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Anti-IFN-gamma-treated mice--a model for testing safety of live Salmonella vaccines
1Molecular Biology Unit, National Public Health Institute, Helsinki, Finland.
Abstract:
Salmonella enterica serovars Typhimurium and Enteritidis are facultative intracellular pathogens which cause in mice a disease similar to human typhoid fever caused by serovar Typhi. An essential phase in the infection process is bacterial replication inside cells of the liver and spleen; the rate of replication is restricted by interferon-gamma (IFN-gamma) produced early in the infection. In the present study the effect of IFN-gamma was neutralized in vivo with monoclonal antibody and the fate of bacteria in the liver and spleen in these mice compared with that in control mice after intravenous challenge. The depletion of IFN-gamma remarkably sensitized the mice to Typhimurium infection. Five different Typhimurium and Enteritidis candidate vaccine strains were tested. Only one of them, the aroA mutant SL3261, was avirulent also in anti-IFN-gamma treated mice. This finding may have important implications for the safety of live attenuated Salmonella vaccines since immunosuppression is likely to cause a state of reduced production of IFN-gamma.
Insights
Neutralizing interferon-gamma (IFN-gamma) in mice significantly increased susceptibility to Salmonella Typhimurium infection. However, the live attenuated Salmonella vaccine strain SL3261 remained avirulent, suggesting its safety even in immunocompromised states.
Area of Science:
- Immunology
- Microbiology
- Vaccinology
Background:
- Salmonella Typhimurium and Enteritidis are facultative intracellular pathogens causing typhoid-like illness in mice.
- Bacterial replication in the liver and spleen is a critical infection phase, normally restricted by early interferon-gamma (IFN-gamma) production.
Purpose of the Study:
- To investigate the role of IFN-gamma in Salmonella infection pathogenesis.
- To evaluate the safety of live attenuated Salmonella vaccine candidates in the absence of IFN-gamma.
Main Methods:
- In vivo neutralization of IFN-gamma using monoclonal antibodies in mice.
- Intravenous challenge with Salmonella Typhimurium and Enteritidis.
- Assessment of bacterial load in the liver and spleen.
- Testing of five candidate Salmonella vaccine strains, including the aroA mutant SL3261.
Main Results:
- IFN-gamma depletion markedly increased mouse susceptibility to Salmonella Typhimurium infection.
- The aroA mutant strain SL3261 demonstrated avirulence even in mice lacking IFN-gamma.
- Other tested vaccine candidates were virulent in the absence of IFN-gamma.
Conclusions:
- IFN-gamma plays a crucial role in controlling Salmonella infection.
- The aroA mutant Salmonella vaccine strain SL3261 shows promise for safety in immunocompromised individuals.
- Findings have significant implications for the safety assessment of live attenuated Salmonella vaccines, particularly concerning immunosuppression and reduced IFN-gamma levels.