In VivoRegulation of the Vi Antigen in Salmonella and Induction of Immune Responses with anIn Vivo-Inducible Promoter

Abstract

ABSTRACTSalmonella entericaserovar Typhi, the agent of typhoid fever in humans, expresses the surface Vi polysaccharide antigen that contributes to virulence. However, Vi expression can also be detrimental to some key steps ofS.Typhi infectivity, for example, invasion, and Vi is the target of protective immune responses. We used a strain ofS.Typhimurium carrying the wholeSalmonellapathogenicity island 7 (SPI-7) to monitorin vivoVi expression within phagocytic cells of mice at different times after systemic infection. We also tested whether it is possible to modulate Vi expression via the use ofin vivo-inducible promoters and whether this would trigger anti-Vi antibodies through the use of Vi-expressing live bacteria. Our results show that Vi expression in the liver and spleen is downregulated with the progression of infection and that the Vi-negative population of bacteria becomes prevalent by day 4 postinfection. Furthermore, we showed that replacing the naturaltviApromoter with the promoter of the SPI-2 genessaGresulted in sustained Vi expression in the tissues. Intravenous or oral infection of mice with a strain ofS.Typhimurium expressing Vi under the control of thessaGpromoter triggered detectable levels of all IgG subclasses specific for Vi. Our work highlights that Vi is downregulatedin vivoand provides proof of principle that it is possible to generate a live attenuated vaccine that induces Vi-specific antibodies after single oral administration.