Research highlights nastier form of MRSA

news@nature.com ^ | 18 January 2007 | Heidi Ledford

[neverdem]

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Published online: 18 January 2007; | doi:10.1038/news070115-10

Research highlights nastier form of MRSA

Toxin-laden bacterium makes for a killer in the community.

Heidi Ledford

Researchers 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

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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References

1. Labandeira-Rey M., et al. Science, doi:10.1126/science.1137165(2007).
2. Garnier F., et al. Emerg. Infect. Dis., 12. 498 - 500 (2006).

[LucyT]

Ping.

[blam]

It's always something. This is bad stuff!

[pandoraou812]

ping

[Mr. Silverback]

My wife's an RN and advises this stuff is the nastiest.

[neverdem]

Staphylococcus aureus Panton Valentine Leukocidin Causes Necrotizing Pneumonia

The Staphylococcus aureus Panton Valentine leukocidin (PVL) is a pore-forming toxin secreted by strains epidemiologically associated with the current outbreak of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and with the often lethal necrotizing pneumonia. To investigate the role of PVL in pulmonary disease, we tested the pathogenicity of clinical isolates, isogenic PVL-negative and PVL-positive S. aureus strains, as well as purified PVL, in a mouse acute pneumonia model. Here we show that PVL is sufficient to cause pneumonia and that the expression of this leukotoxin induces global changes in transcriptional levels of genes encoding secreted and cell-wall-anchored staphylococcal proteins, including the lung inflammatory factor staphylococcal protein A (Spa).

[grey_whiskers]

Another *PING*.

Thanks, neverdem.

Cheers!

[exDemMom]

Interesting. Now that a toxin has been identified, it *may* be possible to design a vaccine for it. So many lives could be saved...

I was just telling my son about a case I recently read about, where a 17 year old boy caught the flu, which led to him getting a fatal pneumonia caused by MRSA. It was so tragic.

[Smokin' Joe]

Ping... (Thanks LucyT!)

[dfwgator]

The results, says Gabriela Bowden, an immunologist at Texas A&M University

Gig 'Em!

[Alamo-Girl]

Thanks for the ping!

[LucyT]

Wait! ... What happened? Were we caught in a time warp?

Check out the date of my original ping.

[Not that it's a problem.]

[Smokin' Joe]

Wow. I know the server has been a little slow....

Maybe I can blame the satellite link?

[Smokin' Joe]

You’re welcome, Alamo-Girl!

[MarMema]

Vanco drops those platelet counts,

[yefragetuwrabrumuy]

What caught my eye in this is the observation, “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.”

“Stickier”, as far as cell adhesion goes, is a critical factor in virulence. During the black plague of the 17th Century, one small village in England developed a genetic mutation which made their cells “smoother”, so that if both parents had the mutation, their children were effectively immune to the plague. And, as it turned out, hundreds of years later, also immune to HIV-AIDS.

Importantly, we know of some substances that can temporarily make our cells “smoother”, significantly reducing the speed of an infection thus giving our immune system more opportunity to overcome the pathogen.

For example, it is known that a high concentration of cranberry juice can block viral and bacterial adhesion of some kinds of viruses and bacteria that cause bladder infections and diarrhea.

However, lung tissue is a lot harder to protect. Hopefully some chemical agent will be devised that will reduce viral and bacterial adhesion in the lungs.

Fortunately there is a lot of ongoing research in just that.