Open AccessIncreased Susceptibility of Humanized NSG Mice to Panton-Valentine Leukocidin and Staphylococcus aureus Skin Infection
Author(s) -
Ching Wen Tseng,
Juan Carlos Biancotti,
Bethany L. Berg,
David Gate,
Stacey L. Kolar,
Sabrina Müller,
Maria Rodriguez,
Kavon RezaiZadeh,
Xuemo Fan,
David O. Beenhouwer,
Terrence Town,
George Y. Liu
Publication year - 2015
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1005292
Subject(s) - staphylococcus aureus , leukocidin , panton–valentine leukocidin , humanized mouse , microbiology and biotechnology , immunology , immune system , biology , staphylococcal infections , skin infection , tropism , nod , medicine , methicillin resistant staphylococcus aureus , virus , in vivo , bacteria , genetics
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)/IL2rγ null (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.