Abstract
We investigated the effects of respiratory syncytial virus (RSV) infections on ovalbumin (OVA)-challenged mice via regulation of Th17/Treg cell responses. BALB/c mice were challenged with OVA, followed by RSV infections twice. In OVA-challenged mice, the secretion of Th2/Th17-type cytokines, airway hyperresponsiveness and inflammation were significantly inhibited by initial RSV infection. Moreover, the in vivo findings demonstrated that initial RSV infection reversed the imbalance of Th17/Treg responses. In contrast, RSV re-infection strengthened Th2/Th17-type cytokine secretion, airway hyperresponsiveness, and inflammation, especially for lymphocyte infiltration in OVA-challenged mice. Meanwhile, RSV re-infection enhanced the imbalanced Th17/Treg responses. Upon all results reveal that RSV-induced respiratory infections may lead to dual effects pertaining to allergic airway inflammation by regulation of Th17/Treg responses.
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Abbreviations
- OVA:
-
Ovalbumin
- RSV:
-
Respiratory syncytial virus
- AHR:
-
Airway hyperresponsiveness
- BALF:
-
Bronchoalveolar lavage fluid
- IL:
-
Interleukin
- IFN-γ:
-
Interferon-γ
- PBS:
-
Phosphate-buffered saline
- i.p.:
-
Intraperitoneal
- PFU:
-
Plaque-forming units
- H&E:
-
Hematoxylin and eosin
- PAS:
-
Periodic acid Schiff
- BSA:
-
Bovine serum albumin
- DNase I:
-
Deoxyribonuclease I
- EDTA:
-
Ethylenediaminetetraacetic acid
- FCM:
-
Flow cytometry
- Ct:
-
Threshold cycles
- PCR:
-
Polymerase chain reaction
- RL :
-
Pulmonary resistance
- Cdyn :
-
Lung dynamic compliance
- Foxp3:
-
Forkhead box P3
- RORγT:
-
Retinoid-related orphan receptor gamma t
- HBSS:
-
Hanks’ balanced salt solution
- FBS:
-
Fetal bovine serum
- DMEM:
-
Dulbecco’s modified Eagle’s medium
REFERENCES
Krishnan, V., G.B. Diette, C.S. Rand, A.L. Bilderback, B. Merriman, N.N. Hansel, and J.A. Krishnan. 2006. Mortality in patients hospitalized for asthma exacerbations in the United States. American Journal of Respiratory and Critical Care Medicine 174: 633–638.
Knudsen, T.B., S.F. Thomsen, H. Nolte, and V. Backer. 2009. A population-based clinical study of allergic and non-allergic asthma. Journal of Asthma 46: 91–94.
Hamid, Q., and M. Tulic. 2009. Immunobiology of asthma. Annual Review of Physiology 71: 489–507.
O’Connor, R.D., E.R. Bleecker, A. Long, D. Tashkin, S. Peters, D. Klingman, and B. Gutierrez. 2010. Subacute lack of asthma control and acute asthma exacerbation history as predictors of subsequent acute asthma exacerbations: evidence from managed care data. Journal of Asthma 47: 422–428.
Shaheen, S.O. 1995. Changing patterns of childhood infection and the rise in allergic disease. Clinical and Experimental Allergy 25: 1034–1037.
Zhao, J., M. Takamura, A. Yamaoka, Y. Odajima, and Y. Iikura. 2002. Altered eosinophil levels as a result of viral infection in asthma exacerbation in childhood. Pediatric Allergy and Immunology 13: 47–50.
Johnston, S.L., P.K. Pattemore, G. Sanderson, S. Smith, F. Lampe, L. Josephs, P. Symington, S. O’Toole, S.H. Myint, and D.A. Tyrrell. 1995. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. British Medical Journal 310: 1225–1229.
Nicholson, K.G., J. Kent, and D.C. Ireland. 1993. Respiratory viruses and exacerbations of asthma in adults. British Medical Journal 307: 982–986.
Sigurs, N., P.M. Gustafsson, R. Bjarnason, F. Lundberg, S. Schmidt, F. Sigurbergsson, and B. Kjellman. 2005. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. American Journal of Respiratory and Critical Care Medicine 171: 137–141.
Sigurs, N., R. Bjarnason, F. Sigurbergsson, B. Kjellman, and B. Bjorksten. 1995. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics 95: 500–505.
Murray, C.S., A. Simpson, and A. Custovic. 2004. Allergens, viruses, and asthma exacerbations. Proceedings of the American Thoracic Society 1: 99–104.
You, D., D. Becnel, K. Wang, M. Ripple, M. Daly, and S.A. Cormier. 2006. Exposure of neonates to respiratory syncytial virus is critical in determining subsequent airway response in adults. Respiratory Research 7: 107–117.
