Strep disease, the UCSD researchers examined whether it could represent a target for therapy. Mice experimentally infected with Strep were treated by injecting a chemical inhibitor of the DNA-degrading enzyme at the site of infection. A dramatic reduction in bacterial counts and tissue injury was observed following the inhibitor treatment, when compared to controls receiving a placebo.
Nizet explained that the researchers' findings could lead to novel treatments for Strep-related diseases. "Instead of attempting to kill the bacteria directly with standard antibiotics, a treatment strategy to inhibit the Strep DNA-degrading enzyme could disarm the pathogen, making it susceptible to clearance by our normal immune defenses," he said.
This study was financed a grant from the National Institutes of Health. Co authors contributing to the study were Amelia Simpson, UCSD undergraduate majoring in biological sciences, Sascha Kristian, Ph.D., UCSD postgraduate researcher in pediatrics, George Liu, M.D., Ph.D., UCSD research fellow in pediatric infectious diseases, and James Feramisco, UCSD Professor of Pharmacology and Medicine. Also collaborating in the research were co-authors Ramy Aziz, Ph.D. and Malak Kotb, Ph.D. of the University of Tennessee-Memphis.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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