Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD
© Baines et al.; licensee BioMed Central Ltd. 2013
Received: 2 November 2012
Accepted: 31 January 2013
Published: 6 February 2013
Rhinovirus (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.
Primary 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.
COPD 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.
COPD 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.
KeywordsCOPD Immune response Viral infection Gene expression
Chronic obstructive pulmonary disease (COPD) is responsible for an increasing burden of illness and death around the world. COPD is chronic airway disease, characterized by incompletely reversible airflow obstruction, and symptoms of cough and sputum production. These symptoms can be worsened with exposure to microbial infections . Rhinoviruses (RVs) are the most frequently detected viruses during acute exacerbation , and infection is associated with rapid decline in lung function and severe symptoms that often requires hospitalization . However the specific mechanism that leads to this enhanced susceptibility and severe symptoms following RV infection is not well understood.
Bronchial epithelial cells (BECs) are the primary site of RV infection, where the infection occurs both in the upper and lower respiratory epithelium equally . RV can infect other cells including airway macrophages, however the virus does not replicate in these cells , which demonstrates the important role of BECs in the first line of defence against invading pathogens. As RVs are endocytosed into BECs viral RNAs are preferentially recognized by the RNA helicase melanoma differentiation-associated gene −5 (MDA-5, also known as IFIH1), which then signals for the induction of type I interferon (IFN-α/β) and type III IFNs (IFN-λ1/2/3). These IFNs then signal for the expression of over 300 IFN-stimulated genes (ISGs) including IFNs, CCL-5, CXCL-10, and the RNA helicases MDA-5 and retinoic acid-inducible gene–I (RIG-I or DDX58) . These ISGs amplify IFN responses and induce apoptosis and limit viral replication. CCL-5 and CXCL-10 recruit cytotoxic T cells to kill virus-infected cells .
RV RNAs are also recognized by toll-like receptor (TLR) -3 and via nuclear factor – kappa B (NF-κB) signalling triggering the release of pro-inflammatory cytokines such as IL-6, leading to acute inflammation and fever . Subjects with COPD are known to have increased inflammatory cytokines that drive increased recruitment of neutrophils due to heightened chemoattractant CXCL-8, and the neutrophils then phagocytose replicating viruses and limit viral spread . However the mechanisms underlying the severe outcomes to infection in COPD and the role of BECs responses to virus infection remains unclear. Here we hypothesized that primary BECs (pBECs) from COPD subjects have an exaggerated inflammatory response and abnormal antiviral response to RV infection compared to healthy control pBECs. In this study, pBECs from subjects with COPD and healthy controls were infected RV-1B, and the immune responses to infection were assessed using whole genome microarray analysis, allowing the opportunity for discovery of novel regulators of abnormal responses in COPD.
RV-1B was obtained from the American Tissue Culture Collection (ATCC, USA). Virus was propagated using RD-ICAM-1 cells, clarified by centrifugation and viral titres were determined using 50% Tissue Culture Infective Dose (TCID50).
Subjects with COPD were recruited; defined by a previous smoking history and fixed airflow limitation on spirometry with an FEV1/FVC ratio < 70%, and FEV1 < 80% predicted and classified by the GOLD criteria. Those with GOLD Stage III (severe COPD) FEV1 30 – 50% predicted, and Stage IV (very severe COPD) FEV1 <30% were included. COPD subjects were ex-smokers (at least one year abstinent) and did not use inhaled corticosteroids for two weeks prior to bronchoscopy. Healthy non-smoking controls with no evidence of airflow obstruction, bronchial hyper-responsiveness to hypertonic saline challenge, or chronic respiratory symptoms were recruited. A clinical history, examination and spirometry were performed. Subjects were excluded if they had symptoms of an acute respiratory tract infection a month prior. All subjects gave written informed consent. The study was approved by The University of Newcastle Human Research Ethics.
