Key to MRSA Virulence in Community Discovered

MONDAY Nov. 12, 2007 -- Researchers have uncovered a cache of molecular weapons that helps make community-associated methicillin-resistant Staphylococcus aureus (MRSA) so virulent.

Though more work must be done, the study "provides a partial explanation of why these strains are so successful in causing infection and gives a starting point in the development of new drug treatments," said Dr. Gregory Moran, a professor of medicine in the departments of emergency medicine and infectious disease at the Olive View-UCLA Medical Center.

Michael Otto, a senior investigator at the National Institute of Allergy and Infectious Disease, Rocky Mountain Laboratories, and his colleagues searched for and found a battery of short, novel peptides that are expressed by community-associated MRSA strains at higher levels than their hospital-associated MRSA cousins.

Deleting the genes encoding these peptides in mouse models of bacterial infection reduced the microbes' ability to kill or induce skin lesions in infected animals, while purified peptides paralyzed -- and paradoxically, activated -- neutrophils, which are the white blood cells whose job it is to prevent bacterial infections and the principal component of pus.

The study was published in the Nov. 11 online issue of Nature Medicine.

According to the U.S. Centers for Disease Control and Prevention, S. aureus, commonly found on the skin and in the nose of healthy individuals, is associated with bacterial skin infections. MRSA, as its name implies, is a particularly nasty strain of S. aureus that is resistant to the class of antibiotics that includes penicillin, amoxicillin and methicillin.

Traditionally, MRSA, which can cause boils, skin necrosis and even death, has been limited to hospital settings and crowded environments such as prisons. Yet, beginning in 1999, community-associated cases of the disease have been on the rise. Last month, a study in the Journal of the American Medical Association found that more people died of MRSA than of AIDS in 2005.

"That [sudden increase] was alarming, and nobody knew why it was happening," said Moran, who co-authored a 2006 study showing that community-associated MRSA accounts for almost 60 percent of skin infections that require a visit to the emergency room. "Something about these strains made them very well-suited to spread throughout the population."

These peptides could explain that virulence, at least in part, said Philip Tierno, director of clinical microbiology & immunology at New York University Medical Center and author of The Secret Life of Germs: Observations and Lessons From a Microbe Hunter."

"Virulence, it seems, is caused by these peptides, which can kill phagocytic cells [neutrophils], which come to your defense when staph is invading your body," he explained.

Staphylococci, Tierno noted, induce pus formation by recruiting and activating white blood cells. "That very induction of phagocytes [neutrophils] is key to your successful eradication of the organisms in the body," he said. However, "Staph has a defense. These peptides that can kill these phagocytic cells, thereby rendering you defenseless."

The genes encoding these toxins are found in the genomes of all sequenced MRSA strains, but community-associated MRSA strains produced the toxins at higher levels than the hospital strains, which typically cannot infect healthy individuals. Thus, they may explain the enhanced virulence of the community-associated strains.

The bacteria would fly under the immune system's radar, so to speak, by not expressing the peptides until the bacteria were either present in very large numbers, or perhaps after being engulfed by neutrophils and enclosed in a small space.

In either case, the mechanism would detect that situation and begin production of the peptides in earnest to fight back against the immune system.

"From the bacterial point of view, the most important thing is to get rid of the neutrophil," Otto said.

According to Moran, these findings suggest new drug possibilities -- antibodies that can remove the peptides from circulation, for instance.

"Any time we can better understand the basic physiology of how infections get around the immune system, it gives a potential target for treatment," he said.

However, Tierno emphasized that focusing exclusively on these peptides would be a mistake, as they represent just one of many mechanisms by which virulent MRSA can harm their hosts; these strains also express toxins that can overwhelm the body in other ways.

"All of these work together to make the organism so deadly," Tierno said. "There is a synergy without question that accounts for a big problem with these organisms."

More information

For more on community-associated MRSA, visit the U.S. Centers for Disease Control and Prevention.

Posted: November 2007


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