Invasive
Salmonella infection is an important health problem that is worsening because of rising antimicrobial resistance and changing Salmonella serovar spectrum. Novel
vaccines with broad serovar coverage are needed, but suitable protective
antigens remain largely unknown. Here, we tested 37 broadly conserved Salmonella
antigens in a mouse
typhoid fever model, and identified
antigen candidates that conferred partial protection against lethal disease.
Antigen properties such as high in vivo abundance or immunodominance in convalescent individuals were not required for protectivity, but all promising
antigen candidates were associated with the Salmonella surface. Surprisingly, this was not due to superior immunogenicity of
surface antigens compared to internal
antigens as had been suggested by previous studies and novel findings for CD4 T cell responses to model
antigens. Confocal microscopy of infected tissues revealed that many live Salmonella resided alone in infected host macrophages with no damaged Salmonella releasing internal
antigens in their vicinity. In the absence of accessible internal
antigens, detection of these infected cells might require CD4 T cell recognition of Salmonella surface-associated
antigens that could be processed and presented even from intact Salmonella. In conclusion, our findings might pave the way for development of an efficacious
Salmonella vaccine with broad serovar coverage, and suggest a similar crucial role of
surface antigens for immunity to both extracellular and intracellular pathogens.