Transcriptome analysis of HeLa cells response to Brucella melitensis infection: a molecular approach to understand the role of the mucosal epithelium in the onset of the Brucella pathogenesis

Rossetti, C; Drake, Kenneth L.; Adams, L. Garry

doi:10.1016/j.micinf.2012.03.003

Cited by 15 publications

(20 citation statements)

References 33 publications

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“…Thus, after attachment to the surface of mucosal epithelial cells, Brucella induces a zipper-like mechanism for internalization. 8 As yet incompletely defined binding molecule(s) are activated before and/or on contact with epithelial cells, Brucella bind to epithelial cell surface receptors that contain sialic acid and sulfated residues. 9 Binding promotes activation of small GTPases that trigger a signaling cascade that reorganizes the actin cytoskeleton to induce a host cell membrane rearrangement along the surface of the pathogen that enhances invasion.…”

Section: Biology Of Brucellamentioning

confidence: 99%

“…Entry occurs within a few minutes after interaction which requires full activation of a mitogen-activated protein kinase signaling pathway. 8 Brucella survive and replicate inside nonprofessional phagocytic cells up to 72 hours in vitro and move across the epithelium in vivo by subverting the mucosal epithelial barrier function to facilitate Brucella transepithelial migration. 6 Simultaneously, this interaction initiates a minimal innate immune response with weak proinflammatory activity.…”

Section: Biology Of Brucellamentioning

confidence: 99%

“…6 Simultaneously, this interaction initiates a minimal innate immune response with weak proinflammatory activity. 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%

See 2 more Smart Citations

Pathogenesis and Immunobiology of Brucellosis

Figueiredo

Ficht

Rice‐Ficht

et al. 2015

The American Journal of Pathology

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365

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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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Section: Biology Of Brucellamentioning

confidence: 99%

Section: Biology Of Brucellamentioning

confidence: 99%

Section: Biology Of Brucellamentioning

confidence: 99%

See 1 more Smart Citation

Pathogenesis and Immunobiology of Brucellosis

Figueiredo

Ficht

Rice‐Ficht

et al. 2015

The American Journal of Pathology

Self Cite

365

270

View full text Add to dashboard Cite

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“…The biological roles of these four genes are shown in Supplemental Table 26 (Table S26 in File S1 ) . Coincidently, Lectin and CCC pathways were found to be up-regulated in Brucella - infected HeLa cells at 4 h post-infection, and MASP2 gene was indicated as a key mechanistic gene in both pathways [26]. Though the Lectin pathway is significantly activated in the early stages, however, the combined CCC pathway is observed to have temporal cyclic response (activation and repression) during the first 4 h p.i.…”

Section: Resultsmentioning

confidence: 89%

Systems Biology Analysis of Brucella Infected Peyer's Patch Reveals Rapid Invasion with Modest Transient Perturbations of the Host Transcriptome

et al. 2013

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Brucella melitensis causes the most severe and acute symptoms of all Brucella species in human beings and infects hosts primarily through the oral route. The epithelium covering domed villi of jejunal-ileal Peyer's patches is an important site of entry for several pathogens, including Brucella. Here, we use the calf ligated ileal loop model to study temporal in vivo Brucella-infected host molecular and morphological responses. Our results document Brucella bacteremia occurring within 30 min after intraluminal inoculation of the ileum without histopathologic traces of lesions. Based on a system biology Dynamic Bayesian Network modeling approach (DBN) of microarray data, a very early transient perturbation of the host enteric transcriptome was associated with the initial host response to Brucella contact that is rapidly averted allowing invasion and dissemination. A detailed analysis revealed active expression of Syndecan 2, Integrin alpha L and Integrin beta 2 genes, which may favor initial Brucella adhesion. Also, two intestinal barrier-related pathways (Tight Junction and Trefoil Factors Initiated Mucosal Healing) were significantly repressed in the early stage of infection, suggesting subversion of mucosal epithelial barrier function to facilitate Brucella transepithelial migration. Simultaneously, the strong activation of the innate immune response pathways would suggest that the host mounts an appropriate protective immune response; however, the expression of the two key genes that encode innate immunity anti-Brucella cytokines such as TNF-α and IL12p40 were not significantly changed throughout the study. Furthermore, the defective expression of Toll-Like Receptor Signaling pathways may partially explain the lack of proinflammatory cytokine production and consequently the absence of morphologically detectable inflammation at the site of infection. Cumulatively, our results indicate that the in vivo pathogenesis of the early infectious process of Brucella is primarily accomplished by compromising the mucosal immune barrier and subverting critical immune response mechanisms.

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“…This information has largely been obtained from in vitro infection experiments. Primary cells taken from naïve human volunteers [8][9][10][11][12][13][14][15] or continuous cell lines [16][17][18][19][20][21][22] have been infected and incubated with a pathogen for different time periods (ranging from 1 to 48 hours) and host gene signatures generated ( Table 1). Microarray studies performed in this way provide insights into the cellular response following infection with, for instance, Monkeypox virus.…”

Section: Dna Microarraysmentioning

confidence: 99%

The Impact of “Omic” and Imaging Technologies on Assessing the Host Immune Response to Biodefence Agents

Tree

Flick-Smith

Elmore

et al. 2014

Journal of Immunology Research

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Understanding the interactions between host and pathogen is important for the development and assessment of medical countermeasures to infectious agents, including potential biodefence pathogens such as Bacillus anthracis, Ebola virus, and Francisella tularensis. This review focuses on technological advances which allow this interaction to be studied in much greater detail. Namely, the use of “omic” technologies (next generation sequencing, DNA, and protein microarrays) for dissecting the underlying host response to infection at the molecular level; optical imaging techniques (flow cytometry and fluorescence microscopy) for assessing cellular responses to infection; and biophotonic imaging for visualising the infectious disease process. All of these technologies hold great promise for important breakthroughs in the rational development of vaccines and therapeutics for biodefence agents.

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Transcriptome analysis of HeLa cells response to Brucella melitensis infection: a molecular approach to understand the role of the mucosal epithelium in the onset of the Brucella pathogenesis

Cited by 15 publications

References 33 publications

Pathogenesis and Immunobiology of Brucellosis

Pathogenesis and Immunobiology of Brucellosis

Systems Biology Analysis of Brucella Infected Peyer's Patch Reveals Rapid Invasion with Modest Transient Perturbations of the Host Transcriptome

The Impact of “Omic” and Imaging Technologies on Assessing the Host Immune Response to Biodefence Agents

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