TY - JOUR
T1 - Rewiring of one carbon metabolism in Salmonella serves as an excellent live vaccine against systemic salmonellosis
AU - Datey, Akshay
AU - Shreenivas, Meghanashree
AU - Chandrasekharan, Giridhar
AU - Joseph, Jeswin
AU - Sah, Shivjee
AU - Aluri, Srinivas
AU - Saha, Sankhanil
AU - Varshney, Umesh
AU - Chakravortty, Dipshikha
N1 - Funding Information:
We thank the financial support from Department of Biotechnology (DBT), Ministry of Science and Technology; Department of Science and Technology , India (DST), Ministry of Science and Technology; DST J. C. Bose Fellowship (to UV). DC acknowledges DAE for the SRC outstanding investigator award and funds. The authors jointly acknowledge the DBT-IISc partnership programme, University Grants Commission, New Delhi for the Centre of Advanced Studies, and the DST-FIST level II infrastructure supports to carry out this work. AD is a PhD scholar and is supported by a senior research fellowship from Department of Biotechnology, India. SS is a Senior Research Associate supported by the Council of Scientific and Industrial Research, New Delhi.
Publisher Copyright:
© 2018 Elsevier Ltd
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/11/29
Y1 - 2018/11/29
N2 - 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 10 4 CFU/animal followed by a booster dose of 10 2 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.
AB - 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 10 4 CFU/animal followed by a booster dose of 10 2 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.
KW - Live attenuated vaccine
KW - Murine model
KW - One-carbon metabolism
KW - Salmonella Typhimurium
KW - Systemic salmonellosis
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U2 - 10.1016/j.vaccine.2018.10.079
DO - 10.1016/j.vaccine.2018.10.079
M3 - Article
C2 - 30385055
AN - SCOPUS:85055507075
SN - 0264-410X
VL - 36
SP - 7715
EP - 7727
JO - Vaccine
JF - Vaccine
IS - 50
ER -
