Henry Chambers and Binh Diep.
Antibiotic-resistant staph infections no longer afflict only hospital patients. Otherwise healthy people are becoming infected, too.
Now infections with the community-associated strain that is most often life-threatening can finally be fruitfully studied in an animal model – the rabbit.
UCSF researchers have used this new model to find out how infection can lead to lung damage and death. Studies with rabbits now may make it easier to identify new targets in the battle against dangerous staph infections, they say. The model may also prove useful for testing new drug candidates.
The researchers, Binh Diep, PhD, and Henry Chambers, MD, report their findings in the March 15 online edition of the Proceedings of the National Academy of Sciences (PNAS).
Infections with community-acquired methicillin-resistant Staphylococcus aureus (CA MRSA) can sometimes spread to the bloodstream with life-threatening consequences. However, the threat of “flesh-eating” bacteria has been sensationalized.
Despite the bacterium’s potential lethality, washing with soap and water is an effective way to prevent infection with CA MRSA, Diep says. Furthermore, in most cases infection is not severe.
Methicillin-resistant Staphylococcus aureus. Photo credit: US Centers for Disease Control and Prevention
“For a large majority, infection is confined to the skin and tends to be mild,” he says. “Simple incision and drainage of abscesses usually is sufficient, without antibiotic treatment.”
When a staph infection becomes life-threatening, it more often is a result of severe pneumonia. These cases are associated with large-scale death of cells in the lungs. A toxin made by CA MRSA plays a key role. Apart from those who already have respiratory disease, it is not clear who might be especially vulnerable, Diep says.
“There are healthy kids and young adults who get severe, lethal infections with community-associated MRSA. We think that the toxin produces such a rapidly lethal course of infection that patients die before they are able to mount an effective response.”
When people who are generally healthy come down with life-threatening, staph-induced pneumonia, it often is associated with concurrent or recent flu. Influenza can cause lungs to become temporarily more vulnerable to additional infections.
Public health officials are concerned about the increase in community-associated staph infections that are resistant to antibiotics, coupled with the unpredictable threat of emerging flu strains.
Wreaking Havoc in Lungs
Until now the reason for the lethality of the USA300 strain of CA MRSA that is responsible for severe cases of pneumonia has remained a mystery. USA300 now accounts for the vast majority of CA MRSA infections. Two years ago, Diep and Chambers estimated that one in 364 San Francisco residents had been exposed to USA300. In their PNAS report, Diep and Chambers describe how USA300 can wreak havoc in lungs.
USA300 makes a poison that researchers have come to suspect is a key contributor to its virulence. Diep and Chambers now have found that -- like a siren trained in jujitsu -- the bacterial poison lures potent immune cells to the lungs, and then turns the tables.
The poison, called PVL, causes the immune cells to come apart. The cells spill their contents all at once. Normally during an immune response the release of inflammatory molecules from these particular immune cells -- first-line defenders called leukocytes -- is carefully controlled through intricate feedback.
However, the rapid release of large amounts of these inflammatory molecules instead triggers the destruction of healthy lung tissue. Alveoli -- tiny air sacs that that take in oxygen and expel carbon dioxide – are destroyed.
Finding Success in Rabbits
Similar effects on leukocytes had earlier been demonstrated in the Petri dish using CA MRSA bacteria and human cells. Efforts to study the disease in lungs had been unsuccessful. Rats and mice are not very susceptible to the lung-damaging effects of PVL. Oddly, non-human primates are not very susceptible either.
Left: lung from rabbit infected with CA MRSA USA300
Right: lung from rabbit infected with CA MRSA USA300 without the bacterial toxin PVL.
Photo credit: Binh Diep
But Diep and Chambers found that the rabbit appears to be a good model in which to study CA MRSA-induced lung disease. When the researchers genetically manipulated the USA300 strain to knock out PVL, infections were much less deadly. This experiment demonstrated the importance of the PVL toxin.
Furthermore, when Diep and Chambers chemically depleted the targeted leukocyte population in the rabbits and then infected them with PVL, the rabbits were less susceptible to lung destruction compared to rabbits with normal amounts of leukocytes. This showed that the combination of toxin and target is important in fomenting life-threatening CA MRSA infections.
Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin induced lung inflammation and injury
Binh An Diep, Liana Chan, Pierre Tattevin, Osamu Kajikawa, Thomas R. Martin, Li Basuino, Thuy T. Mai, Helene Marbach, Kevin R. Braughton, Adeline R. Whitney, Donald J. Gardner, Xuemo Fan, Ching W. Tseng, George Y. Liu, Cedric Badiou, Jerome Etienne, Gerard Lina, Michael A. Matthay, Frank R. DeLeo, and Henry F. Chambers
PNAS (Published Online March 15, 2010)
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