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Brucella spp. Lumazine Synthase Induces a TLR4-Mediated Protective Response against B16 Melanoma in Mice.

ABSTRACT: Brucella Lumazine Synthase (BLS) is a highly immunogenic decameric protein which can accept the fusion of foreign proteins at its ten N-termini. These chimeras are very efficient to elicit systemic and oral immunity without adjuvants. BLS signaling via Toll-Like Receptor 4 (TLR4) regulates innate and adaptive immune responses, inducing dendritic cell maturation and CD8(+) T-cell cytotoxicity. In this work we study the effect induced by BLS in TLR4-expressing B16 melanoma. In order to evaluate the effectiveness of BLS as a preventive vaccine, C57BL/6J mice were immunized with BLS or BLS-OVA, and 35 days later were subcutaneously inoculated with B16-OVA melanoma. BLS or BLS-OVA induced a significant inhibition of tumor growth, and 50% of mice immunized with the highest dose of BLS did not develop visible tumors. This effect was not observed in TLR4-deficient mice. For treatment experiments, mice were injected with BLS or BLS-OVA 2 days after the inoculation of B16 cells. Both treatments induced significant and equal tumor growth delay and increased survival. Moreover, BLS and BLS-OVA stimulation were also effective in TLR4-deficient mice. In order to study whether BLS has a direct effect on tumor cells, B16 cells were preincubated with BLS, and after 48h, cells were inoculated. Tumors induced by BLS-stimulated cells had inhibited growth and survival was increased. In the BLS group, 40% of mice did not develop tumors. This effect was abolished by the addition of TLR4/MD2 blocking antibody to cells before BLS stimulation. Our work demonstrates that BLS immunization induces a preventive antitumor response that depends on mice TLR4. We also show that BLS generates a therapeutic effect in mice inoculated with B16 cells. Our results show that BLS acts directly in cultured tumor cells via TLR4, highly suggesting that BLS elicits its therapeutic effects acting on the TLR4 from B16 melanoma cells.

SUBMITTER: Rossi AH

PROVIDER: S-EPMC4431812 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Brucella spp. Lumazine Synthase Induces a TLR4-Mediated Protective Response against B16 Melanoma in Mice.

Rossi Andrés H AH Farias Ana A Fernández Javier E JE Bonomi Hernán R HR Goldbaum Fernando A FA Berguer Paula M PM

PloS one 20150514 5

Brucella Lumazine Synthase (BLS) is a highly immunogenic decameric protein which can accept the fusion of foreign proteins at its ten N-termini. These chimeras are very efficient to elicit systemic and oral immunity without adjuvants. BLS signaling via Toll-Like Receptor 4 (TLR4) regulates innate and adaptive immune responses, inducing dendritic cell maturation and CD8(+) T-cell cytotoxicity. In this work we study the effect induced by BLS in TLR4-expressing B16 melanoma. In order to evaluate th ...[more]

PMID: 25973756

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Project description:Brucellosis is a zoonotic infectious disease caused by bacteria of the genus Brucella. Brucella melitensis, Brucella abortus, and Brucella suis are the most pathogenic species of this genus causing the majority of human and domestic animal brucellosis. There is a need to develop a safe and potent subunit vaccine to overcome the serious drawbacks of the live attenuated Brucella vaccines. The aim of this work was to discover antigen candidates conserved among the three pathogenic species. In this study, we employed a reverse vaccinology strategy to compute the core proteome of 90 completed genomes: 55 B. melitensis, 17 B. abortus, and 18 B. suis. The core proteome was analyzed by a metasubcellular localization prediction pipeline to identify surface-associated proteins. The identified proteins were thoroughly analyzed using various in silico tools to obtain the most potential protective antigens. The number of core proteins obtained from analyzing the 90 proteomes was 1939 proteins. The surface-associated proteins were 177. The number of potential antigens was 87; those with adhesion score ≥ 0.5 were considered antigen with "high potential," while those with a score of 0.4-0.5 were considered antigens with "intermediate potential." According to a cumulative score derived from protein antigenicity, density of MHC-I and MHC-II epitopes, MHC allele coverage, and B-cell epitope density scores, a final list of 34 potential antigens was obtained. Remarkably, most of the 34 proteins are associated with bacterial adhesion, invasion, evasion, and adaptation to the hostile intracellular environment of macrophages which is adjusted to deprive Brucella of required nutrients. Our results provide a manageable list of potential protective antigens for developing a potent vaccine against brucellosis. Moreover, our elaborated analysis can provide further insights into novel Brucella virulence factors. Our next step is to test some of these antigens using an appropriate antigen delivery system.

Dataset Information

Brucella spp. Lumazine Synthase Induces a TLR4-Mediated Protective Response against B16 Melanoma in Mice.

Publications

Brucella spp. Lumazine Synthase Induces a TLR4-Mediated Protective Response against B16 Melanoma in Mice.

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