Infection with Prevotella nigrescens induces TLR2 signalling and low levels of p65 mediated inflammation in Cystic Fibrosis bronchial epithelial cells

Bertelsen, Anne; Elborn, J. Stuart; Schock, Bettina

doi:10.1016/j.jcf.2019.09.005

Cited by 10 publications

(18 citation statements)

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“…can reduce the growth of P.aeruginosa, P.nigresences and P.histicola may also actively suppress pro-in ammatory P.aeruginosa induced NF-kB signalling in the host cell. Our previous work has shown that P.nigrescens would predominantly utilise TLR2 signalling Together with late NF-κB activation the subsequent MAPK/IL-12 activation may exhibit an antiin ammatory effect (12). Similarly, P.histicola may exert its anti-in ammatory effect through the inhibitory effect of IKKα/RElB (14), overall reducing P.aeruginosa induced NF-κB-driven in ammatory responses (Fig.…”

Section: Discussionmentioning

confidence: 92%

Microbial interaction: Prevotella spp. reduce P.aeruginosa induced inflammation in Cystic Fibrosis bronchial epithelial cells

Bertelsen

Elborn

Schock

2020

Preprint

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Background: In Cystic Fibrosis (CF) airways, mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) lead to dehydrated, thick mucus which promotes the establishment of persistent polymicrobial infections and drives chronic airways inflammation. This also predisposes the airways to further infections, a vicious, self-perpetuating cycle causing lung damage and progressive lung function decline. The airways are a poly-microbial environment, containing both aerobic and anaerobic bacterial species. Pseudomonas aeruginosa (P.aeruginosa) infections contribute to the excessive inflammatory response in CF, but the role of anaerobic Prevotella spp., frequently found in CF airways, is not known.Materials: We assessed innate immune signalling in CF airway epithelial cells in response to clinical strains of P.histicola, P.nigresens and P.aeruginosa. CFBE41o- cells were infected with P.aeruginosa (MOI 100, 2h) followed by infection with P.histicola or P.nigrescens (MOI 100, 2h). Cells were incubated under anaerobic conditions for the duration of the experiments.Results: Our study shows that P.histicola and P.nigresens can reduce the growth of P.aeruginosa and dampen the inflammatory response in airway epithelial cells. We specifically illustrate that the presence of Prevotella spp. reduces Toll-like-receptor (TLR)-4, MAPK, NF-kB(p65) signalling and cytokine release (Interleukin (IL)-6, IL-8) in mixed infections. Conclusion: Our work, for the first time, strongly indicates a relationship between P. aeruginosa and anaerobe Prevotella spp. The observed modified NF-kB and MAPK signalling provides some mechanisms of this interaction that could offer a novel therapeutic approach to combat chronic P.aeruginosa infection in people with CF.

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Section: Discussionmentioning

confidence: 92%

Microbial interaction: Prevotella spp. reduce P.aeruginosa induced inflammation in Cystic Fibrosis bronchial epithelial cells

Bertelsen

Elborn

Schock

2020

Preprint

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“…Prevotella melaninogenica is a causative agent of periodontitis [48]. Prevotella nigrescens, which elicits TLR2 signaling and p65-Mediated In ammation [49], is an oral bacterial species causing for respiratory tract infections. Further, Prevotella intermedia, Prevotella melaninogenica, and Prevotella nanceiensis are 3 periodontopathic bacteria species causing oral malodor and oral health issues [50].…”

Section: Discussionmentioning

confidence: 99%

Tumor-Asociated Microbiota in Esophageal Squamous Cell Carcinoma

Yang

Chen

Jia

et al. 2020

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Background: Human intestinal tract microbiome dysbiosis plays an emerging pivotal role in tumorigenesis of gastrointestinal tract cancers. For esophageal squamous cell carcinoma (ESCC), the esophageal microbiota plays a critical role during the pathogenesis. The microbiome of esophageal can impact its host decades before the onset of ESCC, and can interact with the host’s physiological situation, which are affected by lifestyle factors, including diet, obesity, alcohol and tobacco use, and oral hygiene.Our objective is to analyze the composition of the ESCC-associated microbiota and characterize its contribution to the development of ESCC. The esophageal microbiota was prospectively investigated in 18 patients with ESCC and 11 patients with physiological normal (PN) esophagus by 16S rRNA gene profiling, using next-generation sequencing. Results: The microbiota composition in tumor tissues of ESCC patients is significantly different from that of patients with PN tissues. The ESCC microbiota was characterized by reduced microbial diversity, by decreased abundance of Bacteroidetes, Fusobacteria and Spirochactes. Employing these taxa into a microbial dysbiosis index demonstrated that dysbiosis microbiota had good capacity to discriminate between ESCC and PN esophagus. Functional analysis of the microbiota characterized that ESCC microbiota had altered nitrate reductase and nitrite reductase functions when compared with PN group. The observations were confirmed in other validation cohorts.Conclusions: Detailed analysis of the microbiota of the ESCC patients revealed that tumor exhibit a dysbiotic microbial community when compared with PN groups. We characterized microbial compositional changes, and further identified significant enrichments of Treponema amylovorum, Streptococcus infantis, Prevotella nigrescens, Porphyromonas endodontalis, Veillonella dispar, Aggregatibacter segnis, Prevotella melaninogenica, Prevotella intermedia, Prevotella tannerae, Prevotella nanceiensis and Streptococcus anginosus in ESCC oncogenic progression.Trial registration number: This study was registered at the Chinese Clinical Trial Registry (ChiCTR1800018897). http://www.chictr.org.cn/.

