Sequential <i>Burkholderia cenocepacia</i> Isolates from Siblings with Cystic Fibrosis Show Increased Lung Cell Attachment

Cullen, Louise; O’Connor, Andrew; Dřevı́nek, Pavel; Schaffer, Kirsten; McClean, Siobhán

doi:10.1164/rccm.201607-1360le

Cited by 9 publications

(14 citation statements)

References 11 publications

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“…We previously demonstrated an increase in host cell attachment in both series of isolates from the two patients, which was independent of the location of infection 23 . Our primary aim was to identify global changes in bacterial protein abundance over time of colonization that may contribute to this increased host cell attachment.…”

Section: Resultsmentioning

confidence: 66%

“…These isolates had also previously shown increased attachment to lung epithelial cells over time of colonisation, despite the later isolate being a blood isolate 23 . Consistent with this, many time-dependent alterations in cell surface-related proteins were observed, including proteins involved in LPS synthesis: L-arabinose formyltransferase, UDP-glucuronic acid decarboxylase and a glycosyltransferase which showed reduced abundance over time.…”

Section: Resultsmentioning

confidence: 92%

“…Initial MLST of the sequential isolates used in this study (Supplementary information, Table S1 ) determined that these B . cenocepacia isolates all shared the same unique sequence type (ST867) 23 . Individual isolates were assembled de novo .…”

Section: Resultsmentioning

confidence: 99%

“…We recently showed that two series of sequential isolates from two adult male siblings with CF (referred to as P1 and P2) increased their ability to attach to host epithelial cells over time of colonisation 23 . We conducted whole genome sequencing on six of these isolates (3 per patient) and an in-depth proteomic analysis.…”

Section: Introductionmentioning

confidence: 99%

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The involvement of the low-oxygen-activated locus of Burkholderia cenocepacia in adaptation during cystic fibrosis infection

Cullen¹,

O’Connor

McCormack

et al. 2018

Sci Rep

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Chronic infection with opportunistic pathogens including Burkholderia cepacia complex (Bcc) is a hallmark of cystic fibrosis (CF). We investigated the adaptive mechanisms facilitating chronic lung infection in sequential Bcc isolates from two siblings with CF (P1 and P2), one of whom also experienced intermittent blood-stream infections (P2). We previously showed increased lung cell attachment with colonisation time in both P1 and P2. WGS analysis confirmed that the isolates are closely related. Twelve genes showed three or more mutations, suggesting these were genes under selection. Single nucleotide polymorphisms (SNVs) in 45 regulatory genes were also observed. Proteomic analysis showed that the abundance of 149 proteins increased over 61-months in sputum isolates, and both time- and source-related alterations in protein abundance between the second patient’s isolates. A consistent time-dependent increase in abundance of 19 proteins encoded by a low-oxygen-activated (lxa) locus was observed in both sets of isolates. Attachment was dramatically reduced in a B. cenocepacia K56-2Δlxa-locus deletion mutant, further indicating that it encodes protein(s) involved in host-cell attachment. Time-related changes in virulence in Galleria mellonella or motility were not observed. We conclude that the lxa-locus, associated with anoxic persistence in vitro, plays a role in host-cell attachment and adaptation to chronic colonization in the hypoxic niche of the CF lung.

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Section: Resultsmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The involvement of the low-oxygen-activated locus of Burkholderia cenocepacia in adaptation during cystic fibrosis infection

Cullen¹,

O’Connor

McCormack

et al. 2018

Sci Rep

Self Cite

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“…Besides this cell surrounding material, the airway epithelial cells contain membrane-anchored mucins that represent a group of highly O-glycosylated transmembrane glycoproteins (MUC1, MUC4, and MUC16 as the most representative). These membrane-tethered glycoproteins have signaling functions and serve as a protective barrier against invading pathogens (Cullen, O'Connor, Drevinek, Schaffer, & McClean, 2017;Dhar & Mcauley, 2019;Kim, 2012). In contrast to that, in some bacteria, it has been described the use of the mucin carbohydrate moieties as receptors for host cell infection, followed by the modulation of virulence genes expression (Ohneck et al, 2018;Navabi et al, 2012).…”

