The Effect of Bacterial Toxins on Levels of Intracellular Adenosine Nucleotides and Human Ciliary Beat Frequency

Kanthakumar, K.; Taylor, Graham W.; Cundell, Diana R.; Dowling, Ruth; Johnson, Malcolm; Cole, P J; Wilson, Robert

doi:10.1006/pulp.1996.0028

Cited by 35 publications

(22 citation statements)

References 2 publications

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“…Rhamnolipids are found in the sputum (33) and lung secretions (23) of chronically infected patients at concentrations close to the concentration we tested experimentally (thus sufficiently high to promote P. aeruginosa infiltration). Rhamnolipids have also been reported to have deleterious effects on mucociliary clearance (28) and phagocytosis by macrophages (38) and are involved in fluid-channel formation in and dispersion of biofilms (6,15,17,27,47). Hence, these molecules are candidate targets for future therapeutic strategies aimed at specific modulation of the mucosal barrier.…”

Section: Discussionmentioning

confidence: 99%

Rhamnolipids Are Virulence Factors That Promote Early Infiltration of Primary Human Airway Epithelia byPseudomonas aeruginosa

Zulianello¹,

Canard²,

et al. 2006

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The opportunistic bacterium Pseudomonas aeruginosa causes chronic respiratory infections in cystic fibrosis and immunocompromised individuals. Bacterial adherence to the basolateral domain of the host cells and internalization are thought to participate in P. aeruginosa pathogenicity. However, the mechanism by which the pathogen initially modulates the paracellular permeability of polarized respiratory epithelia remains to be understood. To investigate this mechanism, we have searched for virulence factors secreted by P. aeruginosa that affect the structure of human airway epithelium in the early stages of infection. We have found that only bacterial strains secreting rhamnolipids were efficient in modulating the barrier function of an in vitroreconstituted human respiratory epithelium, irrespective of their release of elastase and lipopolysaccharide. In contrast to previous reports, we document that P. aeruginosa was not internalized by epithelial cells. We further report that purified rhamnolipids, applied on the surfaces of the epithelia, were sufficient to functionally disrupt the epithelia and to promote the paracellular invasion of rhamnolipid-deficient P. aeruginosa. The mechanism involves the incorporation of rhamnolipids within the host cell membrane, leading to tight-junction alterations. The study provides direct evidence for a hitherto unknown mechanism whereby the junctiondependent barrier of the respiratory epithelium is selectively altered by rhamnolipids.The airway mucosa is an efficient barrier to protect the host from infection by pathogens. An essential component of this barrier is the polarity of surface epithelial cells, which allows them to segregate the receptors that trigger the adherence and internalization of several pathogens within the basolateral domain of the membrane (51). Normally, this domain is not accessible to microbial organisms, due to the presence of tight junctions (TJ) that separate the apical from the basolateral membrane components and seal the paracellular space (37). To overcome this protective barrier, several microorganisms have developed strategies to alter either the apical membrane of epithelial cells (39) or the TJ barrier (53). Understanding the mechanism underlying these alterations is a prerequisite for development of novel therapeutic strategies targeted to specific molecular and cellular events. This is particularly necessary in the context of infections, such as those caused by Pseudomonas aeruginosa, which is difficult to eradicate by conventional antibiotic treatments (45).P. aeruginosa is an opportunistic gram negative bacterium that does not invade normal mucosae but causes serious nosocomial infections in immunocompromised individuals and in cystic fibrosis patients (7). The pathogenic mechanism accounting for these infections is not fully clarified and has been variously attributed to the production of different cell-associated and secreted virulence factors (41). The finding that P. aeruginosa is internalized more readily by dispersed and migrating ...

