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Superior protective immunity against murine listeriosis by combined vaccination with CpG DNA and recombinant Salmonella enterica serovar typhimurium.

ABSTRACT: Preexisting antivector immunity can severely compromise the ability of Salmonella enterica serovar Typhimurium live vaccines to induce protective CD8 T-cell frequencies after type III secretion system-mediated heterologous protein translocation in orally immunized mice. To circumvent this problem, we injected CpG DNA admixed to the immunodominant p60(217-225) peptide from Listeria monocytogenes subcutaneously into BALB/c mice and coadministered a p60-translocating Salmonella strain by the orogastric route. The distribution of tetramer-positive p60(217-225)-specific effector and memory CD8 T cells was analyzed by costaining of lymphocytes with CD62L and CD127. In contrast to the single oral application of recombinant Salmonella or single immunization with CpG and p60, in the spleens from mice immunized with a combination of both vaccine types a significantly higher level of p60-specific CD8 T cells with a predominance of the effector memory T-cell subset was detected. In vivo protection studies revealed that this CD8 T-cell population conferred sterile protective immunity against a lethal infection with L. monocytogenes. However, p60-specific central memory CD8 T cells induced by single vaccination with CpG and p60 were not able confer effective protection against rapidly replicating intracellular Listeria. In conclusion, we provide compelling evidence that the combination of Salmonella type III-mediated antigen delivery and CpG immunization is an attractive novel vaccination strategy to modulate CD8 differentiation patterns toward distinct antigen-specific T-cell subsets with favorable protective capacities.

SUBMITTER: Berchtold C

PROVIDER: S-EPMC2786444 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Superior protective immunity against murine listeriosis by combined vaccination with CpG DNA and recombinant Salmonella enterica serovar typhimurium.

Berchtold Christina C Panthel Klaus K Jellbauer Stefan S Köhn Brigitte B Roider Elisabeth E Partilla Miriam M Heesemann Jürgen J Endres Stefan S Bourquin Carole C Rüssmann Holger H

Infection and immunity 20090921 12

Preexisting antivector immunity can severely compromise the ability of Salmonella enterica serovar Typhimurium live vaccines to induce protective CD8 T-cell frequencies after type III secretion system-mediated heterologous protein translocation in orally immunized mice. To circumvent this problem, we injected CpG DNA admixed to the immunodominant p60(217-225) peptide from Listeria monocytogenes subcutaneously into BALB/c mice and coadministered a p60-translocating Salmonella strain by the orogas ...[more]

PMID: 19797070

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Project description:Salmonella enterica serovar Typhimurium genome encodes 13 fimbrial operons. Most of the fimbriae encoded by these operons are not produced under laboratory conditions but are likely to be synthesized in vivo We used an in vivo expression technology (IVET) strategy to identify four fimbrial operons, agf, saf, sti, and stc that are expressed in the spleen. When any three of these operons were deleted, the strain retained wild-type virulence. However, when all four operons were deleted, the resulting strain was completely attenuated, indicating that these four fimbriae play functionally redundant roles critical for virulence. In mice, oral doses of as low as 1 × 105 CFU of the strain with four fimbrial operons deleted provided 100% protection against challenge with 1 × 109 CFU of wild-type S Typhimurium. We also examined the possible effect of these fimbriae on the ability of a Salmonella vaccine strain to deliver a guest antigen. We modified one of our established attenuated vaccine strains, χ9088, to delete three fimbrial operons while the fourth operon was constitutively expressed. Each derivative was modified to express the Streptococcus pneumoniae antigen PspA. Strains that constitutively expressed saf or stc elicited a strong Th1 response with significantly greater levels of anti-PspA serum IgG and greater protective efficacy than strains carrying saf or stc deletions. The isogenic strain in which all four operons were deleted generated the lowest anti-PspA levels and did not protect against challenge with virulent S. pneumoniae Our results indicate that these fimbriae play important roles, as yet not understood, in Salmonella virulence and immunogenicity.IMPORTANCESalmonella enterica is the leading cause of bacterial food-borne infection in the United States. S. Typhimurium is capable of producing up to 13 distinct surface structures called fimbriae that presumably mediate its adherence to surfaces. The roles of most of these fimbriae in disease are unknown. Identifying fimbriae produced during infection will provide important insights into how these bacterial structures contribute to disease and potentially induce protective immunity to Salmonella infection. We identified four fimbriae that are produced during infection. Deletion of all four of these fimbriae results in a significant reduction in virulence. We explored ways in which the expression of these fimbriae may be exploited for use in recombinant Salmonella vaccine strains and found that production of Saf and Stc fimbriae are important for generating a strong immune response against a vectored antigen. This work provides new insight into the role of fimbriae in disease and their potential for improving the efficacy of Salmonella-based vaccines.

Project description:Glycyrrhizin (GL), a triterpenoid glycoside, serves important functions in various biological activities, including antiviral and antitumor immune responses. However, the anti-inflammatory effects of GL on Salmonella enterica serovar Typhimurium (ST)-induced injury in mice and the mechanisms underlying the protection of GL are poorly understood. Here, we investigated the effects of GL on host immune responses against ST infection in mice. A phenotypic analysis using hematoxylin and eosin (H&E) staining and transmission electron microscopy showed that GL relieved ST-induced weight loss and intestinal mucosal injury. A colonization assay showed that GL significantly reduced ST colonization in the ileum and colon and translocation to the liver and spleen. An antibacterial activity assay and real-time PCR revealed that GL had no direct inhibitory impact on ST growth or virulence gene expression. ELISA showed that GL pretreatment significantly decreased proinflammatory cytokine (IFN-?, TNF-?, IL-6) secretion and increased anti-inflammatory cytokine (IL-10) secretion in the ileum, colon and serum of ST-infected mice. Moreover, flora analysis showed that GL reduced Akkermansia, Sutterella, Prevotella and Coprococcus but enriched Parabacteroides and Anaerotruncus in the cecum of ST-infected mice. These results suggest that GL promotes the secretion of immune factors and modulates intestinal flora to prevent further ST infection. We also analyzed the effect of GL on immunocytes and found that GL promoted the phenotypic and functional maturation of murine bone marrow-derived dendritic cells (BMDCs). Flow cytometry and western blotting demonstrated that NF-?B, ERK, and p38 MAPK were required for GL-induced BMDC maturation. The above findings indicate that GL attenuates ST infection by modulating immune function and intestinal flora. This study enriches our current knowledge of GL-mediated immunological function and provides a new perspective on the prevention of Salmonella infection in animals and humans.

Dataset Information

Superior protective immunity against murine listeriosis by combined vaccination with CpG DNA and recombinant Salmonella enterica serovar typhimurium.

Publications

Superior protective immunity against murine listeriosis by combined vaccination with CpG DNA and recombinant Salmonella enterica serovar typhimurium.

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