April 27, 2018
According to the U.S. Centers for Disease Control & Prevention, about one in three people carry Staphylococcus aureus in their noses, and 2% of carry the dreaded methicillin-resistant S. aureus (MRSA) strain that thwarts common antibiotics.
So, how is it that most people never get sick from staph infections? Researchers at the University of Washington School of Medicine have found a clue.
In a study published April 26 in Cell Host & Microbe, the researchers showed that nitric oxide generated by the immune system inhibits the ability of S. aureus to transform from a relatively benign, quiescent colonizing state to its virulent form, which produces toxins to invade and cause disease. This might explain why people's nasal passages typically have very high concentrations of nitric oxide, the researchers said.
The lead author of the paper is Rodolfo Urbano, currently a postdoctoral fellow at Yale University. He conducted the research as a doctoral student in the University of Washington laboratory of Dr. Ferric Fang, a professor of laboratory medicine, microbiology, medicine and pathobiology and the paper's senior author.
"At a time when antibiotic resistance is on the rise, immune molecules that target virulence factors could be used to develop new therapeutics," Urbano said.
The University of Washington team collaborated with colleagues at the University of Pennsylvania and the University of Colorado.
Urbano said a person's immune system uses nitric oxide as a weapon against many microbes, including viruses, parasites, bacteria and fungi. As with most antibiotics, nitric oxide fights most bacteria by limiting their ability to grow. However, S. aureus is able to grow despite the presence of nitric oxide.
To find out how nitric oxide might be keeping S. aureus in check, the researchers set out to identify all the proteins in S. aureus that were modified by nitric oxide. Many proteins were altered, they found, but one protein in particular caught researchers' interest. That protein, called AgrA, plays a key role in the process that switches quiescent S. aureus bacteria into virulent invaders, the announcement noted.
This process is called quorum sensing; it's triggered when bacteria reach a certain density — a "quorum" — and initiate the process in which the bacteria begin to produce virulent factors such as toxins. By modifying AgrA, nitric oxide blocked this quorum-sensing system, Urbano and his colleagues found.
To confirm their hypothesis, the researchers showed that mice with staphylococcal pneumonia that lacked the gene needed to generate nitric oxide developed more severe disease. This demonstrated that nitric oxide can suppress the production of toxins during an infection, Urbano said.
"The same effect may also apply when there is no ongoing infection," he added.
Fang noted that bacteria often find a way to evolve so they can resist the effects of antibiotics, but curiously, S. aureus appears to have not evolved to resist the effect of nitric oxide.
"One could speculate that the arrangement is actually advantageous to the bacterium," Fang said. "The bacterium doesn't want to make its host sick. It prefers to just colonize the host, grow and spread to other people. If the staph colonizing me makes me sick and I die, that doesn't help the staph."
Fang said his team hopes to better understand how nitric oxide protects the body but also why it fails.
"We know that one of the most dangerous things that can happen to you when you get the flu is that you can develop a staph infection. We would like to know whether the flu disrupts the normal balance between staph and the host and whether it has something to do with (nitric oxide)," Fang said.
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