Clones and drones: do variants of Panton-Valentine leukocidin extend the reach of community-associated methicillin-resistant Staphylococcus aureus?

In 1932, Philip N. Panton and his colleagues, as they studied bacterial toxins at the London Hospital, could not have anticipated the scientific revolution coming in microbial genomics. It is ironic, then, that some of the genes encoding those toxins Panton and colleagues discovered well before the midpoint in the 20th century would now be contributing to our knowledge of how bacterial pathogens arise and evolve [2]. Even then, the work of these toxin hunters was specific enough to suggest that some of the toxins, in light of their cellular targets, were separate entities. Their term, “staphylococcal toxin,” included the various toxigenic effects produced by staphylococcal “constituents” that were either hemolytic (hemolysins), necrotic when injected subcutaneously (necrotoxins), destructive for phagocytes when staphylococcal suspensions were diluted 1:16 (leukocidins), or fatal for rabbits after intravenous injection (lethal toxin) [1]. In the early 1930s, there were no therapeutic antimicrobials and no penicillin resistance in staphylococci, let alone the resistance to semisynthetic penicillins introduced some 30 years later [3]. For that reason, in the early part of the last century, the ultimate intent of staphylococcal research was to develop specific antisera against suspected toxins in an attempt to counter the ineffective therapy of the vaccines of the era, which were composed primarily of bacterial debris [4]. It is likely that many of the early isolates of Staphylococcus aureus contained the genes (lukS-PV and lukF-PV) that encode the most important leukocidin, appropriately named “Panton-Valentine leukocidin” (PVL) [5]. In fact, there were reports of antitoxins being used efficaciously to treat staphylococcal infections [4], but those studies did not continue. Monoclonal antibodies to some of the MSCRAMMs (microbial surface components recognizing adhesive matrix molecules), on the other hand, have shown new promise for immune-based therapy [6]. Conversely, the exact role played by leukocidins such as PVL in the pathogenesis of staphylococcal infection remains controversial [7]. PVL-containing S. aureus continues to cause severe necrotizing communityacquired pneumonia [8], and PVL has been shown to be sufficient to cause necrotizing pneumonia when administered to mice [9]. In 2006, an extraordinary finding was reported concerning the spread in the community of a predominant strain of methicillin-resistant S. aureus (MRSA) termed “USA300,” which displayed an easily identifiable pattern when analyzed by pulsed-field gel electrophoresis (PFGE) and elaborated PVL [10]. The “USA” designations originally published in 2003 derived from the most common PFGE patterns of US isolates of MRSA [11]. USA300 isolates arose primarily from outbreaks in correctional institutions, among athletic teams, and in nurseries [12]. Oxacillin (methicillin) resistance had historically been linked to multiple resistance determinants housed within a large, complex mobile genetic element termed “staphylococcal chromosome cassette” (SCCmec) [13]. In contrast, community-associated MRSA (CA-MRSA) isolates such as USA 300 usually contained a smaller, truncated SCCmec [14]. Community strains containing SCCmec Received 16 August 2007; accepted 16 August 2007; electronically published 4 January 2008. Potential conflicts of interest: J.F.J. has served as a consultant to Cubist, bioMérieux, and Gilead; has in the past received research funding from Merck; and has participated in speakers’ bureaus with Pfizer, Cubist, and Bayer. J.A.L. has received grant support from Enzon Pharmaceuticals. Reprints or correspondence: Dr. Joseph F. John, 109 Bee St. (14), Charleston, SC 29401 ([email protected]). The Journal of Infectious Diseases 2008; 197:175– 8 © 2007 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19702-0001$15.00 DOI: 10.1086/524693 E D I T O R I A L C O M M E N T A R Y