Humanized Mice Exhibit Increased Susceptibility toStaphylococcus aureusPneumonia

Abstract

Staphylococcus aureus is a highly successful human pathogen that has evolved in response to human immune pressure. The common USA300 methicillin-resistant S. aureus (MRSA) strains express a number of toxins, such as Panton-Valentine leukocidin and LukAB, that have specificity for human receptors. Using nonobese diabetic (NOD)-scid IL2Rγnull (NSG) mice reconstituted with a human hematopoietic system, we were able to discriminate the roles of these toxins in the pathogenesis of pneumonia. We demonstrate that expression of human immune cells confers increased severity of USA300 infection. The expression of PVL but not LukAB resulted in more-severe pulmonary infection by the wild-type strain (with a 30-fold increase in the number of colony-forming units/mL; P < .01) as compared to infection with the lukS/F-PV (Δpvl) mutant. Treatment of mice with anti-PVL antibody also enhanced bacterial clearance. We found significantly greater numbers (by 95%; P < .05) of macrophages in the airways of mice infected with the Δpvl mutant compared with those infected with the wild-type strain, as well as significantly greater expression of human tumor necrosis factor and interleukin 6 (84% and 51% respectively; P < .01). These results suggest that the development of humanized mice may provide a framework to assess the contribution of human-specific toxins and better explore the roles of specific components of the human immune system in protection from S. aureus infection.