Antibiotic-resistant bacteria loose in the community can be particularly aggressive - and deadly.GettyResearchers have unpicked why a particularly nasty form of antibiotic-resistant Staphylococcus aureus, which can strike down otherwise healthy victims outside of the hospital, is quite so vicious.
The results, says Gabriela Bowden, an immunologist at Texas A&M University in Houston and an author on the study, could be used to derive new therapies to combat the troublesome bug.
The study, published in this week's Science, shows that a toxin produced by the bacterium, called Panton Valentine leukocidin (PVL), causes a lethal form of pneumonia1. It also weakens the immune system and makes S. aureus boost production of proteins thought to make the bacterium stickier, allowing it to adhere more easily to skin and other tissues, boosting its infectivity.
Doctors already knew that patients with this type of pneumonia were typically infected with PVL-producing S. aureus strains. "These strains are much nastier and more aggressive than other strains," says Mark Enright, an epidemiologist at Imperial College London, UK. But the specific role the toxin plays in making the infection so serious wasn't known until now.
Home infections
Antibiotic-resistant S. aureus — often called MRSA for 'methicillin-resistant S. aureus ' — has plagued hospitals for decades, and infection rates have been steadily climbing. According to the US Centers for Disease Control and Prevention, MRSA infections accounted for 22% of the total number of S. aureus infections in 1995. By 2004, the proportion had increased to 63%.
Meanwhile, outbreaks of MRSA outside of hospital grounds are also on the rise. In the United States, 12% of clinical MRSA infections in 2003 were community-associated rather than found in hospitals.
The two forms of MRSA are very different, says Bowden. Community-associated MRSA, although resistant to methicillin and a few other antibiotics including penicillin, is sensitive to many other antibiotics. Hospital-associated MRSA is resistant to most.
Although easier to tackle with drugs, community-associated MRSA can be more aggressive, felling even healthy young athletes within days of infection. These are the strains that tend to produce VPL.
The bacterium can enter the bloodstream through wounds in the skin and cause a condition called 'necrotizing pneumonia'. This affects only about 2% of S. aureus patients, but when it hits, the consequences are rapid and deadly - 75% of patients with necrotizing pneumonia die, typically within four days.2 "Your chances of survival are very limited if the disease has gone that far," says Frank DeLeo, a microbiologist at the US National Institutes of Health's Rocky Mountain Laboratories in Hamilton, Montana.
Threefold attack
Studies in cell cultures have previously shown that PVL can weaken the immune system by forming pores in immune-cell membranes, causing the cells to burst. To test the impact of the toxin, Bowden and her colleagues injected mice with purified PVL toxin. At the highest dose, roughly 90% of the mice developed signs of pneumonia and died.
The team also checked to see how much of a difference this toxin makes to an S. aureus infection, by engineering a version of MRSA without the gene for making PVL. They found that mice infected with the PVL-less strain had normal lungs and 100% survival, whereas those infected with PVL-producing bacteria had inflamed lungs and only 20% survival.
The PVL toxin also boosted expression of several S. aureus proteins that could promote virulence. One of these is similar to proteins that make bacteria stickier, allowing them to colonize tissues more effectively. Another induced protein, known as protein A, is known to promote inflammation.
Targeted toxin
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DeLeo says the study provides an important mouse model for future work, but points out that the work was performed using a lab strain of MRSA rather than a clinical isolate. Those strain differences can be important, he says, so an important next step will be to verify these results in strains of MRSA that have been isolated from the community. Bowden says her colleagues are currently doing just that, and initial results support their findings using the lab strain.
Although several new MRSA treatments are reportedly in the pipeline, the current therapy for community-associated MRSA is antibiotic treatment. But that can't always rescue a patient suffering from necrotizing pneumonia, cautions Enright. "It all happens so quickly," he says. "And even if you kill the bacteria, the toxin can still go on to destroy the lung tissue."
Bowden hopes to design therapeutic antibodies that will target and disable the toxin itself, rather than focusing solely on the bacterium.
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