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Section: Discussionmentioning

confidence: 99%

Rhamnolipids Are Virulence Factors That Promote Early Infiltration of Primary Human Airway Epithelia byPseudomonas aeruginosa

Zulianello¹,

Canard²,

et al. 2006

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“…Inhaled pathogens fail to be cleared and chronic infection ensues. Airway damage arises from a combination of toxic bacterial products [10,11] and an exaggerated host inflammatory response [12]. In addition to the hydration of the ASL, there may be other factors which could impair MCC in CF.…”

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confidence: 99%

Normal nasal mucociliary clearance in CF children: evidence against a CFTR‐related defect

McShane

Davies

Wodehouse³

et al. 2004

Eur Respir J

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Studies on mucociliary clearance (MCC) in cystic fibrosis (CF) have produced conflicting results. This study aimed to differentiate primary (ion transportrelated) from secondary (inflammatory) causes of delayed MCC in CF.Nasal MCC was measured in 50 children (CF, primary ciliary dyskinesia (PCD) and no respiratory disease). Nasal lavage fluid was analysed for interleukin (IL)-8 and tumour necrosis factor-a. Similar measurements were obtained in adult CF patients with and without chronic sinusitis (CS).Children with CF had neither delayed MCC nor increased levels of cytokines. Conversely, children with PCD had prolonged MCC times (all w30 min) and significantly raised levels of IL-8. CS-positive CF adults had significantly slower MCC than CS-negative subjects, but IL-8 levels were low and similar in both groups.Decreased airway surface liquid and delayed mucociliary clearance are the postulated primary mechanisms in cystic fibrosis. However, the current study reports that cystic fibrosis children have normal nasal mucociliary clearance. Abnormalities appeared in cystic fibrosis adults with symptoms of chronic sinus disease, suggesting a secondary rather than primary phenomenon. Studies to explore this mechanism in the distal, more sparsely-ciliated airways could aid an understanding of pathogenesis and the development of new treatments. Eur Respir J 2004; 24: 95-100.

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“…Inhibition of aconitase is not surprising given its known susceptibility to inactivation by O 2 Ϫ ⅐ (15,16,18,19,24,32). However, to what extent both cytoplasmic and mitochondrial aconitase is affected was not directly examined (14,29). Furthermore, the assay used to measure aconitase activity relies on the detection of NADPH production from NADP ϩ by aconitase.…”

mentioning

confidence: 99%

Subcellular localization ofPseudomonaspyocyanin cytotoxicity in human lung epithelial cells

O’Malley¹,

Abdalla

McCormick

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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The Pseudomonas aeruginosa secretory product pyocyanin damages lung epithelium, likely due to redox cycling of pyocyanin and resultant superoxide and H2O2 generation. Subcellular site(s) of pyocyanin redox cycling and toxicity have not been well studied. Therefore, pyocyanin's effects on subcellular parameters in the A549 human type II alveolar epithelial cell line were examined. Confocal and electron microscopy studies suggested mitochondrial redox cycling of pyocyanin and extracellular H2O2 release, respectively. Pyocyanin decreased mitochondrial and cytoplasmic aconitase activity, ATP levels, cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, and mitochondrial membrane potential. These effects were transient at low pyocyanin concentrations and were linked to apparent cell-mediated metabolism of pyocyanin. Overexpression of MnSOD, but not CuZnSOD or catalase, protected cellular aconitase, but not ATP, from pyocyanin-mediated depletion. This suggests that loss of aconitase activity is not responsible for ATP depletion. How pyocyanin leads to ATP depletion, the mechanism of cellular metabolism of pyocyanin, and the impact of mitochondrial pyocyanin redox cycling on other cellular events are important areas for future study.

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The Effect of Bacterial Toxins on Levels of Intracellular Adenosine Nucleotides and Human Ciliary Beat Frequency

Cited by 35 publications

References 2 publications

Rhamnolipids Are Virulence Factors That Promote Early Infiltration of Primary Human Airway Epithelia byPseudomonas aeruginosa

Rhamnolipids Are Virulence Factors That Promote Early Infiltration of Primary Human Airway Epithelia byPseudomonas aeruginosa

Normal nasal mucociliary clearance in CF children: evidence against a CFTR‐related defect

Subcellular localization ofPseudomonaspyocyanin cytotoxicity in human lung epithelial cells

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