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

Respiratory Research

Peter AB Wark²  Peter G Gibson²  Lakshitha P Gunawardhana¹  Melinda Tooze¹  Alan C-Y Hsu¹  Katherine J Baines¹ 

[1] Virus, Infections/Immunity, Vaccines, & Asthma, Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, New Lambton Heights, NSW, Australia;Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, NSW, Australia

关键词: Gene expression;    Viral infection;    Immune response;    COPD;   

Others  :  796537
DOI  :  10.1186/1465-9921-14-15

 received in 2012-11-02, accepted in 2013-01-31,  发布年份 2013

【 摘 要 】

Background

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.

Methods

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.

Results

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.

Conclusions

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.

【 授权许可】

   
2013 Baines et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]MacNee W: Pathogenesis of Chronic Obstructive Pulmonary Disease. Proc Am Thor Soc 2005, 2:258-266.
• [2]Mallia P, Message SD, Kebadze T, Parker HL, Kon OM, Johnston SL: An experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study. Respir Res 2006, 7:116. BioMed Central Full Text
• [3]Mosser AG, Brockman-Schneider R, Amineva S, Burchell L, Sedgwick JB, Busse WW, Gern JE: Similar Frequency of Rhinovirus-Infectible Cells in Upper and Lower Airway Epithelium. J Infect Dis 2002, 185:734-743.
• [4]Gern JE, Dick EC, Lee WM, Murray S, Meyer K, Handzel ZT, Busse WW: Rhinovirus enters but does not replicate inside monocytes and airway macrophages. J Immunol 1996, 156:621-627.
• [5]Seth RB, Sun L, Chen ZJ: Antiviral innate immunity pathways. Cell Res 2006, 16:141-147.
• [6]Chaouat A, Savale L, Chouaid C, Tu L, Sztrymf B, Canuet M, Maitre B, Housset B, Brandt C, Le Corvoisier P, Weitzenblum E, Eddahibi S, Adnot S: Role for interleukin-6 in COPD-related pulmonary hypertension. Chest 2009, 136:678-687.
• [7]Costa C, Rufino R, Traves SL, Lapa ESJR, Barnes PJ, Donnelly LE: CXCR3 and CCR5 chemokines in induced sputum from patients with COPD. Chest 2008, 133:26-33.
• [8]Hsu AC, Barr I, Hansbro PM, Wark PA: Human influenza is more effective than avian influenza at antiviral suppression in airway cells. Am J Resp Cell Mol Biol 2011, 44:906-913.
• [9]Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG: Transcriptional Phenotypes of Asthma Defined by Gene Expression Profiling of Induced Sputum Samples. J Allergy Clin Immunol 2011, 127:153-160.
• [10]Hsu AC, Parsons K, Barr I, Lowther S, Middleton D, Hansbro PM, Wark PAB: Critical role of type I interferon response in bronchial epithelial cell to influenza infection. PLoS One 2012, 7:e32947.
• [11]Cornwell WD, Kim V, Song C, Rogers TJ: Pathogenesis of Inflammation and Repair in Advanced COPD. Semin Respir Crit Care Med 2010, 31:257, 266.
• [12]Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare PD: The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004, 350:2645-2653.
• [13]Bozinovski S, Cross M, Vlahos R, Jones JE, Hsuu K, Tessier PA, Reynolds EC, Hume DA, Hamilton JA, Geczy CL, Anderson GP: S100A8 Chemotactic Protein Is Abundantly Increased, but Only a Minor Contributor to LPS-Induced, Steroid Resistant Neutrophilic Lung Inflammation in Vivo. J Proteome Res 2005, 4:136-145.
• [14]Castaldi PJ, Cho MH, Litonjua AA, Bakke P, Gulsvik A, Lomas DA, Anderson W, Beaty TH, Hokanson JE, Crapo JD, Laird N, Silverman EK, COPDGene ft, and Investigators E: The Association of Genome-Wide Significant Spirometric Loci with Chronic Obstructive Pulmonary Disease Susceptibility. Am J Resp Cell Mol Biol 2011, 45:1147-1153.
• [15]Bochkov YA, Hanson KM, Keles S, Brockman-Schneider RA, Jarjour NN, Gern JE: Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma. Mucosal Immunol 2010, 3:69-80.
• [16]Schneider D, Ganesan S, Comstock AT, Meldrum CA, Mahidhara R, Goldsmith AM, Curtis JL, Martinez FJ, Hershenson MB, Sajjan U: Increased cytokine response of rhinovirus-infected airway epithelial cells in chronic obstructive pulmonary disease. Am J Resp Crit Care Med 2010, 182:332-340.
• [17]Chang M, Jin W, Sun SC: Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production. Nat Immunol 2009, 10:1089-1095.
• [18]Keating SE, Maloney GM, Moran EM, Bowie AG: IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF-6 ubiquitination. J Biol Chem 2007, 282:33435-33443.