Siegle, J.S., N. Hansbro, C. Herbert, H.F. Rosenberg, J.B. Domachowske, K.L. Asquith, P.S. Foster, and R.K. Kumar. 2010. Early-life viral infection and allergen exposure interact to induce an asthmatic phenotype in mice. Respiratory Research 11: 14.
Barends, M., A. Boelen, L. de Rond, J. Kwakkel, T. Bestebroer, J. Dormans, H. Neijens, and T. Kimman. 2002. Influence of respiratory syncytial virus infection on cytokine and inflammatory responses in allergic mice. Clinical and Experimental Allergy 32: 463–471.
Barends, M., M. van Oosten, C.G. De Rond, J.A. Dormans, A.D. Osterhaus, H.J. Neijens, and T.G. Kimman. 2004. Timing of infection and prior immunization with respiratory syncytial virus (RSV) in RSV-enhanced allergic inflammation. Journal of Infectious Diseases 189: 1866–1872.
Peebles, R.S., J.R. Sheller, J.E. Johnson, D.B. Mitchell, and B.S. Graham. 1999. Respiratory syncytial virus infection prolongs methacholine-induced airway hyperresponsiveness in ovalbumin-sensitized mice. Journal of Medical Virology 57: 186–192.
Aeffner, F., and I.C. Davis. 2012. Respiratory syncytial virus reverses airway hyperresponsiveness to methacholine in ovalbumin-sensitized mice. PLoS One 7: e46660.
Munitz, A., E.B. Brandt, M. Mingler, F.D. Finkelman, and M.E. Rothenberg. 2008. Distinct roles for IL-13 and IL-4 via IL-13 receptor alpha1 and the type II IL-4 receptor in asthma pathogenesis. Proceedings of the National Academy of Sciences of the United States of America 105: 7240–7245.
Kips, J.C., K.G. Tournoy, and R.A. Pauwels. 2001. New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5. European Respiratory Journal 17: 499–506.
Lloyd, C.M., and E.M. Hessel. 2010. Functions of T cells in asthma: more than just T(H)2 cells. Nature Reviews Immunology 10: 838–848.
McKenzie, B.S., R.A. Kastelein, and D.J. Cua. 2006. Understanding the IL-23-IL-17 immune pathway. Trends in Immunology 27: 17–23.
Bettelli, E., T. Korn, M. Oukka, and V.K. Kuchroo. 2008. Induction and effector functions of T(H)17 cells. Nature 453: 1051–1057.
Bettelli, E., M. Oukka, and V.K. Kuchroo. 2007. T(H)-17 cells in the circle of immunity and autoimmunity. Nature Immunology 8: 345–350.
Chakir, J., J. Shannon, S. Molet, M. Fukakusa, J. Elias, M. Laviolette, L.P. Boulet, and Q. Hamid. 2003. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. Journal of Allergy and Clinical Immunology 111: 1293–1298.
Molet, S., Q. Hamid, F. Davoine, E. Nutku, R. Taha, N. Page, R. Olivenstein, J. Elias, and J. Chakir. 2001. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. Journal of Allergy and Clinical Immunology 108: 430–438.
Ji, X., J. Li, L. Xu, W. Wang, M. Luo, S. Luo, L. Ma, K. Li, S. Gong, and L. He. 2013. IL-4 and IL-17A provide a Th2/Th17-polarized inflammatory milieu in favor of TGF-beta1 to induce bronchial epithelial-mesenchymal transition (EMT). International Journal of Clinical and Experimental Pathology 6: 1481–1492.
Ryanna, K., V. Stratigou, N. Safinia, and C. Hawrylowicz. 2009. Regulatory T cells in bronchial asthma. Allergy 64: 335–347.
Durant, L.R., S. Makris, C.M. Voorburg, J. Loebbermann, C. Johansson, and P.J. Openshaw. 2013. Regulatory T cells prevent Th2 immune responses and pulmonary eosinophilia during respiratory syncytial virus infection in mice. Journal of Virology 87: 10946–10954.
Rudd, B.D., E. Burstein, C.S. Duckett, X. Li, and N.W. Lukacs. 2005. Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression. Journal of Virology 79: 3350–3357.
Prince, G.A., A.B. Jenson, R.L. Horswood, E. Camargo, and R.M. Chanock. 1978. The pathogenesis of respiratory syncytial virus infection in cotton rats. American Journal of Pathology 93: 771–791.
van Schaik, S.M., G. Enhorning, I. Vargas, and R.C. Welliver. 1998. Respiratory syncytial virus affects pulmonary function in BALB/c mice. Journal of Infectious Diseases 177: 269–276.