Cell culture and viral infection
Human pBECs were obtained by endobronchial brushing during fibre-optic bronchoscopy in accordance with standard guidelines, and cultured as described previously . Cells were seeded at 1 x 105 and cultured in BEBM basal media with supplements (BEGM, Lonza). At passage 2 when the cells reached 80% confluency in 24-well plates, virus infection was performed at a multiplicity of infection (MOI) of 20 for 1 hour with shaking. After 1 hour incubation viral inoculum was removed and fresh BEBM basal media supplemented with 0.5% BSA was then added. For IFN pre-treatment experiments, human recombinant IFN-β (10U) and IFN-λ1 protein (1ng/mL; R&D Systems) was used to pre-treat pBECs for 24hrs before RV-1B infection in the designated experiments. For all experiments samples were collected at 6hrs for whole genome gene expression microarray and real-time PCR (qPCR) and 24hrs for ELISA/CBA and viability/apoptosis.
Whole genome gene expression microarray
pBEC RNA was extracted, 500ng amplified and 750ng cRNA hybridised to Illumina’s HumanRef-8 V3 BeadChips as previously described .
Real-time PCR (qPCR)
RNA was extracted, reverse transcribed to cDNA and real-time PCR was performed as previously described . Briefly, RNA (200ng) was reverse-transcribed to cDNA using the high capacity cDNA reverse transcription kit (Applied Biosystems, Foster City,USA). Taqman qPCR primer and probes for the target genes were purchased in kit form (Applied Biosystems, Foster City,USA). PCR primers and probes were combined with Taqman gene expression master mix as per manufacturer’s instructions in duplicate singleplex real-time PCRs (7500 Real Time PCR System, Applied Biosystems). Fold change results were calculated using 2-ΔΔCt relative to the internal reference gene (18S) and the mean of all samples.
IFN-λ1/3, CXCL-10, IL-6, TNF-α and CCL-5 concentration was assessed using ELISA kit (IFN-λ1/3, R&D Systems, lower detection limit of 31.25pg/mL) and cytometric bead array (CXCL-10, IL-6, TNF-α and CCL-5, BD Biosciences, lower detection limit of 10pg/mL) according to the manufacturer’s instructions.
Apoptosis was measured using Annexin V-PE Apoptosis Detection Kit I (Becton Dickinson) according to manufacturer’s instructions . Briefly, infected and non-infected cells were stained with Annexin V-PE and 7-AAD analysed by flow cytometry. Annexin V-PE positive and 7-AAD negative were determined to be apoptotic, Annexin V-PE and 7-AAD positive were necrotic and Annexin V-PE and 7-AAD negative were live cells.
Viral replication was determined using both TCID50 and relative RNA copy number using a standard curve created using serial dilution of RV-1B RNA.
Data analysis preformed using Stata 9 or GraphPad Prism 5 and reported as mean with standard error of means (SEM) for normally distributed data and median (quartile [Q] 1, Q3) for nonparametric data. Statistical comparisons were performed by using multiple comparisons ANOVA for parametric data and the Kruskal-Wallis test for nonparametric data. P<0.05 was considered significant.
Whole genome gene expression microarray analysis
Microarray data were exported by using Genome Studio (Illumina) and analyzed by using GeneSpring GX11 (Agilent Technologies). Data were log-transformed, normalized, and baseline-converted to the median of all samples. Data were filtered, and only genes flagged as present (< 0.05 detection P value) in all samples were included in the further analysis. Hierarchical clustering analysis was performed by using the Pearson centered algorithm with complete linkage. The Pearson algorithms cluster samples on the basis of their correlation coefficients, whereas complete linkage measures that the distance between 2 clusters is the greatest distance between the members of the 2 clusters. Differential gene expression was determined by using ANOVA with Tukey post hoc testing (P < 0.05 adjusted for multiple comparisons by using the Benjamini-Hochberg method) and fold change >2.
