CD8+ T cell adjuvant effects of Salmonella FliCd flagellin in live vaccine vectors or as purified protein

Abstract

Salmonella flagellin, the flagellum structural subunit, has received particular interest as a vaccine adjuvant conferring enhanced immunogenity to soluble proteins or peptides, both for activation of antibody and cellular immune responses. In the present study, we evaluated the Salmonella enterica FliCd flagellin as a T cell vaccine adjuvant using as model the 9-mer (SYVPSAEQI) synthetic H2(d)-restricted CD8(+) T cell-specific epitope (CS(280-288)) derived from the Plasmodium yoelii circumsporozoite (CS) protein. The FliCd adjuvant effects were determined under two different conditions: (i) as recombinant flagella, expressed by orally delivered live S. Dublin vaccine strains expressing the target CS(280-288) peptide fused at the central hypervariable domain, and (ii) as purified protein in acellular vaccines in which flagellin was administered to mice either as a recombinant protein fused or admixed with the target CS(280-288) peptide. The results showed that CS(280-288)-specific cytotoxic CD8(+) T cells were primed when BALB/c mice were orally inoculated with the expressing the CS(280-288) epitope S. Dublin vaccine strain. In contrast, mice immunized with purified FliCd admixed with the CS(280-288) peptide and, to a lesser extent, fused with the target peptide developed specific cytotoxic CD8(+) T cell responses without the need of a heterologous booster immunization. The CD8(+) T cell adjuvant effects of flagellin, either fused or not with the target peptide, correlated with the in vivo activation of CD11c(+) dendritic cells. Taken together, the present results demonstrate that Salmonella flagellins are flexible adjuvant and induce adaptative immune responses when administered by different routes or vaccine formulations.

Igg Subclasses Targeting the Flagella of Salmonella Enterica Serovar Typhimurium Can Mediate Phagocytosis and Bacterial Killing

“…In addition, the efficient intracellular bacterial killing by phagocytic cells is critical to containment of the infection which could lead to a faster resolution of the disease. Other studies have also illustrated a role for flagella in T-cell immunity and its association with protection in mice [31,34,52,53].…”

“…The flagellum is a polymer of flagellin and hence acts as a multivalent antigen expressing multiple copies of the epitope. Flagella have been used as a carrier for foreign antigens and have shown efficient antibody induction to both the flagellin and foreign epitopes [34][35][36]. Being surface exposed, both the flagellin and the foreign epitopes are efficiently presented to the immune system.…”

“…Given the increasing interest in the use of flagella as an antigen target and as a carrier [34][35][36]38], we aimed to examine the potential efficacy of targeting the FliC protein with antibodies to enhance phagocyte functions known to be essential for protective immunity against Salmonella. We have previously shown that targeting the surface-abundant OmpA protein with human IgGs can increase the uptake and killing of bacteria by human phagocytic cells, the efficiency of these functions depending both on the subclass of the IgG and the FcR that is available for antibody binding [39].…”

Chimeric flagellin expressed by Salmonella typhimurium induces an ESAT-6-specific Th1-type immune response and CTL effects following intranasal immunization

“…Similarly, Braga et al also demonstrated that recombinant S. dublin flagella expressing the target CS (280-288) (the 9-mer (SYVPSAEQI) synthetic H2(d)-restricted CD8 1 T cell-specific epitope) peptide fused at the central hypervariable domain were able to prime cytotoxic CD8 1 T cells. 13 Therefore, flagellated Salmonella may also offer protection by inducing efficient CTL responses.…”

“…12 Salmonella flagellins are flexible adjuvants and induce adaptive immune responses when administered by different routes or in vaccine formulations. 13 Therefore, the aim of the present study was to assess whether efficient cellmediated immune responses and specific CTL effects could be stimulated by i.n. administration of flagellated Salmonella containing the ESAT-6 antigen coding sequences of MTB inserted in the highly variable region of Salmonella flagellin gene fliC i .…”