Non-typhoidal Salmonella (NTS) causes gastrointestinal infection, which is commonly self-limiting in healthy humans but may lead to invasive infection at extraintestinal sites, leading to bacteremia and focal systemic infections in the immunocompromised. However, a prophylactic vaccine against invasive NTS has not yet been developed. In this work, we explored the potential of a yjeK mutant strain as a live attenuated vaccine against invasive NTS infection. YjeK in combination with YjeA is required for the post-translational modification of elongation factor P (EF-P), which is critical for bacterial protein synthesis. Therefore, malfunction of YjeK and YjeA-mediated EF-P activation might extensively influence protein expression during Salmonella infection. Salmonella lacking YjeK showed substantial alterations in bacterial motility, antibiotics resistance, and virulence. Interestingly, deletion of the yjeK gene increased the expression levels of Salmonella pathogenicity island (SPI)-1 genes but decreased the transcription levels of SPI-2 genes, thereby influencing bacterial invasion and survival abilities in contact with host cells. In a mouse model, the yjeK mutant strain alleviated the levels of splenomegaly and bacterial burdens in the spleen and liver in comparison with the wild-type strain. However, mice immunized with the yjeK mutant displayed increased Th1-and Th2-mediated immune responses at 28 days post-infection, promoting cytokines and antibodies production. Notably, the Th2-associated antibody response was highly induced by administration of the yjeK mutant strain. Consequently, vaccination with the yjeK mutant strain protected 100% of the mice against challenge with lethal invasive Salmonella and significantly relieved bacterial burdens in the organs. Collectively, these results suggest that the yjeK mutant strain can be exploited as a promising live attenuated NTS vaccine.

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Non-typhoidal Salmonella (NTS) is one of the primary causes of foodborne gastroenteritis; occasionally, it causes invasive infection in humans. Because of its broad host range, covering diverse livestock species, foods of animal origin pose a critical threat of NTS contamination. However, there is currently no licensed vaccine against NTS infection. FruR, also known as Cra (catabolite repressor/activator), was initially identified as the transcriptional repressor of the fructose (fru) operon, and then found to activate or repress the transcription of many different genes associated with carbon and energy metabolism. In view of its role as a global regulator, we constructed a live attenuated vaccine candidate, ΔfruR, and evaluated its prophylactic effect against NTS infection in mice. A Salmonella Typhimurium mutant strain lacking fruR was defective in survival inside macrophages and exhibited attenuated virulence in infected mice. Immunization with the ΔfruR mutant stimulated the production of antibodies, including the IgG, IgM, and IgG subclasses, and afforded a protection of 100% to mice against the challenge of lethal infection with a virulent Salmonella strain. The prophylactic effect obtained after ΔfruR immunization was also validated by the absence of signs of hepatosplenomegaly, as these mice had comparable liver and spleen weights in comparison with healthy mice. These results suggest that the ΔfruR mutant strain can be further exploited as a promising vaccine candidate against Salmonella lethal infection.