Host and Bacterial Factors Affecting Induction of Immune Responses to Flagellin Expressed by AttenuatedSalmonellaVaccine Strains

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Abstract
Previous observations demonstrated that the delivery of recombinantSalmonella entericaserovar Dublin strains to mice via mucosal routes did not efficiently activate systemic and secreted antibody responses to either typedflagellin or genetically fused heterologous B-cell epitopes, thus reducing the usefulness of the protein as a carrier of epitopes for vaccine purposes. In this work, we investigated murine systemic and mucosal flagellin immunogenicity after oral immunization with attenuatedSalmonellastrains. The reduced anti-typedflagellin antibody responses in mice immunized via mucosal routes with three doses of flagellatedS. entericaserovar Dublin strains were not caused by oral tolerance and could not be restored by coadministration of a mucosal adjuvant. The induction of antibody responses toSalmonellaflagellins was shown to differ according to the genetic background, but not the haplotype, of the mouse lineage. Moreover, BALB/c mice orally immunized withS. entericaserovar Typhimurium strains developed anti-typeiflagellin sera and secreted antibody responses, which indicated that the serovar of theSalmonellavaccine strain also affected flagellin immunogenicity. Analyses of cytokine responses of BALB/c mice immunized with three oral doses of flagellatedS. entericaserovar Dublin vaccine strains showed that, in spite of the lack of antibody responses, elevated typedflagellin-specific CD4-cell-activation-dependent gamma interferon (IFN-γ) and interleukin-10 responses were elicited after the administration of the vaccine strains via either parenteral or mucosal routes. Similar cytokine production patterns were detected to a T-cell heterologous epitope, derived from the CFA/I fimbriae of enterotoxigenicEscherichia coli(ETEC), in mice orally immunized with aSalmonellavaccine strain expressing hybrid flagella. These results indicate that the immunogenicities ofSalmonellaflagellins can differ significantly, depending on the murine host and on the bacterial vector used, and demonstrate that the induction of CD4-cell-activation-dependent IFN-γ production represents a major immune response triggered by flagellin and in-frame fused heterologous T-cell epitopes after the oral administration of recombinantS. entericaserovar Dublin vaccine strains.

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