H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM‐1 and TLR3 expression

Abstract

Rhinovirus (RV) is an important trigger of chronic obstructive pulmonary disease (COPD) exacerbations. In addition, respiratory viruses are more likely to be isolated in patients with a history of frequent exacerbations, suggesting that these patients are more susceptible to viral infection. To examine potential mechanisms for cooperative effects between bacterial and viral infection in COPD, we studied the responses of cultured human airway epithelial cells to nontypeable Hemophilus influenzae and RV. In both 16HBE14o- and primary mucociliary-differentiated cells, preincubation with H. influenzae enhanced RV serotype 39-induced protein expression of interleukin (IL)-8, epithelial-derived neutrophil attractant-78, and growth-related oncogene-alpha. H. influenzae infection also increased the binding of RV39 to cultured cells, as well as expression of intercellular adhesion molecule (ICAM)-1 and Toll-like receptor (TLR)-3, receptors for RV and dsRNA, respectively. Neutralizing antibody against tumor necrosis factor-alpha inhibited IL-8 expression induced by H. influenzae and RV39. Finally, siRNA against TLR3 attenuated RV-induced IL-8 expression. We conclude that H. influenzae infection increases airway epithelial cell ICAM-1 and TLR3 expression, leading to enhanced binding of RV and a potentiation of RV-induced chemokine release. These data provide a cellular mechanism by which H. influenzae infection may increase the susceptibility of COPD patients to RV-induced exacerbations.

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

“…Presented data are representative for two independent experiments. *p , 0.05, **p , 0.01. evidence that TLR3 is also involved in antibacterial responses (13,14). Beyond that, upon activation, TLR3 induces the same TRIFdependent signaling events as endosomal TLR4, resulting in activation of the MyD88-independent pathway.…”

“…However, recent studies have shown that TLR3 may also be associated with bacterial infection. Sajjan et al (13) have reported that TLR3 expression is upregulated in airway epithelial cells during infection with nontypeable Haemophilus influenzae (NTHi), resulting in enhanced rhinovirus-induced chemokine release. In addition, NTHi is capable of directly activating TLR3 (14).…”

Efficacy and safety of a triple active sore throat lozenge in the treatment of patients with acute pharyngitis: Results of a multi-centre, randomised, placebo-controlled, double-blind, parallel-group trial (DoriPha)

“…The other second hypothesis claims that virus infections of the respiratory tract imbalance the respiratory microbial community7, 8 and thus predispose to bacterial superinfections2, 8, 9, 10: Longitudinal studies have revealed a clear and positive association between viral and bacterial infections of the airway as acute otitis media, sinusitis, purulent nasopharyngitis, acute bronchitis, tonsillitis and pneumonia all often occur after local viral infection 2, 5, 7. Interactions between viruses and bacteria in the pathogenesis of respiratory infections have been investigated by others applying techniques used in microbiology and molecular biology1, 2, 7, 8, 9: The mechanisms by which viruses influence bacterial colonisation and invasion are diverse and include disruption of the epithelium barrier, upregulation of adhesion proteins, production of viral factors and dysfunction of immune system components 1, 2, 7, 9…”

“…Interactions between viruses and bacteria in the pathogenesis of respiratory infections have been investigated by others applying techniques used in microbiology and molecular biology1, 2, 7, 8, 9: The mechanisms by which viruses influence bacterial colonisation and invasion are diverse and include disruption of the epithelium barrier, upregulation of adhesion proteins, production of viral factors and dysfunction of immune system components 1, 2, 7, 9…”

“…In particular, sore throat and dysphagia affect patients during their everyday life. In the majority of cases, the infection that causes pharyngitis is initially viral in nature1, 2 and may be superinfected by bacteria due to inadequate use of antibiotics and disturbed microflora3, 4, 5, 6 or diverse viral mechanisms which include disruption of the epithelial barrier, upregulation of adhesion proteins, production of viral factors, and dysfunction of immune system components 1, 2, 7, 8, 9, 10…”