Abstract
Staphylococcus aureus is a leading cause of nosocomial and community-associated infection worldwide; however, there is no licensed vaccine available. S. aureus initiates infection via the mucosa; therefore, a mucosal vaccine is likely to be a promising approach against S. aureus infection. Lactobacilli, a non-pathogenic bacterium, has gained increasing interest as a mucosal delivery vehicle. Hence, we attempted to develop an oral S. aureus vaccine based on lactobacilli to cushion the stress of drug resistance and vaccine needs. In this study, we designed, constructed, and evaluated recombinant Lactobacillus strains synthesizing S. aureus nontoxic mutated α-hemolysins (HlaH35L). The results from animal clinical trials showed that recombinant Lactobacillus can persist for at least 72 h and can stably express heterologous protein in vivo. Recombinant L. plantarum WXD234 (pNZ8148-Hla) could induce robust mucosal immunity in the GALT, as evidenced by a significant increase in IgA and IL-17 production and the strong proliferation of T-lymphocytes derived from Peyer’s patches. WXD234 (pNZ8148-Hla) conferred up to 83% protection against S. aureus pulmonary infection and significantly reduced the abscess size in a S. aureus skin infection model. Of particular interest is the sharp reduction of the protective effect offered by WXD234 (pNZ8148-Hla) vaccination in γδ T cell-deficient or IL-17-deficient mice. In conclusion, for the first time, genetically engineered Lactobacillus WXD234 (pNZ8148-Hla) as an oral vaccine induced superior mucosal immunity, which was associated with high protection against pulmonary and skin infections caused by S. aureus. Taken together, our findings suggest the great potential for a delivery system based on lactobacilli and provide experimental data for the development of mucosal vaccines for S. aureus.
Highlights
Introduction iationsStaphylococcus aureus is normally a non-harmful commensal bacterium in humans and other mammals, but occasionally becomes invasive and produces serious diseases, including sepsis, infective endocarditis, pleurisy, septic arthritis, skin infection, and soft tissue infection [1]
The location of HlaH35L was analyzed by confocal laser scanning microscopy (CLSM), with SXJ29 and WXD234 as negative controls
It became apparent that fluorescent lactobacilli was contained in the intestinal contents of the mice 6 h post-administration (Figure 3f). These results indicate that recombinant Lactobacillus can persist in the intestine for at least 72 h and that heterologous protein can be stably expressed in the intestine
Summary
Staphylococcus aureus is normally a non-harmful commensal bacterium in humans and other mammals, but occasionally becomes invasive and produces serious diseases, including sepsis, infective endocarditis, pleurisy, septic arthritis, skin infection, and soft tissue infection [1]. Indiscriminate use of antibiotics during recent decades has resulted in the increasing development of drug-resistant strains, especially methicillinresistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), characterized by wide spreading ability, high pathogenicity, multidrug resistance, and limited or no options for therapeutic intervention [2,3]. Morbidity and mortality due to serious diseases and their sequelae are high despite use of antibiotics to which these strains are susceptible [4]. Vaccination is a promising method, in theory, for preventing and combating S. aureus infections without risking the development of drug-resistant strains [5].
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