Update on the role of innate immune receptors during Brucella abortus infection

Oliveira, Sérgio C.; Almeida, Leonardo Augusto de; Carvalho, Natália B.; Oliveira, Fernanda S.; Lacerda, Thaís Lourdes Santos

doi:10.1016/j.vetimm.2011.05.036

Cited by 22 publications

(18 citation statements)

References 87 publications

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“…Another report also documents selective suppression of ER stress signaling by LPS [26]. Brucella stimulates both TLR2 and TLR4 and the TLR adaptor MyD88 appears to be essential for controlling infection in vivo [27]. To further elucidate the role of TLR-MyD88 signaling in UPR induction by Brucella , XBP1 splicing and UPR target gene expression was examined in primary bone marrow derived macrophages from MyD88 deficient mice (Figure 4).…”

Section: Resultsmentioning

confidence: 98%

Brucella Induces an Unfolded Protein Response via TcpB That Supports Intracellular Replication in Macrophages

et al. 2013

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Brucella melitensis is a facultative intracellular bacterium that causes brucellosis, the most prevalent zoonosis worldwide. The Brucella intracellular replicative niche in macrophages and dendritic cells thwarts immune surveillance and complicates both therapy and vaccine development. Currently, host-pathogen interactions supporting Brucella replication are poorly understood. Brucella fuses with the endoplasmic reticulum (ER) to replicate, resulting in dramatic restructuring of the ER. This ER disruption raises the possibility that Brucella provokes an ER stress response called the Unfolded Protein Response (UPR). In this study, B. melitensis infection up regulated expression of the UPR target genes BiP, CHOP, and ERdj4, and induced XBP1 mRNA splicing in murine macrophages. These data implicate activation of all 3 major signaling pathways of the UPR. Consistent with previous reports, XBP1 mRNA splicing was largely MyD88-dependent. However, up regulation of CHOP, and ERdj4 was completely MyD88 independent. Heat killed Brucella stimulated significantly less BiP, CHOP, and ERdj4 expression, but induced XBP1 splicing. Although a Brucella VirB mutant showed relatively intact UPR induction, a TcpB mutant had significantly compromised BiP, CHOP and ERdj4 expression. Purified TcpB, a protein recently identified to modulate microtubules in a manner similar to paclitaxel, also induced UPR target gene expression and resulted in dramatic restructuring of the ER. In contrast, infection with the TcpB mutant resulted in much less ER structural disruption. Finally, tauroursodeoxycholic acid, a pharmacologic chaperone that ameliorates the UPR, significantly impaired Brucella replication in macrophages. Together, these results suggest Brucella induces a UPR, via TcpB and potentially other factors, that enables its intracellular replication. Thus, the UPR may provide a novel therapeutic target for the treatment of brucellosis. These results also have implications for other intracellular bacteria that rely on host physiologic stress responses for replication.

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Section: Resultsmentioning

confidence: 98%

Brucella Induces an Unfolded Protein Response via TcpB That Supports Intracellular Replication in Macrophages

et al. 2013

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“…Data regarding the recognition of brucellae through TLRs are ambiguous and both TLR2 and TLR4 have been reported to be involved depending on the bacterial species and strains as well as on the experimental conditions used [35]. In order to extend these results to S19, we employed a TLR overexpression system based on the human embryonal kidney cell line HEK293 that is usually unresponsive to bacterial stimuli [34], and analyzed TLR4/MD2, TLR2/TLR1, and TLR2/TLR6 heterodimers.…”

Section: Resultsmentioning

confidence: 99%

“…Whether non-leukocytes, e.g., endothelial cells that produce pro-inflammatory cytokines in response to the infection with B. abortus in vitro [58], contribute to the induction of specific immune responses in vivo needs to be determined. Other receptors possibly involved in S19-induced DC-activation comprise cytosolic receptors recognizing bacterial nucleic acids, e.g., those of the Rig-I like receptor (RLR) family, or other yet undefined DNA sensor receptors [35].…”

