Abstract
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 ΔyjeK 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 ΔyjeK 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 ΔyjeK 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 ΔyjeK mutant strain. Consequently, vaccination with the ΔyjeK 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 ΔyjeK mutant strain can be exploited as a promising live attenuated NTS vaccine.
Highlights
Non-typhoidal Salmonella (NTS) is one of the main causative agents of foodborne gastrointestinal diseases in humans [1]
A continuous sequence comprising the majority of yjeK was deleted in the chromosome of serovar Typhimurium 1120 (ST1120) using the λ red recombination method [19] (Figure S1A)
Transcription of efp was hardly influenced by the deletion in the yjeK mutant strain, ruling out the possibility of a polar effect on elongation factor P (EF-P) activity in the yjeK strain yjeK Vaccine Against invasive NTS (iNTS) Diseases
Summary
Non-typhoidal Salmonella (NTS) is one of the main causative agents of foodborne gastrointestinal diseases in humans [1]. NTS infections in the gastrointestinal tract are generally mild, manifesting with symptoms such as abdominal cramps, nausea, diarrhea, mild fever, vomiting, dehydration, and/or headache [2, 3]. NTS is often invasive and can enter the bloodstream with very serious consequences, including sepsis, pneumonia, meningitis or osteomyelitis, hepatosplenomegaly, and/or respiratory symptoms [3,4,5]. Invasive NTS (iNTS) is fatal to young children as well as to individuals suffering from malnutrition and immunocompromised patients, including those with HIV/AIDS and organ recipients [6]. Despite the serious challenge of NTS infection, there is currently no NTS vaccine available for humans. Development of an NTS vaccine is considered one of the most upmost issues in healthcare at present
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