Gene expression profiles of healthy control and COPD pBECs at baseline and in response to RV-1B infection
Differential gene expression between baseline COPD pBECs and healthy control pBECs
Protease and Antiproteases
Matrix metallopeptidase 10
Peptidase inhibitor 3 (Elafin)
ADAM metallopeptidase domain 19
S100 calcium binding protein A8
S100 calcium binding protein A9
Epithelial cell related processes
Rh family, C glycoprotein
Small proline-rich protein 2E
Twenty two genes were increased in RV-1B infection of COPD pBECs but not changed RV-1B infection of healthy pBECs
Interferon, beta 1
Retinoic acid-inducible gene – I
Activating transcription factor 3
Chemokine (C-X3-C motif) ligand 1
Chemokine (C-X-C motif) ligand 9
Melanoma differentiation-associated gene −5
Zinc finger CCCH-type, antiviral 1
Phorbol-12-myristate-13-acetate-induced protein 1
DEXH (Asp-Glu-X-His) box polypeptide 58
NFS1 nitrogen fixation 1 homolog
CCR4 carbon catabolite repression 4-like
Interleukin-1 receptor-associated kinase 2
Pellino homolog 1
Nuclear receptor coactivator 7
Plasminogen activator, urokinase receptor
DEAD (Asp-Glu-Ala-Asp) box polypeptide 60
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta
Guanylate binding protein 4
Dual specificity phosphatase 19
RV-1B infection of COPD pBECs induced higher inflammatory and antiviral responses compared to healthy controls
Microarray analysis showed that COPD pBECs induced an overall higher level of inflammatory and antiviral gene expression after RV-1B infection (Additional file 1: Table S2). The increase of selected genes detected by microarray were further validated by qPCR and confirmed by ELISA at the protein level.
Surprisingly the high inflammatory and antiviral induction in COPD pBECs did not affect viral replication (Additional file 1: Figure S1 of the online supplement), as viral RNA and viral titre at 24hr was similar in healthy and COPD pBECs. RV-1B infection in both healthy and COPD pBECs resulted in a significant decrease in cell viability (Additional file 1: Figure S2A of the online supplement), however there was more apoptosis in the RV infected COPD pBECs (Additional file 1: Figure S2B and E2C of the online supplement).
The heightened inflammatory response in COPD pBECs is due to enhanced immune signalling caused by RV-1B infection
Pre-treatment with IFN-β and IFN-λ1 led to enhanced antiviral responses to RV-1B infection in both healthy and COPD pBECs
People with COPD are more susceptible to viral infection and suffer severe complications with worsened symptoms and frequent exacerbations following infection. This study investigated the transcriptional response of pBECs to RV infection and how this is altered in COPD. We show that the immune response of healthy and COPD cells was characterised by a robust up-regulation of pro-inflammatory and antiviral pathways. However there were clear differences between the COPD and healthy pBECs, including up-regulation of inflammatory genes at baseline and dramatically exaggerated responses to RV infection. We identified 9 genes associated with COPD at baseline and 22 genes altered in COPD but not healthy pBECs in response to RV, not previously reported in COPD, but likely to be important in regulating the exaggerated virus induced inflammation. The increased gene expression in RV infected COPD pBECs also correlated with the corresponding protein release, and enhanced apoptosis; however this enhanced immune response did not reduce viral titre. Furthermore, IFN-β/λ1 pre-treatment resulted in enhanced responses to RV-1B in COPD and healthy pBECs, however COPD pBECs were unresponsive in terms of MDA-5/RIG-I and IFN-β gene induction. Despite this abnormality IFN-β/λ1 pre-treatment still led to significantly reduced viral titre.
The airway epithelium in COPD is exposed chronically to enhanced airway inflammation with increased numbers of neutrophils and lymphocytes that correlate with more severe airflow obstruction, despite the fact that the majority of subjects have ceased smoking, indicating that the airway inflammatory response in COPD becomes self-perpetuating [11, 12]. We found several novel associations with 9 up-regulated genes in COPD pBECs, including the calgranulins S100A8 and S100A9, and proteases ADAM19 and MMP10. S100A8/A9 are small calcium-binding proteins with pro-inflammatory activity and have been reported to increase with steroid resistant neutrophilic inflammation . ADAM19 and MMP10 are involved in tissue repair and remodelling, and single nucleotide polymorphisms in the gene locus containing ADAM19 has been associated with COPD . These observations are consistent with other studies suggesting that the airways of COPD subjects undergo constant cellular repair due to the damages caused by cigarette smoke exposure . Interestingly MMP10 and ADAM19 gene expression has also been shown to be upregulated in pBECs from subjects with asthma .