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“…This culture was used for infection experiments. P. histicola was identified by 16S rRNA sequencing, PGFE and RAPD analysis as described [9,22]. P. aeruginosa (clinical isolate B021, identified using 16S rRNA screening [22]) was grown under aerobic conditions on Columbia blood agar (CBA) (37˚C, 5% CO 2 , 95% mixed gas) over night.…”

Section: Bacterial Culturementioning

confidence: 99%

“…The minimum amount of bacteria required to provoke a significant response from CFBE41o-cells (0-4h, anaerobic conditions) was determined by screening of 3 different P. aeruginosa isolates as described [9]. Growth curves of P. histicola and P. aeruginosa under anaerobic conditions revealed no differences in the growth rates between the two species (S1 Fig).…”

Section: Bacterial Culturementioning

confidence: 99%

“…has a positive correlation with higher lung function and reduced C-reactive protein (CRP) [8]. Furthermore, we recently showed that a strain of P. nigrescens isolated from a person with CF induced a lower proinflammatory cytokine expression in CF bronchial epithelial cells than P. aeruginosa, suggesting that the presence of certain Prevotella species in CF lungs may lower the inflammatory response and could therefore be beneficial to the host [9].…”

Section: Introductionmentioning

confidence: 99%

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Toll like Receptor signalling by Prevotella histicola activates alternative NF-κB signalling in Cystic Fibrosis bronchial epithelial cells compared to P. aeruginosa

2020

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Cystic Fibrosis (CF), caused by mutations affecting the CFTR gene, is characterised by viscid secretions in multiple organ systems. CF airways contain thick mucus, creating a gradient of hypoxia, which promotes the establishment of polymicrobial infection. Such inflammation predisposes to further infection, a self-perpetuating cycle in mediated by NF-κB. Anaerobic Gram-negative Prevotella spp. are found in sputum from healthy volunteers and CF patients and in CF lungs correlate with reduced levels of inflammation. Prevotella histicola (P. histicola) can suppress murine lung inflammation, however, no studies have examined the role of P. histicola in modulating infection and inflammation in the CF airways. We investigated innate immune signalling and NF-kB activation in CF epithelial cells CFBE41o-in response to clinical stains of P. histicola and Pseudomonas aeruginosa (P. aeruginosa). Toll-Like Receptor (TLR) expressing HEK-293 cells and siRNA assays for TLRs and IKKα were used to confirm signalling pathways. We show that P. histicola infection activated the alternative NF-kB signalling pathway in CF bronchial epithelial cells inducing HIF-1α protein. TLR5 signalling was responsible for the induction of the alternative NF-kB pathway through phosphorylation of IKKα. The induction of transcription factor HIF-1α was inversely associated with the induction of the alternative NF-kB pathway and knockdown of IKKα partially restored canonical NF-kB activation in response to P. histicola. This study demonstrates that different bacterial species in the respiratory microbiome can contribute differently to inflammation, either by activating inflammatory cascades (P. aeruginosa) or by muting the inflammatory response by modulating similar or related pathways (P. histicola). Further work is required to assess the complex interactions of the lung microbiome in response to mixed bacterial infections and their effects in people with CF.

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Infection with Prevotella nigrescens induces TLR2 signalling and low levels of p65 mediated inflammation in Cystic Fibrosis bronchial epithelial cells

Cited by 10 publications

References 50 publications

Microbial interaction: Prevotella spp. reduce P.aeruginosa induced inflammation in Cystic Fibrosis bronchial epithelial cells

Microbial interaction: Prevotella spp. reduce P.aeruginosa induced inflammation in Cystic Fibrosis bronchial epithelial cells

Tumor-Asociated Microbiota in Esophageal Squamous Cell Carcinoma

Toll like Receptor signalling by Prevotella histicola activates alternative NF-κB signalling in Cystic Fibrosis bronchial epithelial cells compared to P. aeruginosa

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