HOUSTON (October 24, 2011) - A worldwide epidemic of penicillin-resistant Staphylococcus aureus in the late 1950s -- whose underpinnings had vexed medical researchers at the time -- was probably caused by mutations in two genes that increased the bacterium's virulence, say researchers at The Methodist Hospital Research Institute and four other institutions in the Proceedings of the National Academy of Sciences USA (early edition, Oct. 24).
James M. Musser, M.D., Ph.D. was part of the group of 15 researchers who showed, using genome sequencing of 50-year-old strains, that Staph populations responsible for the epidemic in the U.S., U.K., Canada, and Australia were all descended from a recent common ancestor. Dr. Musser is director of the Center for Molecular and Translational Human Infectious Diseases Research at The Methodist Hospital Research Institute, and Chair, Department of Pathology and Genomic Medicine, The Methodist Hospital System.
Penicillin resistance in the epidemic-causing Staphylococcus aureus phage-type 80/81 made infections very difficult to treat successfully. Musser and colleagues discovered that the strain's increased virulence was due to mutations in two key chromosomal genes, agrC and hla, which encode accessory gene regulator C and alpha-hemolysin, respectively.
AgrC is known to be a quorum-sensing protein, that is, part of a system that tells the bacterial cell whether it is among a lot of its kind. Bacterial behavior often shifts with changes in bacterial density. Some pathogenic bacterial species, for example, only express genes that attack host cells when cells are dense enough to form mats, or biofilms, nearby.
Hla's effects are more direct -- once excreted from Staphylococcus aureus, alpha-hemolysin that inserts itself into host immune cell membranes, forcing open large pores that allow the leakage of ions into the surrounding medium and eventually, cell death.
Dr. Frank R. DeLeo of the National Institute of Allergy and Infectious Diseases (NIAID) was the PNAS report's lead author and Barry N. Kreiswirth at the University of Medicine and Dentistry of New Jersey (UMDNJ) was a key collaborator. Musser assisted in experimental design, data analysis, and the writing of the PNAS paper.
The research was funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the Region V "Great Lakes" Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Consortium, and the Canadian Institutes for Health Research.
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