Jin, H., Q. Luo, Y. Zheng, M. Nurahmat, J. Wu, B. Li, Y. Lv, G. Wang, X. Duan, and J. Dong. 2013. CD4+CD25+Foxp3+ T cells contribute to the antiasthmatic effects of Astragalus membranaceus extract in a rat model of asthma. International Immunopharmacology 15: 42–49.
Glaab, T., A. Daser, A. Braun, U. Neuhaus-Steinmetz, H. Fabel, Y. Alarie, and H. Renz. 2001. Tidal midexpiratory flow as a measure of airway hyperresponsiveness in allergic mice. American Journal of Physiology - Lung Cellular and Molecular Physiology 280: L565–L573.
Underwood, S., M. Foster, D. Raeburn, S. Bottoms, and J.A. Karlsson. 1995. Time-course of antigen-induced airway inflammation in the guinea-pig and its relationship to airway hyperresponsiveness. European Respiratory Journal 8: 2104–2113.
Rigaux, P., K.E. Killoran, Z. Qiu, and H.F. Rosenberg. 2012. Depletion of alveolar macrophages prolongs survival in response to acute pneumovirus infection. Virology 422: 338–345.
Bosnjak, B., B. Stelzmueller, K.J. Erb, and M.M. Epstein. 2011. Treatment of allergic asthma: modulation of Th2 cells and their responses. Respiratory Research 12: 114.
Webb, D.C., A.N. McKenzie, A.M. Koskinen, M. Yang, J. Mattes, and P.S. Foster. 2000. Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity. Journal of Immunology 165: 108.
Busse, W.W., and R.F. Lemanske. 2001. Asthma. New England Journal of Medicine 344: 350–362.
McKinley, L., J.F. Alcorn, A. Peterson, R.B. Dupont, S. Kapadia, A. Logar, A. Henry, C.G. Irvin, J.D. Piganelli, A. Ray, and J.K. Kolls. 2008. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. Journal of Immunology 181: 4089–4097.
Wakashin, H., K. Hirose, Y. Maezawa, S. Kagami, A. Suto, N. Watanabe, Y. Saito, M. Hatano, T. Tokuhisa, Y. Iwakura, P. Puccetti, I. Iwamoto, and H. Nakajima. 2008. IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in mice. American Journal of Respiratory and Critical Care Medicine 178: 1023–1032.
Kaminska, M., S. Foley, K. Maghni, C. Storness-Bliss, H. Coxson, H. Ghezzo, C. Lemière, R. Olivenstein, P. Ernst, Q. Hamid, and J. Martin. 2009. Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction. Journal of Allergy and Clinical Immunology 124(45–51): e1–e4.
Milovanovic, M., G. Drozdenko, C. Weise, M. Babina, and M. Worm. 2010. Interleukin-17A promotes IgE production in human B cells. Journal of Investigative Dermatology 130: 2621–2628.
Saitoh, T., T. Kusunoki, T. Yao, K. Kawano, Y. Kojima, K. Miyahara, J. Onoda, H. Yokoi, and K. Ikeda. 2010. Role of interleukin-17A in the eosinophil accumulation and mucosal remodeling in chronic rhinosinusitis with nasal polyps associated with asthma. International Archives of Allergy and Immunology 151: 8–16.
Agache, I., C. Ciobanu, C. Agache, and M. Anghel. 2010. Increased serum IL-17 is an independent risk factor for severe asthma. Respiratory Medicine 104: 1131–1137.
Doe, C., M. Bafadhel, S. Siddiqui, D. Desai, V. Mistry, P. Rugman, M. McCormick, J. Woods, R. May, M.A. Sleeman, I.K. Anderson, and C.E. Brightling. 2010. Expression of the T helper 17-associated cytokines IL-17A and IL-17 F in asthma and COPD. Chest 138: 1140–1147.
Song, C., L. Luo, Z. Lei, B. Li, Z. Liang, G. Liu, D. Li, G. Zhang, B. Huang, and Z.H. Feng. 2008. IL-17-producing alveolar macrophages mediate allergic lung inflammation related to asthma. Journal of Immunology 181: 6117–6124.
Wilson, R.H., G.S. Whitehead, H. Nakano, M.E. Free, J.K. Kolls, and D.N. Cook. 2009. Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness. American Journal of Respiratory and Critical Care Medicine 180: 720–730.
Yamashita, T., T. Iwakura, K. Matsui, H. Kawaguchi, M. Obana, A. Hayama, M. Maeda, Y. Izumi, I. Komuro, Y. Ohsugi, M. Fujimoto, T. Naka, T. Kishimoto, H. Nakayama, and Y. Fujio. 2011. IL-6-mediated Th17 differentiation through RORγt is essential for the initiation of experimental autoimmune myocarditis. Cardiovascular Research 91: 640–648.
