Abstract
A vaccine that effectively targets methicillin-resistant Staphylococcus aureus (MRSA) is urgently needed, and has been the focus of studies by numerous research groups, but with limited success to date. Recently, our team found that exopolysaccharides derived from probiotic Lactobacillus casei strain WXD030 as an adjuvant-formulated OVA could upregulate IFN-γ and IL-17 expression in CD4+ T cells. In this study, we developed a vaccine (termed rMntC-EPS) composed of S. aureus antigen MntC and Lactobacillus casei exopolysaccharides, which conferred high levels of protection against S. aureus infection. Methods: Six–eight-week-old female mice were vaccinated with purified rMntC-EPS30. The immune protection function of rMntC-EPS30 was assessed by the protective effect of rMntC-EPS30 to S. aureus-induced pulmonary and cutaneous infection in mice, bacterial loads and H&E in injury site, and ELISA for inflammation-related cytokines. The protective mechanism of rMntC-EPS30 was assessed by ELISA for IgG in serum, cytokines in the spleen and lungs of vaccinated mice. In addition, flow cytometry was used for analyzing cellular immune response induced by rMntC-EPS30. For confirmation of our findings, three kinds of mice were used in this study: IL-17A knockout mice, IFN-γ knockout mice and TCRγ/δ knockout mice. Results: rMntC-EPS30 conferred up to 90% protection against S. aureus pulmonary infection and significantly reduced the abscess size in the S. aureus cutaneous model, with clearance of the pathogen. The rMntC-EPS vaccine could induce superior humoral immunity as well as significantly increase IL-17A and IFN-γ production. In addition, we found that rMntC-EPS vaccination induced robust Th 17/γδ T 17 primary and recall responses. Interestingly, this protective effect was distinctly reduced in the IL-17A knockout mice but not in IFN-γ knockout mice. Moreover, in TCRγ/δ knockout mice, rMntC-EPS vaccination neither increased IL-17A secretion nor provided effective protection against S. aureus infection. Conclusions: These data demonstrated that the rMntC formulated with a novel Lactobacillus-derived Exopolysaccharides adjuvant provided high protection against Staphylococcus aureus. The rMntC-EPS vaccine induced γδ T cells and IL-17A might play substantial roles in anti-S. aureus immunity. Our findings provided direct evidence that rMntC-EPS vaccine is a promising candidate for future clinical application against S. aureus-induced pulmonary and cutaneous infection.
Highlights
Staphylococcus aureus is a gram-positive bacterium with a complex pathogenesis mechanism
Using mouse pulmonary and cutaneous models, we demonstrated that γδ T cells and IL-17A induced by rMntC-EPS30 may promote resistance to S. aureus infection
We developed a novel vaccine composed of S. aureus antigen manganese transport protein C (MntC) and Lactobacillus casei exopolysaccharides, which conferred up to 90% protection against S. aureus pulmonary infection and induced strong protection against S. aureus cutaneous infection
Summary
Staphylococcus aureus is a gram-positive bacterium with a complex pathogenesis mechanism. S. aureus-induced pneumonia accounts for 20–50% of nosocomial pneumonia cases and ~25% of cases of community-acquired pneumonia, which causes severe pulmonary infection, with high morbidity and mortality [1,2]. S. aureus skin infections have been an increasingly serious public health problem in recent decades. Methicillin-resistant S. aureus (MRSA) strains have appeared and become increasingly resistant to multiple antibiotics [4]; an effective prophylactic vaccine that targets S. aureus is urgently needed. StaphVAX and IsdB did not provide effective protection against S. aureus bacteremia in phase III clinical trials, most likely because of overemphasis on humoral immune responses, suggesting that the design of next-generation vaccines should focus on targeted T cell responses [5,6]
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