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Staphylococcus aureus (S. aureus) is one of the most common bacterial infections worldwide, and antibiotic resistant strains such as Methicillin-Resistant S. aureus (MRSA) are a major threat and burden to public health. MRSA not only infects immunocompromised patients but also healthy individuals and has rapidly spread from the healthcare setting to the outside community. However, all vaccines tested in clinical trials to date have failed. Immunocompromised individuals such as patients with HIV or decreased levels of CD4+ T cells are highly susceptible to S. aureus infections, and they are also at increased risk of developing fungal infections. We therefore wondered whether stimulation of antifungal immunity might promote the type of immune responses needed for effective host defense against S. aureus. Here we show that vaccination of mice with a fungal β-glucan particle (GP) loaded with S. aureus antigens provides protective immunity to S. aureus. We generated glucan particles loaded with the four S. aureus proteins ClfA, IsdA, MntC, and SdrE, creating the 4X-SA-GP vaccine. Vaccination of mice with three doses of 4X-SA-GP promoted protection in a systemic model of S. aureus infection with a significant reduction in the bacterial burden in the spleen and kidneys. 4X-SA-GP vaccination induced antigen-specific Th1 and Th17 CD4+ T cell and antibody responses and provided long-term protection. This work suggests that the GP vaccine system has potential as a novel approach to developing vaccines for S. aureus., Author summary Staphylococcus aureus (S. aureus) is a serious burden to public health as it is a leading cause of antibiotic-resistant infections worldwide. Vaccines aimed at targeting S. aureus have failed in clinical trials, and the reason for this lack of success remains unclear. As this pathogen continues to rapidly spread on a global scale, it is vital that new approaches to S. aureus vaccination are developed. In this study, we show that activation of antifungal immunity with a β-glucan particle vaccine can be harnessed to direct protection against S. aureus systemic infections in mice. This work broadens the use of the β-glucan particle vaccine system for potential use as a much-needed vaccine targeting S. aureus.

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.