Section: Discussionmentioning

confidence: 99%

The Attenuated Brucella abortus Strain 19 Invades, Persists in, and Activates Human Dendritic Cells, and Induces the Secretion of IL-12p70 but Not IL-23

et al. 2013

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BackgroundBacterial vectors have been proposed as novel vaccine strategies to induce strong cellular immunity. Attenuated strains of Brucella abortus comprise promising vector candidates since they have the potential to induce strong CD4+ and CD8+ T-cell mediated immune responses in the absence of excessive inflammation as observed with other Gram-negative bacteria. However, some Brucella strains interfere with the maturation of dendritic cells (DCs), which is essential for antigen-specific T-cell priming. In the present study, we investigated the interaction of human monocyte-derived DCs with the smooth attenuated B. abortus strain (S) 19, which has previously been employed successfully to vaccinate cattle.Methodology/Principal findingsWe first looked into the potential of S19 to hamper the cytokine-induced maturation of DCs; however, infected cells expressed CD25, CD40, CD80, and CD86 to a comparable extent as uninfected, cytokine-matured DCs. Furthermore, S19 activated DCs in the absence of exogeneous stimuli, enhanced the expression of HLA-ABC and HLA-DR, and was able to persist intracellularly without causing cytotoxicity. Thus, DCs provide a cellular niche for persisting brucellae in vivo as a permanent source of antigen. S19-infected DCs produced IL-12/23p40, IL-12p70, and IL-10, but not IL-23. While heat-killed bacteria also activated DCs, soluble mediators were not involved in S19-induced activation of human DCs. HEK 293 transfectants revealed cellular activation by S19 primarily through engagement of Toll-like receptor (TLR)2.Conclusions/SignificanceThus, as an immunological prerequisite for vaccine efficacy, B. abortus S19 potently infects and potently activates (most likely via TLR2) human DCs to produce Th1-promoting cytokines.

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“…At this time, we cannot discern whether clearance of the Δ rpoE1 strain is mediated or enhanced by these antibodies, or if antibody production is simply a consequence of antigen release triggered by host clearance of Δ rpoE1 by innate or cell-mediated mechanisms known to control Brucella spp. infection in mice (43, 45-48). …”

Section: Discussionmentioning

confidence: 99%

Brucella abortus Δ rpoE1 confers protective immunity against wild type challenge in a mouse model of brucellosis

Willett

Herrou

Czyż

et al. 2016

Vaccine

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The Brucella abortus general stress response (GSR) system regulates activity of the alternative sigma factor, σE1, which controls transcription of approximately 100 genes and is required for persistence in a BALB/c mouse chronic infection model. We evaluated the host response to infection by a B. abortus strain lacking σE1 (ΔrpoE1), and identified pathological and immunological features that distinguish ΔrpoE1-infected mice from wild-type (WT), and that correspond with clearance of ΔrpoE1 from the host. ΔrpoE1 infection was indistinguishable from WT in terms of splenic bacterial burden, inflammation and histopathology up to 6 weeks post-infection. However, Brucella-specific serum IgG levels in ΔrpoE1-infected mice were 5 times higher than WT by 4 weeks post-infection, and remained significantly higher throughout the course of a 12-week infection. Total IgG and Brucella-specific IgG levels peaked strongly in ΔrpoE1-infected mice at 6 weeks, which correlated with reduced splenomegaly and bacterial burden relative to WT-infected mice. Given the difference in immune response to infection with wild-type and ΔrpoE1, we tested whether ΔrpoE1 confers protective immunity to wild-type challenge. Mice immunized with ΔrpoE1 completely resisted WT infection and had significantly higher serum titers of Brucella-specific IgG, IgG2a and IFN-γ after WT challenge relative to age-matched naïve mice. We conclude that immunization of BALB/c mice with the B. abortus GSR pathway mutant, ΔrpoE1, elicits an adaptive immune response that confers significant protective immunity against WT infection.

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Update on the role of innate immune receptors during Brucella abortus infection

Cited by 22 publications

References 87 publications

Brucella Induces an Unfolded Protein Response via TcpB That Supports Intracellular Replication in Macrophages

Brucella Induces an Unfolded Protein Response via TcpB That Supports Intracellular Replication in Macrophages

The Attenuated Brucella abortus Strain 19 Invades, Persists in, and Activates Human Dendritic Cells, and Induces the Secretion of IL-12p70 but Not IL-23

Brucella abortus Δ rpoE1 confers protective immunity against wild type challenge in a mouse model of brucellosis

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