Non-typeable Haemophilus influenzae decreases cilia beating via protein kinase C epsilon

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Abstract

Background

Haemophilus influenzae infection of the nasal epithelium has long been associated with observations of decreased nasal ciliary beat frequency (CBF) and injury to the ciliated epithelium. Previously, we have reported that several agents that slow CBF also have the effect of activating protein kinase C epsilon (PKCϵ) activity in bronchial epithelial cells. The subsequent auto-downregulation of PKCϵ or the direct inhibition of PKCϵ leads to the specific detachment of the ciliated cells. METHODS: Primary cultures of ciliated bovine bronchial epithelial cells were exposed to filtered conditioned media supernatants from non-typeable H. influenzae (NTHi) cultures. CBF and motile points were measured and PKCϵ activity assayed.

Results

NTHi supernatant exposure significantly and rapidly decreased CBF in a dose-dependent manner within 10 minutes of exposure. After 3 hours of exposure, the number of motile ciliated cells significantly decreased. Direct measurement of PKCϵ activity revealed a dose-dependent activation of PKCϵ in response to NTHi supernatant exposure. Both CBF and PKCϵ activity changes were only observed in fresh NTHi culture supernatant and not observed in exposures to heat-inactivated or frozen supernatants.

Conclusions

Our results suggest that CBF slowing observed in response to NTHi is consistent with the stimulated activation of PKCϵ. Ciliated cell detachment is associated with PKCϵ autodownregulation.

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Most cited references 15

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Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease.

L Brauer, Andrew Schiffmacher, George Murphy … (2004)

Nontypeable Haemophilus influenzae colonizes the respiratory tract of adults with chronic obstructive pulmonary disease (COPD) and causes intermittent exacerbations. Isolates of H. influenzae collected monthly in a prospective study were subjected to molecular typing. During a 7-year study spanning 345 patient-months of observation, 122 episodes of negative cultures lasting 1 month or more, and that were preceded and followed by isolation of an apparently identical strain of H. influenzae, were found. Seventeen such episodes of negative cultures, lasting 6 months or more and spanning 203 patient-months, were studied in detail to test the hypothesis that these periods of negative cultures represented continuous colonization by the same strain of H. influenzae. Molecular typing by three independent methods established that the strains preceding and following the episodes of negative cultures were indeed identical. Strain-specific H. influenzae DNA was detected in some of the sputum samples that had yielded negative cultures. These results indicate that some patients with COPD are persistently colonized with H. influenzae and that sputum cultures underestimate the frequency of colonization of the respiratory tract by H. influenzae in COPD. This observation has a significant impact on understanding bacterial colonization in COPD.

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All-digital image capture and whole-field analysis of ciliary beat frequency.

Mary Ammons, T. Wyatt, Tamara J Stoner … (2003)

We hypothesized that a high-speed all-digital video imaging system, with computerized analysis, would precisely capture and measure ciliary beat frequency (CBF) and would shorten the time from data capture to data analysis. We compared a conventional analog video system with a new high-speed digital system we developed for CBF analysis. Using ciliated primary bovine bronchial epithelial cells we made simultaneous analog and digital CBF measurements of the same region of interest (ROI) while temperature was varied. This yielded nearly identical data over a wide range of frequencies (7-15 Hz) using either system. Unlike the digital system however, the analog system did not accurately detect CBF above 15 Hz (temperatures higher than 30 degrees C). We also compared ROI analysis with a new analysis algorithm we have named whole-field analysis (WFA). WFA measurement of CBF agreed with ROI and reduced operator time required to analyse data by more than 90% compared with the analog system. We conclude that all-digital computerized CBF analysis correlates closely with standard video methods, markedly speeds up data analysis and provides new ways, including WFA, to analyse entire fields of motile cilia simultaneously. We have termed this system 'Sisson-Ammons Video Analysis' (SAVA).

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Protein D of Haemophilus influenzae: a protective nontypeable H. influenzae antigen and a carrier for pneumococcal conjugate vaccines.

Arne Forsgren, Håkan Janson, Kristian Riesbeck (2008)

Protein D (PD) is a highly conserved 42 kDa surface lipoprotein found in all Haemophilus influenzae, including nontypeable (NT) H. influenzae. PD is involved in the pathogenesis of respiratory tract infections, in the context of which it has been shown to impair ciliary function in a human nasopharyngeal tissue culture model and to augment the capacity to cause otitis media in rats. A likely mechanism indicating that PD is a virulence factor is its glycerophosphodiesterase activity, which leads to the release of phosphorylcholine from host epithelial cells. PD has been demonstrated to be a promising vaccine candidate against experimental NT H. influenzae infection. Rats vaccinated with PD cleared NT H. influenzae better after middle ear and pulmonary bacterial challenge, and chinchillas vaccinated with PD showed significant protection against NT H. influenzae-dependent acute otitis media. In a clinical trial involving children, PD was used as an antigenically active carrier protein in an 11-valent pneumococcal conjugate investigational vaccine; significant protection was achieved against acute otitis media not only caused by pneumococci but also caused by NT H. influenzae. This may have great clinical implications, because PD is the first NT H. influenzae antigen that has induced protective responses in humans.

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Author and article information

Journal

Journal ID (nlm-ta): Respir Res

Journal ID (iso-abbrev): Respir. Res

Title: Respiratory Research

Publisher: BioMed Central

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Print): 2012

Publication date (Electronic): 19 June 2012

Volume: 13

Issue: 1

Page: 49

Affiliations

[1 ]VA Nebraska-Western Iowa Health Care System Research Service, Department of Veterans Affairs Medical Center, 4101 Woolworth Avenue, Omaha, NE, 68105, USA

[2 ]Department of Environmental, Agricultural, and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198-5910, USA

[3 ]Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, 985300 Nebraska Medical Center, Omaha, NE, 68198-5300, USA

[4 ]Department of Epidemiology, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198-5910, USA

Article

Publisher ID: 1465-9921-13-49

DOI: 10.1186/1465-9921-13-49

PMC ID: 3487807

PubMed ID: 22712879

SO-VID: 47996d86-b121-45e8-8299-2cb1ee6f3e33

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Non-typeable Haemophilus influenzae decreases cilia beating via protein kinase C epsilon

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Abstract

Background

Results

Conclusions

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Inflamed lung in vitro co-culture models

Most cited references 15

Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease.

All-digital image capture and whole-field analysis of ciliary beat frequency.

Protein D of Haemophilus influenzae: a protective nontypeable H. influenzae antigen and a carrier for pneumococcal conjugate vaccines.

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