Panton–Valentine Leukocidin Enhances the Severity of Community-Associated Methicillin-Resistant Staphylococcus aureus Rabbit Osteomyelitis

Abstract

BackgroundExtensive spread of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in the United States, and the concomitant increase in severe invasive staphylococcal infections, including osteomyelitis, in healthy children, has led to renewed interest in Panton-Valentine leukocidin (PVL). However, the pathogenetic role of PVL in staphylococcal infections remains controversial, possibly because it depends on the site of infection.Methodology/Principal FindingsWe compared the course of experimental rabbit osteomyelitis due to the PVL-positive CA-MRSA strain USA 300 (LAC) and its PVL-negative isogenic derivative (LACΔpvl), using a low and a high inoculum (8×105 and 4×108 CFU). With the low inoculum, bone infection was less frequent on day 7 (D7) and day 28 (D28) with LACΔpvl than with LAC (respectively 12/19 and 18/19 animals, p = 0.042). With the high inoculum of both strains, all the animals were infected on D7 and the infection persisted on D28 in almost every case. However, tibial bacterial counts and the serum CRP concentration fell significantly between D7 and D28 with LACΔpvl but not with LAC. Respectively 67% and 60% of LAC-infected rabbits had bone deformation and muscle/joint involvement on D7, compared to 0% and 7% of LACΔpvl-infected rabbits (p = 0.001 and p = 0.005 respectively). Between D0 and D28, the anti-PVL antibody titer increased significantly only with the high inoculum of LAC.Conclusions/SignificancePVL appears to play a role in the persistence and rapid local extension of rabbit osteomyelitis, in keeping with the greater severity of human bone infections due to PVL-positive S. aureus. The possible therapeutic implications of these findings are discussed.

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

“…Introduction of PVL into a laboratory S. aureus strain changed the expression of other virulence factors (143), but deletion of PVL from the USA300 and USA400 clinical isolates had no influence on global gene expression (147). Experiments on mice and rabbits have usually confirmed a role for PVL in virulence (143,(145)(146)(147)(148)(149)469), whereas studies using rats and primates, and occasionally mice and rabbits, have not identified a role for PVL in infection (155,345,470,471). Given the relative insensitivity of mouse and rat PMNs to PVL, rabbits appear to be a better model for studying the effects of PVL, as their PMNs are more sensitive to PVL, more closely resembling the human situation (145).…”

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

“…In rabbit bacteremia models, PVL plays a negligible role in virulence (214). In contrast, PVL may contribute to S. aureus persistence in a model of osteomyelitis (Table 1) (215). Additional studies in primates were unable to uncover a role for PVL in a pneumonia model (216).…”

Incidence, Risk Factors, and Outcomes of Panton-Valentine Leukocidin-Positive Methicillin-Susceptible Staphylococcus aureus Infections in Auckland, New Zealand

“…PVL has been linked to skin and soft tissue infections (SSTIs), necrotizing pneumonia, and bone and joint infections in humans (3,11,17). Rabbit and human leukocytes are highly sensitive to PVL-mediated leukocytosis (18), and animal studies have shown that PVL causes moresevere disease in dermonecrosis (7,27), osteomyelitis (6), and necrotizing pneumonia models (B. A. Diep, L. Chan, and P. Tattevin, presented at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 2009).…”