The role of innate immune receptors in the control of Brucella abortus infection: Toll-like receptors and beyond

Oliveira, Sérgio C.; Oliveira, Fernanda S.; Macedo, Gilson Costa; Almeida, Leonardo Augusto de; Carvalho, Natália B.

doi:10.1016/j.micinf.2008.07.005

Cited by 71 publications

(56 citation statements)

References 39 publications

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“…The involvement of the other intracellular TLRs (TLR7 and TLR9) in the IFN-b response to infection was reported with other intracellular bacteria, including Listeria monocytogenes (28), Brucella abortus (29,30), and phagocytosed Group B streptococci (31). Bm1.11 OE cells do not express mRNA for TLRs 7,8,or 9 (12).…”

Section: Chlamydia-induced Ifn-b Synthesis Does Not Require Tlr9 In Omentioning

confidence: 80%

The Chlamydia muridarum-Induced IFN-β Response Is TLR3-Dependent in Murine Oviduct Epithelial Cells

Derbigny¹,

Johnson²,

Toomey³

et al. 2010

The Journal of Immunology

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Epithelial cells lining the murine genital tract act as sentinels for microbial infection, play a major role in the initiation of the early inflammatory response, and can secrete factors that modulate the adaptive immune response when infected with Chlamydia. C. muridarum-infected murine oviduct epithelial cells secrete the inflammatory cytokines IL-6 and GM-CSF in a TLR2-dependent manner. Further, C. muridarum infection induces IFN-β synthesis in the oviduct epithelial cells in a TRIF-dependent manner. Because murine oviduct epithelial cells express TLR3 but not TLRs 4, 7, 8, or 9, we hypothesized that TLR3 or an unknown TRIF-dependent pattern recognition receptor was the critical receptor for IFN-β production. To investigate the role of TLR3 in the Chlamydia-induced IFN-β response in oviduct epithelial cells, we used small interfering RNA, dominant-negative TLR3 mutants, and TLR3-deficient oviduct epithelial cells to show that the IFN-β secreted during C. muridarum infection requires a functional TLR3. Interestingly, we demonstrate that the TLR3 signaling pathway is not required for IFN-β synthesis in C. muridarum-infected macrophages, suggesting that there are alternate and redundant pathways to Chlamydia-induced IFN-β synthesis that seem to be dependent upon the cell type infected. Finally, because there is no obvious dsRNA molecule associated with Chlamydia infection, the requirement for TLR3 in Chlamydia-induced IFN-β synthesis in infected oviduct epithelial cells implicates a novel ligand that binds to and signals through TLR3.

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Section: Chlamydia-induced Ifn-b Synthesis Does Not Require Tlr9 In Omentioning

confidence: 80%

The Chlamydia muridarum-Induced IFN-β Response Is TLR3-Dependent in Murine Oviduct Epithelial Cells

Derbigny¹,

Johnson²,

Toomey³

et al. 2010

The Journal of Immunology

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“…Pathogen recognition is triggered by pattern recognition receptors, including TLRs (44), NLRs (45), and RIG-I-like receptors (46), and is followed by proinflammatory responses characteristic of infection. Recent studies by our group (25,47) and other investigators (28) revealed the intracellular signaling cascades involved in the TLR-initiated immune response to Brucella spp. infection.…”

Section: Discussionmentioning

confidence: 97%

“…In humans, B. abortus causes undulant fever, endocarditis, arthritis, and osteomyelitis; in animals, it leads to abortion and infertility, resulting in serious economic losses (23,24). The innate immune response against B. abortus infection begins with the recognition of molecular structures related to this pathogen by receptors, such as TLRs (25). It was shown that Brucella is recognized by several TLR-associated pathways, triggering proinflammatory responses that impact both the nature and the intensity of the immune response (26)(27)(28).…”

mentioning

confidence: 99%

Critical Role of ASC Inflammasomes and Bacterial Type IV Secretion System in Caspase-1 Activation and Host Innate Resistance to Brucella abortus Infection

