Primary ciliary dyskinesia ciliated airway cells show increased susceptibility to Haemophilus influenza biofilm formation

Abstract

Nontypeable Haemophilus influenzae (NTHi) is the most common pathogen in primary ciliary dyskinesia (PCD) patients. We hypothesized that abnormal ciliary motility and low airway nitric oxide (NO) levels on airway epithelial cells from PCD patients might be permissive for NTHi colonization and biofilm evelopment. We used a primary epithelial cell co-culture model to investigate NTHi infection. Primary airway epithelial cells from PCD and non-PCD patients were differentiated to ciliation using air-liquid interface culture and then co-cultured with NTHi. NTHi adherence was greater on PCD epithelial cells compared to non-PCD cells (P<0.05) and the distribution of NTHi on PCD epithelium showed more aggregated NTHi in biofilms (P<0.001). Apart from defective ciliary motility, PCD cells did not significantly differ from non-PCD epithelial cells in the degree of ciliation and epithelial integrity or in cytokine, LL-37 and NO production. Treatment of PCD epithelia using exogenous NO and antibiotic significantly reduced NTHi viability in biofilms compared to antibiotic treatment alone. Impaired ciliary function was the primary defect in PCD airway epithelium underlying susceptibility to NTHi biofilm development compared with non-PCD epithelium. Although NO responses were similar, use of targeted NO with antibiotics enhanced killing of NTHi in biofilms, suggesting a novel therapeutic approach.

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Identifiers

ORCID for Claire Jackson: orcid.org/0000-0002-1200-0935

ORCID for Samuel, Anthony Collins: orcid.org/0000-0003-1571-7410

ORCID for Benjamin L. Nicholas: orcid.org/0000-0003-1467-9643

ORCID for David Johnston: orcid.org/0000-0001-6703-6014

ORCID for Peter Lackie: orcid.org/0000-0001-7138-3764

ORCID for Saul Faust: orcid.org/0000-0003-3410-7642

ORCID for Jane Lucas: orcid.org/0000-0001-8701-9975

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