Upon RV-1B infection, both pBEC groups mounted a robust inflammatory response; however the response was more exaggerated in COPD pBECs. This was in accordance with other studies that showed a more vigorous inflammatory response in COPD pBECs against RV infection . We have identified a number of novel genes whose expression were strongly up-regulated in COPD pBECs in response to RV-1B but not in healthy pBECs. These include important signalling molecules downstream of IL-1 and TLR2, 3 and 4 pathways such as PELI1 , IRAK2  and CH25H . We have previously shown that PELI1 and IRAK2 are up-regulated in the sputum of subjects with neutrophilic asthma . This suggests that IRAK2 and PELI1 play a role promoting neutrophilic airway inflammation, which is triggered by RV infection of the epithelium in COPD. Recently, PELI1 has been shown to be important in regulating the innate immune response of the epithelium to RV, including CXCL-8 production and neutrophil recruitment, without interfering with IFN responses and viral replication . Mouse models have shown that IRAK2 is critical in sustaining late phase inflammatory responses after TLR stimulation, leading to increased production of inflammatory cytokines . These molecules may also be important in T cell related functions, such as T cell tolerance , and promotion of Th17 cell development .
Other important signalling proteins induced by RV in COPD pBECs include PMAIP1, ATF3 and GBP4. PMAIP1, a mitochondria-associated protein, promotes apoptosis . ATF3 senses oxidative stress  and functions to reduce TLR4-mediated NF-κB signalling, therefore serving as negative feedback . GBP4 is an IFN-inducible GTPase that has been shown to disrupt IRF7 activation, thereby inhibiting the induction of type I IFNs . Also potentially important is the up-regulation of Chemokine (C-X3-C motif) ligand 1 (CX3CL1), more commonly known as fractalkine, by RV-1B in COPD pBECs. Soluble CX3CL1 has a chemo-attractant activity for T cells and monocytes; whereas membrane bound protein promotes adhesion of these leukocytes .
Antiviral responses such as IFN-β and -λ1 are critical in limiting viral replication, and were significantly higher in COPD pBECs. This was associated with the higher level of apoptosis after infection, but surprisingly did not affect viral titre in COPD, which was similar to the healthy group. This was in contrast to the study by Schneider et al. that showed enhanced antiviral responses associated with increased replication of RV-39 after infection in COPD . Other studies have examined transcriptional responses to in vivo RV infection of healthy controls using nasal epithelial scrapings , or in vitro RV infection of healthy pBECs . There are many similarities between the changes in gene expression found in reported studies compared to the current study, which includes upregulation of ISGs, antiviral genes, chemokines, and cytokines. However there are also differences in the healthy pBEC responses, including some genes previously reported to be upregulated by RV (e.g. IFNB1, and IL6) that were unchanged in this study. These differences are likely explained by altered experimental conditions, such as differing strains of RV, culture or sampling methods including submerged culture versus air-liquid interface culture versus in vitro infection, time points of RNA sampling, microarray platforms and microarray analysis methods. Nevertheless, this well controlled study adds significant knowledge regarding the differences between healthy and COPD innate immune responses to RV-1B infection under the conditions investigated, which warrant further investigation.
The underlying mechanisms of unchanged viral replication despite induced antiviral responses in COPD pBECs after RV-1B infection is currently unclear. It is possible that the IFNs produced by infection did not efficiently initiate the subsequent inductions of ISGs in COPD pBECs, therefore leading to an unchanged viral titre. However this would not explain the high apoptosis induction in COPD pBECs by RV-1B infection and marked reduction of RV-1B viral replication following IFN pre-treatment. ISGs such as protein kinase R (PKR) have been shown to induce apoptosis via the Fas-associated death domain (FADD) , and induction of which by RV-1B infection in COPD pBECs was higher compared to that in healthy pBECs. Pre-treatment with IFNs also significantly reduced viral replication, further suggesting IFN signalling leading to ISG induction may be functional in COPD. Nevertheless, it is also possible that ISGs were ineffectively up-regulated in COPD pBECs, and apoptosis could also have been induced by other signalling pathways including TNF-α/TNFR1 pathway , and compensated for the reduced ISGs production. This may explain the excess tissue damage and high inflammation that can be caused by high levels of apoptosis in the airways of those with COPD .
