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Rapid Neutrophil Destruction following Phagocytosis of Staphylococcus aureusKobayashi S.D.a · Braughton K.R.a · Palazzolo-Ballance A.M.a · Kennedy A.D.a · Sampaio E.d, g · Kristosturyan E.d · Whitney A.R.a · Sturdevant D.E.b · Dorward D.W.c · Holland S.M.d · Kreiswirth B.N.e · Musser J.M.f · DeLeo F.R.a
aLaboratory of Human Bacterial Pathogenesis, and Research Technologies Section, bGenomics and cMicroscopy Units, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Mont., dLaboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., ePublic Health Research Institute and the University of Medicine and Dentistry of New Jersey, Newark, N.J., and fCenter for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, The Methodist Hospital Research Institute, Houston, Tex., USA; gLeprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil Corresponding Author
Dr. Frank R. DeLeo
Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories
National Institute of Allergy and Infectious Diseases, National Institutes of Health
903 South 4th Street, Hamilton, MT 59840 (USA)
Tel. +1 406 363 9448, Fax +1 406 363 9394, E-Mail email@example.com
Mechanisms underlying the enhanced virulence phenotype of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are incompletely defined, but presumably include evasion of killing by human polymorphonuclear leukocytes (PMNs or neutrophils). To better understand this phenomenon, we investigated the basis of rapid PMN lysis after phagocytosis of USA300, a prominent CA-MRSA strain. Survival of USA300 clinical isolates after phagocytosis ultimately resulted in neutrophil lysis. PMNs containing ingested USA300 underwent morphological changes consistent with apoptosis, but lysed rapidly thereafter (within 6 h), whereas cells undergoing FAS-mediated apoptosis or phagocytosis-induced cell death remained intact. Phagosome membranes remained intact until the point of PMN destruction, suggesting lysis was not caused by escape of S. aureus from phagosomes or the cytolytic action of pore-forming toxins. Microarray analysis of the PMN transcriptome after phagocytosis of representative community-associated S. aureus and healthcare-associated MRSA strains revealed changes unique to community-associated S. aureus strains, such as upregulation of transcripts involved in regulation of calcium homeostasis. Collectively, the data suggest that neutrophil destruction after phagocytosis of USA300 is in part a form of programmed necrosis rather than direct lysis by S. aureus pore-forming toxins. We propose that the ability of CA-MRSA strains to induce programmed necrosis of neutrophils is a component of enhanced virulence.
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