CDC, JANICE HANEY CARR
There seems to be no stopping methicillin-resistant Staphylococcus aureus (MRSA) from wreaking havoc in hospitals and communities around the globe. But identifying the molecular factors underlying the rapid and virulent spread of the superbug, which is resistant to common antibiotics, could be the first step. Now, researchers have identified a once rare but increasingly common gene that appears to be driving the spread and virulence of MRSA infections in Chinese hospitals.
The study is one of the first to analyze both the frequency and biological function of a gene in drug-resistant staph infections. The identified gene—a mobile genetic element that can move around a genome and jump from one bacterium to another—is evidence that horizontal gene transfer among bacteria drives MRSA epidemics. The gene could prove to be an effective therapeutic target against the pathogen, the authors said.
“There’s always been the hypothesis that there are genes associated with advanced transmissibility [of MRSA], but those genes haven’t been definitively identified,” said Frank Lowy, who studies the transmission of S. aureus at the Division of Infectious Diseases at Columbia University Medical Center in New York and was not involved in the research. The analysis of this new virulence gene is “really comprehensive,” he said.
In 2010, researchers at the Wellcome Trust Sanger Institute in the United Kingdom sequenced the genome of a particularly virulent strain of MRSA responsible for an outbreak at a London hospital between 2002 and 2004. The sequencing revealed a gene of unknown function, present in only a handful of sequenced MRSA strains around the world, that seemingly originated in Asia.
Min Li at Shanghai Medical College in China, along with her former postdoc advisor, Michael Otto of the National Institute of Allergy and Infectious Disease in the United States, decided to further investigate the presence and frequency of the gene, named sasX, in MRSA strains in China. At the time, “it was not clear it would be a bigger story,” said Otto, “but then we found that there is actually quite a high number, and a significantly increasing number, of invasive strains with this gene in Chinese hospitals.”
The team tested 800 randomly selected S. aureus isolates taken from patients at three large Chinese teaching hospitals between 2003 and 2011. They found sasX increased in frequency in MRSA isolates by 21 to 39 percent over those 9 years, while the gene’s increase in methicillin-sensitive S. aureus samples was not significant. Additionally, while sasX was once exclusive to MRSA clone ST239, it is now present in several other major MRSA variants.
“This is direct evidence of horizontal gene transfer from one group of MRSA strains to another,” said Otto. The finding “supports earlier studies that a lot of virulence genes and antimicrobial resistance genes are highly transmissible, and this appears to be another example of that,” agreed Lowy.
To see how sasX’s increasing frequency in MRSA isolates might be driving the Asian epidemic, the researchers investigated its mechanism of action. Through numerous in vitro and in vivo studies, they identified several roles for sasX during infection. Expressed on the cell surface, the sasX protein enhances the ability of MRSA to colonize the nose, which is the typical route by which the bacteria infect individuals. In addition, sasX promotes disease by facilitating the formation of large bacterial aggregates—clumps of MRSA that the immune system cannot clear away. In mouse models with S. aureus skin and lung infections, mice infected with sasX strains developed worse infections than those infected with strains without the gene.
Based on the epidemiological and functional evidence, the authors concluded that sasX is likely a driving force behind the MRSA epidemic in Asia, increasing the bacteria’s ability to spread as well as its deadliness once in the body. The finding supports the idea that mobile genetic elements, passed from one bacterium to another, are a major mechanism behind the spread of MRSA.
Because of its growing prevalence, sasX is a potential therapeutic target, said Otto, for either drug therapy or a vaccine against MRSA. To date, all clinical trials for a MRSA vaccine have been unsuccessful, said Lowy, and teams are now attempting to combine multiple virulence proteins in a single vaccine, for which sasX could be a promising candidate. “It depends on how prevalent it is,” he said. “The hope is if we have multiple targets, perhaps we’ll have a more effective vaccine.”
M. Li, et al., “MRSA epidemic linked to a quickly spreading colonization and virulence determinant,” Nat Med, doi:10.1038/nm.2692, 2012.