Weaver, C.T., and R.D. Hatton. 2009. Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective. Nature Reviews Immunology 12: 883–889.
Campbell, D.J., and S.F. Ziegler. 2007. FOXP3 modifies the phenotypic and functional properties of regulatory T cells. Nature Reviews Immunology 7: 305–310.
Boulet, L.P., H. Turcott, S. Plante, and J. Chakir. 2012. Airway function, inflammation and regulatory T cell function in subjects in asthma remission. Canadian Respiratory Journal 19: 19–25.
Boudousquie, C., C. Pellaton, N. Barbier, and F. Spertini. 2009. CD4+CD25+ T cell depletion impairs tolerance induction in a murine model of asthma. Clinical and Experimental Allergy 39: 1415–1426.
Krishnamoorthy, N., A. Khare, T.B. Oriss, M. Raundhal, C. Morse, M. Yarlagadda, S.E. Wenzel, M.L. Moore, R.S. Peebles, A. Ray, and P. Ray. 2012. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nature Medicine 18: 1525–1530.
Ito, T., S. Hanabuchi, Y.H. Wang, W.R. Park, K. Arima, L. Bover, F.X. Qin, M. Gilliet, and Y.J. Liu. 2008. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 28: 870–880.
Fu, C.L., Y.H. Chuang, L.Y. Chau, and B.L. Chiang. 2006. Effects of adenovirus-expressing IL-10 in alleviating airway inflammation in asthma. Journal of Gene Medicine 8: 1393–1399.
Eskdale, J., D. Kube, H. Tesch, and G. Gallagher. 1997. Mapping of the human IL10 gene and further characterization of the 5' flanking sequence. Immunogenetics 46: 120–128.
Zhang, L., J. Liu, E. Wang, B. Wang, S. Zeng, J. Wu, Y. Kimura, and B. Liu. 2013. Respiratory Syncytial Virus Protects Against the Subsequent Development of Ovalbumin-induced Allergic Responses by Inhibiting Th2-Type γδ T Cells. Journal of Medical Virology 85: 149–156.
Jiang, X.B., M. Huang, X.F. Cui, Y. Zhu, K.S. Yin, and K. Yao. 2012. Respiratory syncytial virus infection differentiates airway dysfunction in the central and peripheral airways in OVA-sensitized mice. Experimental Lung Research 38: 453–462.
Carroll, K.N., P. Wu, T. Gebretsadik, M.R. Griffin, W.D. Dupont, E.F. Mitchel, and T.V. Hartert. 2009. The severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma. Journal of Allergy and Clinical Immunology 123: 1055–1061.
Sigurs, N., F. Aljassim, B. Kjellman, P.D. Robinson, F. Sigurbergsson, R. Bjarnason, and P.M. Gustafsson. 2010. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax 65: 1045–1052.
Essilfie, A.T., J.L. Simpson, J.C. Horvat, J.A. Preston, M.L. Dunkley, P.S. Foster, P.G. Gibson, and P.M. Hansbro. 2011. Haemophilus influenzae infection drives IL-17-mediated neutrophilic allergic airways disease. PLoS Pathogens 7: e1002244.
Wark, P.A., S.L. Johnston, I. Moric, J.L. Simpson, M.J. Hensley, and P.G. Gibson. 2002. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. European Respiratory Journal 19: 68–75.
Gelfand, E.W., A. Joetham, Z.H. Cui, A. Balhorn, K. Takeda, C. Taube, and A. Dakhama. 2004. Induction and maintenance of airway responsiveness to allergen challenge are determined at the age of initial sensitization. Journal of Immunology 173: 1298–1306.
Burchell, J.T., M.E. Wikstrom, P.A. Stumbles, P.D. Sly, and D.J. Turner. 2009. Attenuation of allergen-induced airway hyperresponsiveness is mediated by airway regulatory T cells. American Journal of Physiology - Lung Cellular and Molecular Physiology 296: L307–L319.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China (No.81173390/H2902), the National Basic Science Program of China (No.2009CB523000), and the Shanghai Science and Technology Committee (No.09XD1400700). We gratefully acknowledge the technical assistance generously provided by Doc. Hongfu Li.
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Wang, J., Kong, L., Luo, Q. et al. Dual Effects of Respiratory Syncytial Virus Infections on Airway Inflammation by Regulation of Th17/Treg Responses in Ovalbumin-Challenged Mice. Inflammation 37, 1984–2005 (2014). https://doi.org/10.1007/s10753-014-9931-0
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DOI: https://doi.org/10.1007/s10753-014-9931-0