Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury.
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.
Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, CA 94110, USA. bdiep@medsfgh.ucsf.edu
Binh An
BA
Diep
Liana
L
Chan
Pierre
P
Tattevin
Osamu
O
Kajikawa
Thomas R
TR
Martin
Li
L
Basuino
Thuy T
TT
Mai
Helene
H
Marbach
Kevin R
KR
Braughton
Adeline R
AR
Whitney
Donald J
DJ
Gardner
Xuemo
X
Fan
Ching W
CW
Tseng
George Y
GY
Liu
Cedric
C
Badiou
Jerome
J
Etienne
Gerard
G
Lina
Michael A
MA
Matthay
Frank R
FR
DeLeo
Henry F
HF
Chambers
D055371:Acute Lung Injury / Q000209:etiology* / Q000382:microbiology / Q000473:pathology; D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000633:toxicity*; D004195:Disease Models, Animal; D005098:Exotoxins / Q000235:genetics / Q000633:toxicity*; D017353:Gene Deletion; D005798:Genes, Bacterial; D005816:Genetic Complementation Test; D006801:Humans; D066298:In Vitro Techniques; D007956:Leukocidins / Q000235:genetics / Q000633:toxicity*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000235:genetics / Q000472:pathogenicity*; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D011023:Pneumonia, Staphylococcal / Q000209:etiology* / Q000382:microbiology / Q000473:pathology; D011817:Rabbits; D014774:Virulence / Q000235:genetics
D001427:Bacterial Toxins; D005098:Exotoxins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin