Live attenuated Salmonella typhimurium vaccines delivering SaEsxA and SaEsxB via type III secretion system confer protection against Staphylococcus aureus infection

Background: Staphylococcus aureus (S. aureus) causes a wide range of infectious diseases in human and animals. The emergence of antibiotic-resistant strains demands novel strategies for prophylactic vaccine development In this study, live attenuated S. enterica subsp. enterica serotype Typhimurium (S. Typhimurium) vaccine against S. aureus infection was developed, in which Salmonella Pathogenesis Island-1 Type 3 Secretion System (SPI-1 T3SS) was employed to deliver SaEsxA and SaEsxB, two of ESAT-6-like (Early Secreted Antigenic Target-6) virulence factors of S. aureus. Methods: Antigens SaEsxA and SaEsxB were fused with the N-terminal secretion and translocation domain of SPI-1 effector SipA. And cytosolic delivery of Staphylococcal antigens into macrophages was examined by western blot. BALB/c mice were orally immunized with S. Typhimurium-SaEsxA and S. Typhimurium-SaEsxB vaccines. Antigen-specific humoral and Th1/Th17 immune responses were examined by ELISA and ELISPOT assays 7-9 days after the 2nd booster. For ELISPOT assays, the statistical significance was determined by Students t test The vaccine efficacy was evaluated by lethal challenge with two S. aureus clinical isolates Newman strain and USA 300 strain. Statistical significance was determined by Log rank (Mantel-Cox) analysis. And a P value of < 0.05 was considered statistically significant. Results: Oral administration of S. Typhimurium-SaEsxA and S. Typhimurium-SaEsxB vaccines induced antigen-specific humoral and Th1/Th17 immune responses, which increased the survival rate for vaccinated mice when challenged with S. aureus strains. Conclusions: The newly developed S. Typhimurium-based vaccines delivering SaEsxA and SaEsxB by SPI-1 T3SS could confer protection against S. aureus infection. This study provides evidence that translocation of foreign antigens via Salmonella SPI-1 T3SS into the cytosol of antigen presenting cells (APCs) could induce potent immune responses against pathogens.