title: Increased Susceptibility of Humanized NSG Mice to Panton-Valentine Leukocidin and Staphylococcus aureus Skin Infection.
abstract: Staphylococcus aureus is a leading cause of skin and soft-tissue infections worldwide. Mice are the most commonly used animals for modeling human staphylococcal infections. However a supra-physiologic S. aureus inoculum is required to establish gross murine skin pathology. Moreover, many staphylococcal factors, including Panton-Valentine leukocidin (PVL) elaborated by community-associated methicillin-resistant S. aureus (CA-MRSA), exhibit selective human tropism and cannot be adequately studied in mice. To overcome these deficiencies, we investigated S. aureus infection in non-obese diabetic (NOD)/severe combined immune deficiency (SCID)/IL2rγnull (NSG) mice engrafted with human CD34+ umbilical cord blood cells. These "humanized" NSG mice require one to two log lower inoculum to induce consistent skin lesions compared with control mice, and exhibit larger cutaneous lesions upon infection with PVL+ versus isogenic PVL- S. aureus. Neutrophils appear important for PVL pathology as adoptive transfer of human neutrophils alone to NSG mice was sufficient to induce dermonecrosis following challenge with PVL+ S. aureus but not PVL- S. aureus. PMX53, a human C5aR inhibitor, blocked PVL-induced cellular cytotoxicity in vitro and reduced the size difference of lesions induced by the PVL+ and PVL- S. aureus, but PMX53 also reduced recruitment of neutrophils and exacerbated the infection. Overall, our findings establish humanized mice as an important translational tool for the study of S. aureus infection and provide strong evidence that PVL is a human virulence factor.
authors.affiliation: Division of Pediatric Infectious Diseases and the Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.|Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
authors.forename: Ching Wen
authors.initials: CW
authors.lastname: Tseng
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Biancotti
authors.affiliation: Division of Pediatric Infectious Diseases and the Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.|Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Berg
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Gate
authors.affiliation: Division of Pediatric Infectious Diseases and the Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.|Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Kolar
authors.affiliation: Division of Pediatric Infectious Diseases and the Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.|Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Müller
authors.affiliation: Division of Pediatric Infectious Diseases and the Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.|Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Rodriguez
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Kavon
authors.initials: K
authors.lastname: Rezai-Zadeh
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Xuemo
authors.initials: X
authors.lastname: Fan
authors.affiliation: Division of Infectious Diseases, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.|Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
authors.forename: David O
authors.initials: DO
authors.lastname: Beenhouwer
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.affiliation: Division of Pediatric Infectious Diseases and the Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.|Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
authors.forename: George Y
authors.initials: GY
authors.lastname: Liu
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology*; D005098:Exotoxins / Q000494:pharmacology*; D006801:Humans; D007956:Leukocidins / Q000494:pharmacology*; D051379:Mice; D013207:Staphylococcal Skin Infections / Q000188:drug therapy / Q000382:microbiology*; D013211:Staphylococcus aureus
chemical_list: D001427:Bacterial Toxins; D005098:Exotoxins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin