Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD

Abstract

BackgroundRhinovirus (RV) is a major cause of chronic obstructive pulmonary disease (COPD) exacerbations, and primarily infects bronchial epithelial cells. Immune responses from BECs to RV infection are critical in limiting viral replication, and remain unclear in COPD. The objective of this study is to investigate innate immune responses to RV infection in COPD primary BECs (pBECs) in comparison to healthy controls.MethodsPrimary bronchial epithelial cells (pBECs) from subjects with COPD and healthy controls were infected with RV-1B. Cells and cell supernatant were collected and analysed using gene expression microarray, qPCR, ELISA, flow cytometry and titration assay for viral replication.ResultsCOPD pBECs responded to RV-1B infection with an increased expression of antiviral and pro-inflammatory genes compared to healthy pBECs, including cytokines, chemokines, RNA helicases, and interferons (IFNs). Similar levels of viral replication were observed in both disease groups; however COPD pBECs were highly susceptible to apoptosis. COPD pBECs differed at baseline in the expression of 9 genes, including calgranulins S100A8/A9, and 22 genes after RV-1B infection including the signalling proteins pellino-1 and interleukin-1 receptor associated kinase 2. In COPD, IFN-β/λ1 pre-treatment did not change MDA-5/RIG-I and IFN-β expression, but resulted in higher levels IFN-λ1, CXCL-10 and CCL-5. This led to reduced viral replication, but did not increase pro-inflammatory cytokines.ConclusionsCOPD pBECs elicit an exaggerated pro-inflammatory and antiviral response to RV-1B infection, without changing viral replication. IFN pre-treatment reduced viral replication. This study identified novel genes and pathways involved in potentiating the inflammatory response to RV in COPD.

Efficacy of IFN-λ1 to Protect Human Airway Epithelial Cells against Human Rhinovirus 1B Infection

“…Similar results were found when HeLa cells were infected with HRV1a [44]. Consistent with these observations, one very recent study also showed no induction of IFN-β after HRV1B infection in primary bronchial epithelial cells, which were isolated from healthy persons [45]. Likewise, in the present study, we also did not observe an up-regulation of the IFNs or ISGs mRNA expression after infection of A549 or PBECs with HRV1B.…”

Mediators of Neutrophil Function in Children With Protracted Bacterial Bronchitis

“…23 We have previously reported the upregulation of PELI1 and IRAK2 in response to rhinovirus infection of human primary bronchial epithelial cells in COPD. 24 Th is evidence collectively suggests that IRAK2 and PELI1 promote neutrophilic airway infl ammation triggered by infection and IL-1 b and that this response is dysregulated in PBB and contributes to disease recurrence.…”

Antiviral immunity is impaired in COPD patients with frequent exacerbations

“…Evaluation of baseline expression of antiviral and proinflammatory mediators. Since viruses are a major cause of exacerbations and deficient antiviral immunity has been observed in some, but not all, studies of COPD (1,17,20,22), we hypothesized that frequent exacerbators would have reduced baseline expression of antiviral immune mediators and, thus, an impaired potential to mount protective responses to virus infections. We examined baseline sputum cell mRNA expression of type I and III IFNs and ISGs in 36 patients from the community-based COPD cohort and found that frequent exacerbators had significantly reduced sputum IFN␤ and IFN2/3 mRNA expression with no difference in IFN1 (Fig.…”

“…Viruses are a major etiological trigger for exacerbations (28,30), and data exist to suggest that COPD may be associated with deficient antiviral immunity (17,22). However, not all studies have shown this abnormality (1,20), suggesting that it may vary according to disease phenotype. Frequent exacerbators could represent one subgroup in whom defective antiviral immunity is more prominent.…”