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Importance of toxins in the pathogenesis of S. aureus infections
Abstract & Commentary
By Joseph F. John, Jr., MD, FACP, FIDSA, FSHEA, Associate Chief of Staff for Education, Ralph H. Johnson Veterans Administration Medical Center; Professor of Medicine, Medical University of South Carolina, Charleston, SC, is Associate Editor for Infectious Disease Alert.
Dr. John does research for Merck, is a consultant for Cubist, Roche, and bioMerieux, and is on the speaker's bureau for Pharmacia, GSK, Merck, Bayer, and Wyeth.
Source: Labandeira-Rey M, et al. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. 2007;315:1130-1133.
A group of staphylococcal investigators from Lyon, France, and Houston, Texas, have been working for years to show the importance of toxins in the pathogenesis of S. aureus infections. The group of Jerome Etienne and Francois Vandenesch in Lyon have already shown the propensity of strains containing the PVL toxin to produce fatal necrotizing pneumonia in children. There is debate, however, on its role in skin and soft tissue infection and in pneumonia in adults. What the group shows in this work is that, in mice, PVL alone is responsible for necrotizing pneumonia and has multiple other important interactions. This paper is likely to become a landmark citation.
PVL was discovered decades ago. It is carried in S.aureus by a phage. When mice are injected wild-type strains containing PVL and with PVL alone, in the hands of these investigators, a proliferative pneumonitis along with other severe symptoms occurs. PVL itself was found within tissues infected with the PVL-positive staphylococci. The workers next show that engineered strains lacking only the PVL genes caused minimal change in lung architecture.
Other staphylococcal products are affected by PVL. PVL-positive strains adhere to injured airway epithelium. The work by Magnus Hook (one of the coauthors in this paper) and colleagues had established over many years that staphylococci produce cell-surface associated structures known as MSCRAMMS. PVL actually upregulates these surface molecules probably explaining the persistence of these strains in pulmonary tissue. The upregulation of the cell-wall-anchored proteins is likely accompanied by a down regulation of secreted proteins and other toxins, both regulated by a central effector of global regulation, RNAIII. Among bacteria, this type of regulation through RNA is nearly unique, thus contributing to the challenge of understanding infection due to S. aureus.
Another interesting finding of the present study features Spa, staphylococcal protein A. Spa is a known virulence factor in mice. What was not known is the interaction of Spa and PVL. In the current work, deletion of Spa in PVL-positive strains was not associated with lethality, suggesting that Spa and PVL could act synergistically.
Men are not mice but sometimes mice are the best we can do to in order to understand pathogenesis. The scourge of community-associated MRSA infections justifies this work in mice since we have a poor understanding about why the currently circulating CA-MRSA is so virulent. Almost all community strains of MRSA are PVL positive, but there have been divergent findings about the role of PVL in pathogenesis.
The work of Labandeira-Rey et al solidifies, for the first time, evidence that PVL is absolutely crucial to pneumonitis and that its absence renders the strains tested nearly non-pathogenic. Additionally, they show that PVL has many crucial interactions with other staphylococcal genes, particularly adherence genes. Hopefully, new targets for antimicrobial inhibition will arise out of this work. Earlier work that used strategies to inhibit MSCRAMMS showed that there were alternative adherence mechanisms that preserved virulence. The current work shows that PVL does interact with global regulators supporting a developing theme that in pathogenic bacterial global regulators may be the best next-generation of antibacterial targets. There are hints in this paper that shutting off certain of these global regulators like RNAIII could reduce toxins like PVL and markedly reduce tissue necrosis. Several labs are working on molecules that could shut off RNAIII activity in S.aureus.