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confidence: 99%

Burkholderia cenocepacia–host cell contact controls the transcription activity of the trimeric autotransporter adhesin BCAM2418 gene

2020

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Cell‐to‐cell early contact between pathogens and their host cells is required for the establishment of many infections. Among various surface factors produced by bacteria that allow an organism to become established in a host, the class of adhesins is a primary determinant. Burkholderia cenocepacia adheres to the respiratory epithelium of cystic fibrosis patients and causes chronic inflammation and disease. Cell‐to‐cell contacts are promoted by various kinds of adhesins, including trimeric autotransporter adhesins (TAAs). We observed that among the 7 TAA genes found in the B. cenocepacia K56‐2 genome, two of them (BCAM2418 and BCAS0236) express higher levels of mRNA following physical contact with host cells. Further analysis revealed that the B. cenocepacia K56‐2 BCAM2418 gene shows an on–off switch after an initial colonization period, exhibits a strong expression dependent on the host cell type, and enhances its function on cell adhesion. Furthermore, our analysis revealed that adhesion to mucin‐coated surfaces dramatically increases the expression levels of BCAM2418. Abrogation of mucin O‐glycans turns BCAM2418 gene expression off and impairs bacterial adherence. Overall, our findings suggest that glycosylated extracellular components of host membrane might be a binding site for B. cenocepacia and a signal for the differential expression of the TAA gene BCAM2418.

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Protein with negative surface charge distribution, Bnr1, shows characteristics of a DNA‐mimic protein and may be involved in the adaptation of Burkholderia cenocepacia

Dennehy¹,

Duggan

Dignam³

et al. 2022

MicrobiologyOpen

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Adaptation of opportunistic pathogens to their host environment requires reprogramming of a vast array of genes to facilitate survival in the host. Burkholderia cenocepacia, a Gram‐negative bacterium with a large genome of ∼8 Mb that colonizes environmental niches, is exquisitely adaptable to the hypoxic environment of the cystic fibrosis lung and survives in macrophages. We previously identified an immunoreactive acidic protein encoded on replicon 3, BCAS0292. Deletion of the BCAS0292 gene significantly altered the abundance of 979 proteins by 1.5‐fold or more; 19 proteins became undetectable while 545 proteins showed ≥1.5‐fold reduced abundance, suggesting the BCAS0292 protein is a global regulator. Moreover, the ∆BCAS0292 mutant showed a range of pleiotropic effects: virulence and host‐cell attachment were reduced, antibiotic susceptibility was altered, and biofilm formation enhanced. Its growth and survival were impaired in 6% oxygen. In silico prediction of its three‐dimensional structure revealed BCAS0292 presents a dimeric β‐structure with a negative surface charge. The ΔBCAS0292 mutant displayed altered DNA supercoiling, implicated in global regulation of gene expression. Three proteins were identified in pull‐downs with FLAG‐tagged BCAS0292, including the Histone H1‐like protein, HctB, which is recognized as a global transcriptional regulator. We propose that BCAS0292 protein, which we have named Burkholderia negatively surface‐charged regulatory protein 1 (Bnr1), acts as a DNA‐mimic and binds to DNA‐binding proteins, altering DNA topology and regulating the expression of multiple genes, thereby enabling the adaptation of B. cenocepacia to highly diverse environments.

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Sequential Burkholderia cenocepacia Isolates from Siblings with Cystic Fibrosis Show Increased Lung Cell Attachment

Cited by 9 publications

References 11 publications

The involvement of the low-oxygen-activated locus of Burkholderia cenocepacia in adaptation during cystic fibrosis infection

The involvement of the low-oxygen-activated locus of Burkholderia cenocepacia in adaptation during cystic fibrosis infection

Burkholderia cenocepacia–host cell contact controls the transcription activity of the trimeric autotransporter adhesin BCAM2418 gene

Protein with negative surface charge distribution, Bnr1, shows characteristics of a DNA‐mimic protein and may be involved in the adaptation of Burkholderia cenocepacia

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