A Crucial Role of Flagellin in the Induction of Airway Mucus Production by Pseudomonas aeruginosa

Mohamed, Fatima Ben; García-Verdugo, Ignacio; Medina, Mathieu; Balloy, Viviane; Chignard, Michel; Ramphal, Reuben; Touqui, Lhousseine

doi:10.1371/journal.pone.0039888

Cited by 31 publications

(31 citation statements)

References 38 publications

(52 reference statements)

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“…Importantly, flagellin-deficient P. aeruginosa bacteria were significantly impaired in inducing MDSCs, supporting the idea that the effect of P. aeruginosa in vivo and in vitro is mainly mediated through flagellin. The significance of the flagellin-TLR5 axis in P. aeruginosa-host interactions has been previously demonstrated in numerous studies, including experimental infection models using epithelial cells (1,2,5,17,19,20), macrophages (21), neutrophils (18), or in vivo infection strategies (3,22,23). Our study thereby confirms and extends the concept that flagellin acts as a key player in shaping the innate but also the adaptive immune response to P. aeruginosa in CF lung disease and beyond.…”

Section: Discussionsupporting

confidence: 87%

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Rieber

Brand

Hector

et al. 2013

The Journal of Immunology

118

127

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Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa–infected CF patient ex vivo–isolated as well as flagellin or P. aeruginosa in vitro–generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell–mediated host defense in CF and other P. aeruginosa–associated chronic lung diseases.

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Section: Discussionsupporting

confidence: 87%

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Rieber

Brand

Hector

et al. 2013

The Journal of Immunology

118

127

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“…The cytokines diffuse from the surface epithelium to the glands located ∼150 μm away (31,32), stimulating CFTR-dependent ASL secretion (13). Flagellin also will induce mucin expression within 18-24 h and further contribute to bacteria clearance (33,34).…”

Section: Resultsmentioning

confidence: 99%

Pseudomonas aeruginosa triggers CFTR-mediated airway surface liquid secretion in swine trachea

Luan

Campanucci

Nair

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Cystic fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding for the anion channel cystic fibrosis transmembrane conductance regulator (CFTR). Several organs are affected in CF, but most of the morbidity and mortality comes from lung disease caused by the failure to clear bacteria. Bacterial clearance depends on a layer of airway surface liquid (ASL) covering the airways, rich in antimicrobial compounds and mucins, that removes bacteria from the airway through mucociliary clearance. This study provides the first demonstration that inhalation of bacteria triggers CFTR-dependent ASL secretion. We suggest that this response to inhaled pathogens is an important but previously unknown part of the innate immune response that would be missing in CF patients, resulting in reduced bacterial killing and facilitating infection.

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“…The primer for murine HPRT has been described in our recent study [17]. Other primers were designed using the Oligo Explorer 1.1.…”

Section: Methodsmentioning

confidence: 99%

Toll-Like Receptor 9 Deficiency Protects Mice against Pseudomonas aeruginosa Lung Infection

BenMohamed

Medina

et al. 2014

PLoS ONE

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Pseudomonas aeruginosa is an opportunistic pathogen involved in nosocomial infections. While a number of studies have demonstrated the roles of TLR2, TLR4 and TLR5 in host defense againt P. aeruginosa infection, the implication of TLR9 in this process has been overlooked. Here, we show that P. aeruginosa DNA stimulates the inflammatory response through TLR9 pathway in both a cell line and primary alveolar macrophages (AMs). This activation requires asparagine endopeptidase- and endosomal acidification. Interestingly, TLR9-/- mice resisted to lethal lung infection by P. aeruginosa, compared to WT C57BL/6 mice. The resistance of TLR9-/- mice to P. aeruginosa infection was associated with: (i) a higher ability of TLR9-/- AMs to kill P. aeruginosa; (ii) a rapid increase in the pro-inflammatory cytokines such as TNFα, IL-1β and IL-6 production; and (iii) an increase in nitric oxide (NO) production and inductible NO synthase expression in AMs. In addition, inhibition of both IL-1β and NO production resulted in a significant decrease of P. aeruginosa clearance by AMs. Altogether these results indicate that TLR9 plays a detrimental role in pulmonary host defense toward P. aeruginosa by reducing the AMs clearance activity and production of IL-1β and NO necessary for bacteria killing.

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A Crucial Role of Flagellin in the Induction of Airway Mucus Production by Pseudomonas aeruginosa

Cited by 31 publications

References 38 publications

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Pseudomonas aeruginosa triggers CFTR-mediated airway surface liquid secretion in swine trachea

Toll-Like Receptor 9 Deficiency Protects Mice against Pseudomonas aeruginosa Lung Infection

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