Date Published: November 30, 2015
Publisher: Public Library of Science
Author(s): Ching Wen Tseng, Juan Carlos Biancotti, Bethany L. Berg, David Gate, Stacey L. Kolar, Sabrina Müller, Maria D. Rodriguez, Kavon Rezai-Zadeh, Xuemo Fan, David O. Beenhouwer, Terrence Town, George Y. Liu, Rachel M McLoughlin.
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.
Staphylococcus aureus is an aggressive human pathogen that causes a wide range of diseases and represents a major threat to public health. S. aureus is the most common cause of bacterial skin and soft tissue infection in the United States and is responsible for over 70% of soft tissue infections treated in emergency rooms . Staphylococcal soft tissue diseases range from superficial infections such as impetigo and abscesses to complicated and life threatening infections such as myositis, pyomyositis, and necrotizing fasciitis.
In recent years, investigation of S. aureus toxins has uncovered a number of human immune receptors that serve as receptors for the bacterial toxins, for example LukAB-CD11b and LukED-CCR5 . In the report describing LukED virulence functions, CCR5-deficient mice were shown to be resistant to a lethal challenge with LukED+S. aureus, suggesting that blockade of host immune receptors could be a generalized strategy to block S. aureus toxin effects to ameliorate S. aureus infection [2,15]. In our study, PMX53 treatment appears to exacerbate infection as may be expected from blockade of a major innate immune receptor. Because the binding sites for C5a and PVL are overlapping but different, it may still be feasible to find an inhibitor that blocks PVL-hC5aR interaction without interfering with normal C5a immune functions. Of note, a recently published study has identified several additional C5aR blockers that inhibit PVL cytolytic activity in vitro . However, our data suggest that administration of PMX53 after infection is not effective at reducing pathology and therefore the utility of this approach may be limited.