The Protein Moiety of <i>Brucella abortus</i> Outer Membrane Protein 16 Is a New Bacterial Pathogen-Associated Molecular Pattern That Activates Dendritic Cells In Vivo, Induces a Th1 Immune Response, and Is a Promising Self-Adjuvanting Vaccine against Systemic and Oral Acquired Brucellosis

Pasquevich, Karina A.; Samartino, Clara García; Coria, Lorena M.; Estein, Silvia Marcela; Zwerdling, Astrid; Ibáñez, Andrés; Barrionuevo, Paula; Oliveira, Fernanda S.; Carvalho, Natália B.; Borkowski, Julia; Oliveira, Sérgio C.; Warzecha, Heribert; Giambartolomei, Guillermo H.; Cassataro, Juliana

doi:10.4049/jimmunol.0902209

Cited by 72 publications

(63 citation statements)

References 74 publications

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“…90 Of note, a recent study using unlipidated outer membrane protein 16 of B. abortus indicated that the production of pro-inflammatory cytokines induced by this unlipidated protein is TLR4-dependent. 80 In our study, high levels of antigen-specific Th1-type cytokines such as IFN-c and IL-2 and high levels of protection against B. abortus infection were observed in wild-type mice vaccinated with the rBCSP31 vaccine compared with these parameters in TLR2 2/2 and TLR4 2/2 mice. Furthermore, macrophages from immunized wild-type mice produced significantly higher levels of IL-12 than those from TLR2 2/2 and TLR4 2/2 mice.…”

Section: Discussionmentioning

confidence: 71%

“…79 Unlipidated outer membrane protein 16 of B. abortus has been reported to induce TLR4-dependent production of proinflammatory cytokines and confer 1.15 log units of protection against B. abortus 2308 infection in C57BL/6 mice. 80 Similarly, unlipidated outer membrane protein 19 of B. abortus induces a Th17 immune response and confers 1.12 log units of protection against B. abortus 2308 infection in C57BL/6 mice that is independent of TLR4. 81 Our result indicates that rBCSP31 vaccination provides a similar level of protection (1.10 log units of protection) against B. abortus to these single antigens expressed in E. coli.…”

Section: Discussionmentioning

confidence: 99%

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TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro

Yuan

Gao

et al. 2014

Cell Mol Immunol

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Brucella abortus is a zoonotic Gram-negative pathogen that causes brucelosis in ruminants and humans. Toll-like receptors (TLRs) recognize Brucella abortus and initiate antigen-presenting cell activities that affect both innate and adaptive immunity. In this study, we focused on recombinant Brucella cell-surface protein 31 (rBCSP31) to determine its effects on mouse macrophages. Our results demonstrated that rBCSP31 induced TNF-a, IL-6 and IL-12p40 production, which depended on the activation of mitogen-activated protein kinases (MAPKs) by stimulating the rapid phosphorylation of p38 and JNK and the activation of transcription factor NF-kB in macrophages. In addition, continuous exposure (.24 h) of RAW264.7 cells to rBCSP31 significantly enhanced IFN-c-induced expression of MHC-II and the ability to present rBCSP31 peptide to CD4 1 T cells. Furthermore, we found that rBCSP31 could interact with both TLR2 and TLR4. The rBCSP31-induced cytokine production by macrophages from TLR2 2/2 and TLR4 2/2 mice was lower than that from C57BL/6 macrophages, and the activation of NF-kB and MAPKs was attenuated in macrophages from TLR2 2/2 and TLR4 2/2 mice. In addition, CD4 1 T cells from C57BL/6 mice immunized with rBCSP31 produced higher levels of IFN-c and IL-2 compared with CD4 1 T cells from TLR2 2/2 and TLR4 2/2 mice. Macrophages from immunized C57BL/6 mice produced higher levels of IL-12p40 than those from TLR2 2/2 and TLR4 2/2 mice. Furthermore, immunization with rBCSP31 provided better protection in C57BL/6 mice than in TLR2 2/2 and TLR4 2/2 mice after B. abortus 2308 challenge. These results indicate that rBCSP31 is a TLR2 and TLR4 agonist that induces cytokine production, upregulates macrophage function and induces the Th1 immune response.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro

