Invasive Salmonella infection is an important health problem that is worsening because of rising antimicrobial resistance and the changing Salmonella serovar spectrum. Novel vaccines with broad serovar coverage are needed, but suitable protective antigens remain largely unknown.
This study identified several antigen candidates that mediated protective immunity to Salmonella in a mouse typhoid fever model. Interestingly, all these antigens were associated with the Salmonella surface. This suggested that similar antigen properties might be relevant for CD4 T cell dependent immunity to intracellular pathogens like Salmonella, as for antibody-dependent immunity to extracellular pathogens. Detailed analysis revealed that Salmonella surface antigens were not generally more immunogenic compared to internal antigens. However, internal antigens were inaccessible for CD4 T cell recognition of a substantial number of infected host cells that contained exclusively live intact Salmonella. These results might pave the way for development of an effective Salmonella vaccine, and provide a basis to facilitate antigen identification for Salmonella and possibly other intracellular pathogens.