While we showed a heightened inflammatory response and antiviral response to RV infection in COPD pBECs in this study, we also demonstrated defects in the antiviral pathway. IFN-β/λ1 pre-treatment led to increased IL-6 and TNF-α mRNA in healthy pBECs, however this was not translated to protein production which was either reduced or unchanged with IFN-β/λ1 pre-treatment. Previous studies have shown exogenous IFN-β decreases RV-1B-induced IL-6 release from healthy and asthmatic pBECs via an unidentified pathway . IFN-β/λ1 pre-treatment also enhanced antiviral responses including MDA-5 and RIG-I, and IFN-β mRNAs in healthy pBECs, leading to marked decrease in viral titre. However, in COPD pBECs IFNs pre-treatment failed to induce MDA-5 and RIG-I and IFN-β mRNA, but did enhance CCL-5, CXCL-10, and IFN-λ1 production, resulting in a decreased viral titre. This indicates that MDA-5-initiated antiviral responses were partially impaired in COPD and led to reduced IFN-β level. It is possible that IFN-β/λ1 pre-treatment significantly up-regulated ISGs such as PKR and MxA, that bound and degraded viral RNAs as RV endocytosed into the host cells. This also suggests differential signalling pathways that regulate type III IFNs other than MDA-5/RIG-I and IFN-β. Indeed, a recent study has identified a cluster of NF-κB binding sites on human IFN-λ1 promoter, and NF-κB was critical for IFN-λ1 induction but not for type I IFNs expression . This is consistent with our results as both NF-κB and IFN-λ1were significantly up-regulated in COPD pBECs.
Apoptosis is another important component of antiviral responses, which was significantly increased in COPD pBECs after RV infection. This may correlate with the increased TNF and IFN levels , which can also up-regulate PMAIP1 gene that promotes the induction of apoptosis . However increased apoptosis did not reduce viral titre. The reason for this observation is unclear; however, it is possible that the quantification methods (TCID50) used in this study may not be as sensitive as direct quantification methods such as plaque assays. Detection of RV-1B by qPCR could only measure the level of total viral RNAs and not differentiate live from dead viruses. Alternatively, high levels of oxidative stress could have contributed to this observation. Superoxide dismutase 2 (SOD2) and ATF3 are important anti-oxidative genes that were up-regulated to a greater extent in COPD pBECs after infection when compared with infected healthy pBECs. Lack of SOD2 in mice can lead to increased oxidative damage to DNA , and lack of ATF3 alters DNA repair mechanisms . This indirectly indicates that the level of oxidative stress is higher in RV infected COPD pBECs compared to that in healthy cells.
We have demonstrated that COPD pBECs elicit excessive pro-inflammatory and antiviral responses to RV-1B infection. The greater expression of molecules such as the calgranulins at baseline and pellino-1 and IRAK2 after RV-1B infection may contribute to dysregulated innate immune responses in the airways and potentiation of inflammation as seen in COPD. Additionally, MDA-5/RIG-I and IFN-β induction to exogenous IFN-β/λ1 pre-treatment prior to infection was impaired in COPD. However IFN-λ1 induction by RV-1B infection was sufficient to limit replication in COPD pBECs. This provides novel insight in the immune responses in COPD pBECs to RV infection and may reveal potential therapeutic targets that limit the dysregulated inflammatory response due to RV infection, without compromising antiviral defences in COPD.
KJ Baines and AC-Y Hsu are joint first authors to this manuscript.
Chronic obstructive pulmonary disease
Primary bronchial epithelial cell
Quantitative real-time polymerase chain reaction
Enzyme linked immunosorbent assay
Melanoma differentiation-associated gene −5
Retinoic acid-inducible gene–I
Chemokine (C-X-C) motif ligand 10
Chemokine (C-C motif) ligand 5
Chemokine (C-X-C) motif ligand 8
- FEV1 :
Forced expiratory volume exhaled in 1 second
Global initiative for chronic obstructive lung disease
Multiplicity of infection
Tumor necrosis factor
Standard error of means
Analysis of variance.
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