Yuan

Gao

et al. 2014

Cell Mol Immunol

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“…Some reports demonstrated that the TLR4 mutant mice (C3H/HeJ) had enhanced susceptibility to virulent B. abortus compared to the control (24,42), while other authors observed the independence of TLR4 in host resistance against infection with B. abortus S19 and S2308 (43,44). Furthermore, a TLR4-dependent production of proinflammatory cytokines elicited by the outer membrane protein 16 (OMP16) of B. abortus has been verified recently (45). In our study, we examined the effect of TLR4 blocking on B. abortus uptake and the involvement of the intracellular replication of bacteria in cultured murine macrophages.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4-Linked Janus Kinase 2 Signaling Contributes to Internalization of Brucella abortus by Macrophages

Lee

Kim

et al. 2013

Infect Immun

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e Brucella abortus is an intracellular pathogen that uses a crafty strategy to invade and proliferate within host cells, but the distinct signaling pathways associated with phagocytic mechanisms of B. abortus remain unclear. The present study was performed to test the hypothesis that Toll-like receptor 4 (TLR4)-linked signaling interacting with Janus kinase 2 (JAK2) plays an essential role in B. abortus phagocytosis by macrophages. The effects of TLR4-JAK2 signaling on B. abortus phagocytosis in murine macrophage RAW 264.7 cells were observed through an infection assay and confocal microscopy. We determined that the uptake of B. abortus was negatively affected by the dysfunction of TLR4 and JAK2. F-actin polymerization detected by flow cytometry and F-actin assay was amplified for B. abortus entry, whereas that event was attenuated by the disruption of TLR4 and JAK2. Importantly, JAK2 phosphorylation and actin skeleton reorganization were suppressed immediately after B. abortus infection in bone marrow-derived macrophages (BMDMs) from TLR4 ؊/؊ mice, showing the cooperation of JAK2 with TLR4. Furthermore, small GTPase Cdc42 participated in the intermediate pathway of TLR4-JAK2 signaling on B. abortus phagocytosis. Consequently, TLR4-associated JAK2 activation in the early cellular signaling events plays a pivotal role in B. abortus-induced phagocytic processes in macrophages, implying the pathogenic significance of JAK2-mediated entry. Here, we elucidate that this specific phagocytic mechanism of B. abortus might provide achievable strategies for inhibiting B. abortus invasion.

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“…LPS, ribosomal L7/L12 protein, P39, 31 kDa outer membrane protein (Omp31) and Outer membrane vesicles (OMVs), as mentioned below], which are extracted from Brucella and tested as vaccine candidates on the animal models. Some of mentioned antigens tend to poorly stimulate immune system and require to coadministration with an adjuvant (43).…”

Section: Subunit Vaccines Against Brucellosismentioning

confidence: 99%

Vaccines and Vaccine Candidates against Brucellosis

Mansoori¹,

Pourmand²

2016

IEM

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Brucella is a facultative intracellular pathogen, and brucellosis is commonest zoonotic disease worldwide. Brucella species, isolated from domestic animals, are important pathogen for humans. Annually, more than 500,000 new cases of brucellosis are reported, and this figure is an underestimate due to extended under-reporting cases in several endemic countries. Brucella has a variety of virulence mechanisms that prevent detection and activation of innate immunity, but protection against intracellular pathogen is represented by cell-mediated immunity. As yet, much research has been performed to develop a safe Brucella vaccine to control the disease in human and animals. Despite the availability of several live attenuated vaccine for animals, currently, no effective human vaccine is available. Moreover, due to the potential use of Brucella in bioterrorism or biowarfare, development of an effective vaccine against brucellosis for human use is necessary. In this paper, we aimed to review and discuss the efforts of researchers to develop vaccines against Brucellosis.

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The Protein Moiety of Brucella abortus Outer Membrane Protein 16 Is a New Bacterial Pathogen-Associated Molecular Pattern That Activates Dendritic Cells In Vivo, Induces a Th1 Immune Response, and Is a Promising Self-Adjuvanting Vaccine against Systemic and Oral Acquired Brucellosis

Abstract: Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/03/26/jimmunol.090220

Cited by 72 publications

References 74 publications

TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro

TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro

Toll-Like Receptor 4-Linked Janus Kinase 2 Signaling Contributes to Internalization of Brucella abortus by Macrophages

Vaccines and Vaccine Candidates against Brucellosis

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