Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 12, Pages 5587-5592Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0912403107
Keywords
MRSA; USA300; virulence; pneumonia; rabbit infection model
Categories
Funding
- US Public Health Service National Institute of Allergy and Infectious Diseases [AI070289]
- Intramural Research Program of the NIAID
- National Institutes of Health
- University of California San Francisco Research Evaluation and Allocation Committee Pilot
- College des Universitaires des Maladies Infectieuses et Tropicales
- Pontchaillou University Hospital, Rennes, France
- European Community [222718]
- Pfizer and LeoPharma.
- National Heart, Lung and Blood Institute (NHLBI) [HL081764, HL51854]
- NIAID [AI074832, 2P01A1053194]
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Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is epidemic in the United States, even rivaling HIV/AIDS in its public health impact. The pandemic clone USA300, like other CA-MRSA strains, expresses Panton-Valentine leukocidin (PVL), a pore-forming toxin that targets polymorphonuclear leukocytes (PMNs). PVL is thought to play a key role in the pathogenesis of necrotizing pneumonia, but data from rodent infection models are inconclusive. Rodent PMNs are less susceptible than human PMNs to PVL-induced cytolysis, whereas rabbit PMNs, like those of humans, are highly susceptible to PVL-induced cytolysis. This difference in target cell susceptibility could affect results of experimental models. Therefore, we developed a rabbit model of necrotizing pneumonia to compare the virulence of a USA300 wild-type strain with that of isogenic PVL-deletion mutant and -complemented strains. PVL enhanced the capacity of USA300 to cause severe lung necrosis, pulmonary edema, alveolar hemorrhage, hemoptysis, and death, hallmark clinical features of fatal human necrotizing pneumonia. Purified PVL instilled directly into the lung caused lung inflammation and injury by recruiting and lysing PMNs, which damage the lung by releasing cytotoxic granule contents. These findings provide insights into the mechanism of PVL-induced lung injury and inflammation and demonstrate the utility of the rabbit for studying PVL-mediated pathogenesis.
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