• [19]Diczfalusy U, Olofsson KE, Carlsson A-M, Gong M, Golenbock DT, Rooyackers O, FlÃring U, BjÃrkbacka H: Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide. J Lipid Res 2009, 50:2258-2264.
• [20]Bennett JA, Prince LR, Parker LC, Stokes CA, De Bruin HG, Van Dern Berge M, Heijink IH, Whyte MK, Sabroe I: Pellino-1 Selectively Regulates Epithelial Cell Responses to Rhinovirus. J Virol 2012. epub ahead of print 18 April
• [21]Kawagoe T, Sato S, Matusushita K, Kato H, Matsui K, Kumagai Y, Saitoh T, Kawai T, Takeuchi O, Akira S: Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol 2008, 9:684-691.
• [22]Jin W, Chang M, Sun SC: Peli: a family of signal-responsive E3 ubiquitin ligases mediating TLR signaling and T-cell tolerance. Cell Mol Immunol 2012, 9:113-122.
• [23]Smith PM, Jacque B, Conner JR, Poltorak A, Stadecker MJ: IRAK-2 Regulates IL-1-Mediated Pathogenic Th17 Cell Development in Helminthic Infection. PloS Pathog 2011, 7:e1002272.
• [24]Sun Y, Leaman DW: Involvement of Noxa in Cellular Apoptotic Responses to Interferon, Double-stranded RNA, and Virus Infection. J Biol Chem 2005, 280:15561-15568.
• [25]Chen BP, Wolfgang CD, Hai T: Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10. Mol Cell Biol 1996, 16:1157-1168.
• [26]Suganami T, Yuan X, Shimoda Y, Uchio-Yamada K, Nakagawa N, Shirakawa I, Usami T, Tsukahara T, Nakayama K, Miyamoto Y, Yasuda K, Matsuda J, Kamei Y, Kitajima S, Ogawa Y: Activating Transcription Factor 3 Constitutes a Negative Feedback Mechanism That Attenuates Saturated Fatty Acid/Toll-Like Receptor 4 Signaling and Macrophage Activation in Obese Adipose Tissue. Circ Res 2009, 105:25-32.
• [27]Hu Y, Wang J, Yang B, Zheng N, Qin M, Ji Y, Lin G, Tian L, Wu X, Wu L, Sun B: Guanylate binding protein 4 negatively regulates virus-induced type I IFN and antiviral response by targeting IFN regulatory factor 7. J Immunol 2011, 187:6456-6462.
• [28]Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ: A new class of membrane-bound chemokine with a CX3C motif. Nature 1997, 385:640-644.
• [29]Schneider D, Ganesan S, Comstock AT, Meldrum CA, Mahidhara R, Goldsmith AM, Curtis JL, Martinez FJ, Hershenson MB, Sajjan U: Increased cytokine response of rhinovirus-infected airway epithelial cells in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010, 182:332-340.
• [30]Proud D, Turner RB, Winther B, Wiehler S, Tiesman JP, Reichling TD, Juhlin KD, Fulmer AW, Ho BY, Walanski AA, Poore CL, Mizoguchi H, Jump L, Moore ML, Zukowski CK, Clymer JW: Gene Expression Profiles during In Vivo Human Rhinovirus Infection: Insights into the Host Response. Am J Respir Crit Care Med 2008, 178:962-968.
• [31]Chen Y, Hamati E, Lee P-K, Lee W-M, Wachi S, Schnurr D, Yagi S, Dolganov G, Boushey H, Avila P, Wu R: Rhinovirus Induces Airway Epithelial Gene Expression through Double-Stranded RNA and IFN-Dependent Pathways. American Journal of Respiratory Cell and Molecular Biology 2006, 34:192-203.
• [32]Gil J, Esteban M: The interferon-induced protein kinase (PKR), triggers apoptosis through FADD-mediated activation of caspase 8 in a manner independent of Fas and TNF-alpha receptors. Oncogene 2000, 19:3665-3674.
• [33]Micheau O, Tschopp J: Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003, 114:181-190.
• [34]Hodge S, Hodge G, Holmes M, Reynolds PN: Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation. Eur Respir J 2005, 25:447-454.
• [35]Cakebread JA, Xu Y, Grainge C, Kehagia V, Howarth PH, Holgate ST, Davies DE: Exogenous IFN-beta has antiviral and anti-inflammatory properties in primary bronchial epithelial cells from asthmatic subjects exposed to rhinovirus. J Allergy Clin immunol 2011, 127:1148-1154. e9
• [36]Thomson SJ, Goh FG, Banks H, Krausgruber T, Kotenko SV, Foxwell BM, Udalova IA: The role of transposable elements in the regulation of IFN-lambda1 gene expression. Proc Natl Acad Sci U S A 2009, 106:11564-11569.
• [37]Chawla-Sarkar M, Lindner DJ, Liu YF, Williams BR, Sen GC, Silverman RH, Borden EC: Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. Apoptosis 2003, 8:237-249.
• [38]Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A: Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics 2003, 16:29-37.
• [39]Turchi L, Fareh M, Aberdam E, Kitajima S, Simpson F, Wicking C, Aberdam D, Virolle T: ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress. Cell Death Differ 2009, 16:728-737.