Increased Susceptibility of Humanized NSG Mice to Panton-Valentine Leukocidin and Staphylococcus aureus Skin Infection

Autor: Kavon Rezai-Zadeh, David O. Beenhouwer, George Y. Liu, Maria D. Rodriguez, Xuemo Fan, Stacey L. Kolar, Juan Carlos Biancotti, Terrence Town, David Gate, Ching Wen Tseng, Bethany L. Berg, Sabrina Müller
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: PLoS Pathogens, Vol 11, Iss 11, p e1005292 (2015)
PLoS Pathogens
ISSN: 1553-7374
1553-7366
Popis: 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.
Author Summary S. aureus infection has emerged in the past decade as a major burden to public health and is responsible for a surge in preclinical research. Mice are the most commonly studied animals for modeling of human S. aureus infection. However, it is increasingly evident that available murine models poorly mimic human S. aureus disease. Routinely, a supra-physiologic inoculum is required to establish soft-tissue pathology. Additionally, many S. aureus factors exhibit unique human tropism and cannot be adequately investigated in rodents. Here we investigated S. aureus infection in NSG mice engrafted with human umbilical CD34+ cells. We showed that a one to two log lower infectious inoculum of S. aureus establishes consistent skin lesions in humanized NSG mice. This inoculum is comparable to published inocula required to induce infection in humans. In addition, we showed that Panton-Valentine Leucocidin, a human tropic factor secreted by S. aureus, contributes to the development of dermonecrosis in the humanized mice, and its interaction with human neutrophils and human C5a receptor appears to be important for immunopathology. Overall our study suggests that humanized mice are an improved tool for modeling of human S. aureus infection.
Databáze: OpenAIRE
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