Protective Efficacy and Safety of Brucella melitensis 16MΔ<i>mucR</i>against Intraperitoneal and Aerosol Challenge in BALB/c Mice

Arenas-Gamboa, Ángela M.; Rice‐Ficht, Allison C.; Kahl-McDonagh, Melissa; Ficht, Thomas A.

doi:10.1128/iai.05330-11

Cited by 31 publications

(25 citation statements)

References 37 publications

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“…Like the B. melitensis mucR mutant (23,24), the B. abortus mucR mutant exhibits striking attenuation in the mouse model of chronic infection (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

“…A MucR ortholog was recently identified in the Brucella spp., and this regulator is essential for the virulence of Brucella melitensis 16 M (23). Additionally, a B. melitensis mucR mutant shows promise as a potential candidate vaccine against Brucella infections (24). While it is clear that mucR is important for the pathogenesis of Brucella, the genes regulated by MucR in Brucella remain undefined.…”

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confidence: 99%

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Diverse Genetic Regulon of the Virulence-Associated Transcriptional Regulator MucR in Brucella abortus 2308

et al. 2013

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The Ros-type regulator MucR is one of the few transcriptional regulators that have been linked to virulence in Brucella. Here, we show that a Brucella abortus in-frame mucR deletion strain exhibits a pronounced growth defect during in vitro cultivation and, more importantly, that the mucR mutant is attenuated in cultured macrophages and in mice. The genetic basis for the attenuation of Brucella mucR mutants has not been defined previously, but in the present study the genes regulated by MucR in B. abortus have been elucidated using microarray analysis and real-time reverse transcription-PCR (RT-PCR). In B. abortus 2308, MucR regulates a wide variety of genes whose products may function in establishing and maintaining cell envelope integrity, polysaccharide biosynthesis, iron homeostasis, genome plasticity, and transcriptional regulation. Particularly notable among the MucRregulated genes identified is arsR6 (nolR), which encodes a transcriptional regulator previously linked to virulence in Brucella melitensis 16 M. Importantly, electrophoretic mobility shift assays (EMSAs) determined that a recombinant MucR protein binds directly to the promoter regions of several genes repressed by MucR (including arsR6 [nolR]), and in Brucella, as in other alphaproteobacteria, MucR binds to its own promoter to repress expression of the gene that encodes it. Overall, these studies have uncovered the diverse genetic regulon of MucR in Brucella, and in doing so this work has begun to define the MucR-controlled genetic circuitry whose misregulation contributes to the virulence defect of Brucella mucR mutants.

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“…Like the B. melitensis mucR mutant (23,24), the B. abortus mucR mutant exhibits striking attenuation in the mouse model of chronic infection (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Diverse Genetic Regulon of the Virulence-Associated Transcriptional Regulator MucR in Brucella abortus 2308

et al. 2013

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“…One approach to this task is encapsulation of the attenuated vaccine strain to release the organism over time and to provide the added advantage of providing a natural booster response. 68,98 This approach uses a vaccine depot from which the attenuated Brucella is gradually released over a 30-day period and significantly enhances immune protection by using highly attenuated LAVs to improve both efficacy and safety. 99 In addition, recent cell biology findings have revealed the dependence of Brucella infection on the UPR, specifically IRE1a.…”

Section: Pathogenesis-informed Approaches To Vaccinesmentioning

confidence: 99%

Pathogenesis and Immunobiology of Brucellosis

Figueiredo

Ficht

Rice‐Ficht

et al. 2015

The American Journal of Pathology

378

270

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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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“…One clear cause seems be the empirical nature of research on the Brucella vaccine. Indeed, the vast majority of publications reports only the protective ability of candidate vaccines, limiting their analysis to present CFU counts in the spleen after challenge (14,15). Evaluations of the ability of vaccines to induce IFN-g-producing cells, detected in vitro after restimulation, and/or a humoral response are also often reported (16)(17)(18).…”

mentioning

confidence: 99%

Humoral Immunity and CD4+ Th1 Cells Are Both Necessary for a Fully Protective Immune Response upon Secondary Infection with Brucella melitensis

Vitry

Mambres

Trez

et al. 2014

The Journal of Immunology

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Brucella spp are intracellular bacteria that cause brucellosis, one of the most common zoonoses in the world. Given the serious medical consequences of this disease, a safe and effective human vaccine is urgently needed. Efforts to develop this vaccine have been hampered by our lack of understanding of what constitutes a protective memory response against Brucella. In this study, we characterize the cells and signaling pathways implicated in the generation of a protective immune memory response following priming by the injection of heat-killed or live Brucella melitensis 16M. Using a panel of gene-deficient mice, we demonstrated that during a secondary recall response, both the Brucella-specific humoral response and CD4+ Th1 cells must act together to confer protective immunity in the spleen to B. melitensis infection. Humoral protective immunity is induced by the inoculation of both heat-killed and live bacteria, and its development does not require T cells, MyD88/IL-12p35 signaling pathways, or an activation-induced deaminase–mediated isotype switch. In striking contrast, the presence of memory IFN-γ–producing CD4+ Th1 cells requires the administration of live bacteria and functional MyD88/IL-12p35 pathways. In summary, our work identifies several immune markers closely associated with protective immune memory and could help to define a rational strategy to obtain an effective human vaccine against brucellosis.

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Protective Efficacy and Safety of Brucella melitensis 16MΔmucRagainst Intraperitoneal and Aerosol Challenge in BALB/c Mice

Cited by 31 publications

References 37 publications

Diverse Genetic Regulon of the Virulence-Associated Transcriptional Regulator MucR in Brucella abortus 2308

Diverse Genetic Regulon of the Virulence-Associated Transcriptional Regulator MucR in Brucella abortus 2308

Pathogenesis and Immunobiology of Brucellosis

Humoral Immunity and CD4+ Th1 Cells Are Both Necessary for a Fully Protective Immune Response upon Secondary Infection with Brucella melitensis

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