Gomes

Campos

Oliveira

et al. 2013

The Journal of Immunology

107

133

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Pathogens are detected by innate immune receptors that, upon activation, orchestrate an appropriate immune response. Recent studies revealed the intracellular signaling cascades involved in the TLR-initiated immune response to Brucella abortus infection. However, no report has elucidated the role of inflammasome receptors in Brucella recognition. Therefore, we decided to investigate the function of NLRC4, NLRP3, and AIM2 in sensing Brucella. In this study, we showed that NLRC4 is not required to induce caspase-1 activation and further secretion of IL-1β by B. abortus in macrophages. In contrast, we determined that AIM2, which senses Brucella DNA, and NLRP3 are partially required for caspase-1 activation and IL-1β secretion. Additionally, mitochondrial reactive oxygen species induced by Brucella were implicated in IL-1β production. Furthermore, AIM2, NLRP3, ASC, and caspase-1 knockout mice were more susceptible to B. abortus infection than were wild-type animals, suggesting that multiple ASC-dependent inflammasomes contribute to host protection against infection. This protective effect is due to the inflammatory response caused by IL-1β and IL-18 rather than pyroptosis, because we observed augmented bacterial burden in IL-1R and IL-18 knockout mice. Finally, we determined that bacterial type IV secretion system VirB and live, but not heat-killed, Brucella are required for full inflammasome activation in macrophages during infection. Taken together, our results indicate that Brucella is sensed by ASC inflammasomes that collectively orchestrate a robust caspase-1 activation and proinflammatory response.

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“…8,10 Once translocated through the epithelium, Brucella are engulfed by mucosal phagocytic cells in which <10% of phagocytized bacteria survive an adaptation period. To delay being recognized by the immune system and initiating an immune response, Brucella reduce, modify, or cloak their pathogen-associated molecular patterns 10 ; however, some Toll-like receptors (TLRs; mainly TLR2, TLR4, and TLR9) initiate limited intracellular signaling that activates the transcription factor NF-kB to control expression of inflammatory cytokine genes, 11 although at a level that is 10-fold less than enterobacteria.…”

Section: Biology Of Brucellamentioning

confidence: 99%

Pathogenesis and Immunobiology of Brucellosis

Figueiredo

Ficht

Rice‐Ficht

et al. 2015

The American Journal of Pathology

341

251

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This review of Brucellaehost interactions and immunobiology discusses recent discoveries as the basis for pathogenesis-informed rationales to prevent or treat brucellosis. Brucella spp., as animal pathogens, cause human brucellosis, a zoonosis that results in worldwide economic losses, human morbidity, and poverty. Although Brucella spp. infect humans as an incidental host, 500,000 new human infections occur annually, and no patient-friendly treatments or approved human vaccines are reported. Brucellae display strong tissue tropism for lymphoreticular and reproductive systems with an intracellular lifestyle that limits exposure to innate and adaptive immune responses, sequesters the organism from the effects of antibiotics, and drives clinical disease manifestations and pathology. Stealthy brucellae exploit strategies to establish infection, including i) evasion of intracellular destruction by restricting fusion of type IV secretion systemdependent Brucella-containing vacuoles with lysosomal compartments, ii) inhibition of apoptosis of infected mononuclear cells, and iii) prevention of dendritic cell maturation, antigen presentation, and activation of naive T cells, pathogenesis lessons that may be informative for other intracellular pathogens. Data sets of next-generation sequences of Brucella and host time-series global expression fused with proteomics and metabolomics data from in vitro and in vivo experiments now inform interactive cellular pathways and gene regulatory networks enabling full-scale systems biology analysis. The newly identified effector proteins of Brucella may represent targets for improved, safer brucellosis vaccines and therapeutics. It is noteworthy that long ago in his publication Epidemics, Hippocrates described brucellosis-type syndromes in humans living in the Mediterranean littoral. Many centuries later, British physician, David Bruce, and Greek physician, Themistokles Zammit, in 1886 would discover the causative agent, Micrococcus melitensis, of brucellosis and would identify milk products of goats as the source of infection for military troops on the island of Malta. Even after more than a century of extensive research, Brucella spp. are still serious animal pathogens that cause brucellosis, a zoonosis that results in substantial economic losses, human morbidity, and perpetuates poverty worldwide.1 These Gram-negative bacteria infect a diverse array of land and aquatic mammals,

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The role of innate immune receptors in the control of Brucella abortus infection: Toll-like receptors and beyond

Cited by 71 publications

References 39 publications

The Chlamydia muridarum-Induced IFN-β Response Is TLR3-Dependent in Murine Oviduct Epithelial Cells

The Chlamydia muridarum-Induced IFN-β Response Is TLR3-Dependent in Murine Oviduct Epithelial Cells

Critical Role of ASC Inflammasomes and Bacterial Type IV Secretion System in Caspase-1 Activation and Host Innate Resistance to Brucella abortus Infection

Pathogenesis and Immunobiology of Brucellosis

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