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Rewiring of one carbon metabolism in Salmonella serves as an excellent live vaccine against systemic salmonellosis
- Datey, Akshay, Shreenivas, Meghanashree, Chandrasekharan, Giridhar, Joseph, Jeswin, Sah, Shivjee, Aluri, Srinivas, Saha, Sankhanil, Varshney, Umesh, Chakravortty, Dipshikha
- Vaccine 2018 v.36 no.50 pp. 7715-7727
- Neisseria meningitidis, Salmonella Typhimurium, animal models, antibodies, blood serum, carbon metabolism, cytokines, enzymes, genes, humans, live vaccines, morbidity, mortality, neonates, pathogens, pregnancy, subunit vaccines, typhoid fever, vaccination, virulence, young adults
- Live attenuated vaccines are superior to the killed or subunit vaccines. We designed a Salmonella Typhimurium strain by deleting folD gene (encoding methylenetetrahydrofolate dehydrogenase-cyclohydrolase) in the presence of a heterologous fhs gene (encoding formyltetrahydrofolate synthetase) and tested its vaccine potential under stringent conditions of lethal and sub-lethal challenges with virulent Salmonella in the murine model. The efficacy of the vaccine in conferring protection against Salmonella infection was determined in a wide range of host conditions of systemic infection, corresponding to human young adults, neonates, geriatric age and, importantly, to the immune compromised state of pregnancy. The standardized vaccination regime comprised a primary dose of 104 CFU/animal followed by a booster dose of 102 CFU/animal on day 7. Challenge with the virulent pathogen was done at day 7 post-administration of the booster. Subsequently, the mortality, morbidity, systemic colonization, antibody response and cytokine profiling were determined. The vaccinated cohort showed a strong protection against virulent pathogen in all models tested. The serum anti-Salmonella antibody titers and cytokine levels were significantly higher in the vaccinated cohort compared to the mock vaccinated cohort. Thus, we report the development and validation of a live attenuated vaccine candidate conferring excellent protection against Salmonellosis and typhoid fever.