Rhinoviruses in the pathogenesis of asthma: The bronchial epithelium as a major disease target

Abstract

In the 1950s and early 1960s, David Tyrrell described newly identified small RNA viruses, human rhinoviruses (HRVs), as the cause of the common cold. With more than 100 serotypes comprising major and minor subgroups, HRVs preferentially infect nasal epithelial cells through the intercellular adhesion molecule 1 and low-density lipoprotein receptors, respectively. Virus internalization also involves activation of the acid sphyngomyelinase, which transforms membrane rafts into ceramide-enriched membrane platforms, followed by activation of p38 mitogen-activated protein kinase by the small G protein Rho A. Until the 1990s, HRVs could only be identified by their cytopathic effect on cultured He La cells; however, the advent of improved nucleic acid–based detection methods has provided a diagnostic tool for this and other respiratory viruses.1Garbino J. Gerbase M.W. Wunderli W. Deffernez C. Thomas Y. Rochat T. et al.Lower respiratory viral illnesses: improved diagnosis by molecular methods and clinical impact.Am J Respir Crit Care Med. 2004; 170: 1197-1203Crossref PubMed Scopus (115) Google Scholar, 2Lee B.E. Robinson J.L. Hurana V. Pang X.L. Preiksaitis J.K. Fox J.D. Enhanced identification of viral and atypical bacterial pathogens in lower respiratory tract samples with nucleic acid amplification tests.J Med Virol. 2006; 78: 702-710Crossref PubMed Scopus (42) Google Scholar Stress and a lowering of body temperature predispose to HRV infection, but usually the symptoms are mild and transient, being limited to corrhyza and pharyngitis,3Winther B. Hayden F.G. Hendley J.O. Picornavirus infections in children diagnosed by RT-PCR during longitudinal surveillance with weekly sampling: Association with symptomatic illness and effect of season.J Med Virol. 2006; 78: 644-650Crossref PubMed Scopus (150) Google Scholar with virus nucleic acid being detected in nasopharyngeal,4Pitkaranta A. Roivainen M. Blomgren K. Peltola J. Kaijalainen T. Ray R. et al.Presence of viral and bacterial pathogens in the nasopharynx of otitis-prone children. A prospective study.Int J Pediatr Otorhinolaryngol. 2006; 70: 647-654Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar tonsillar,5Suvilehto J. Roivainen M. Seppanen M. Meri S. Hovit T. Carpen O. et al.Rhinovirus/enterovirus RNA in tonsillar tissue of children with tonsillar disease.J Clin Virol. 2006; 35: 292-297Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar and middle ear6Nosko-Koivisto J. Raty R. Blomqvist S. Kleemola M. Syrjanen R. Pitkaranta A. et al.Presence of specific viruses in the middle ear fluids and respiratory secretions of young children with acute otitis media.J Med Virol. 2004; 72: 241-248Crossref PubMed Scopus (76) Google Scholar fluids. The ability to identify respiratory viruses by their nucleic acid signatures in nasal and lower airway secretions using PCR-based technology led to a series of studies demonstrating the presence of respiratory viruses in 60% to 93% of acute exacerbations of asthma in children and adults with a particular propensity during the fall, winter, and early spring months, when, at a community level, infection with these viruses is most prevalent.7Johnston S.L. Pattemore P.K. Sanderosn G. Smith S. Campbell M.J. Joseph L.K. et al.The relationship between upper respiratory infections and hospital admissions for asthma: a time trend analysis.Am J Respir Crit Care Med. 1996; 154: 654-660Crossref PubMed Scopus (490) Google Scholar The majority of respiratory virus infections are caused by HRVs. Experimental infection of subjects with mild asthma followed by bronchial biopsy has demonstrated virus RNA to be largely restricted to epithelial cells but also present in some mononuclear cells and fibroblasts.8Papadopoulos N.G. Bates P.J. Bardin P.G. Papi A. Leir S.H. Fraenkel D.J. et al.Rhinoviruses infect the lower airways.J Infect Dis. 2000; 181: 1875-1884Crossref PubMed Scopus (436) Google Scholar, 9Mosser A.G. Vrtis R. Burchell L. Lee W.M. Dick C.R. Weisshaar E. et al.Quantitative and qualitative analysis of rhinovirus infection in bronchial tissues.Am J Respir Crit Care Med. 2005; 171: 645-651Crossref PubMed Scopus (181) Google Scholar In vitro, HRV has also been shown to infect smooth muscle cells, but as in the case of macrophages, despite enhancing certain cellular functions,10Gern J.E. Dick E.C. Lee W.M. Murray S. Meyer K. Hardzel Z.T. et al.Rhinovirus enters but does not replicate inside monocytes and airway macrophages.J Immunol. 1996; 56: 621-627Google Scholar, 11Oliver B.G. Johnston S.L. Baraket M. Burgess J.K. King N.J. Roth M. et al.Increased pro-inflammatory responses from asthmatic human airway smooth muscle cells in response to rhinovirus infection.Respir Res. 2006; 7 ([Epub ahead of print]): 71Crossref PubMed Scopus (65) Google Scholar HRVs are unable to replicate in these cells. A high proportion of infant wheezing is associated with HRV infection.12Korppi M. Kotaniemi-Syrjanen A. Waris M. Vainionpaa R. Reijonen T.M. Rhinovirus-associated wheezing in infancy: comparison with respiratory syncytial virus bronchiolitis.Pediatr Infect Dis J. 2004; 23: 995-999Crossref PubMed Scopus (138) Google Scholar The children with HRV infection, when compared with those with respiratory syncytial virus (RSV) infection, were older (13 vs 5 months) and presented more frequently with atopic dermatitis (odds ratio [OR] 16.7; 95% CI, 2.22-100) and blood eosinophilia (OR, 2.22; 95% CI, 1.04-50), suggesting a pathophysiologic link to asthma. A French study of 192 infants age 3 years or less hospitalized for acute bronchiolitis13Jacques J. Bouscambert-Duchamp M. Moret H. Carquin J. Brodard V. Lina B. et al.Association of respiratory picornaviruses with acute bronchiolitis in French infants.J Clin Virol. 2006; 35: 463-466Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar revealed a causative virus in 72.5% of cases comprising RSV (30%), HRV (21%), enterovirus (9%), influenza A (6%), and human metapneumovirus (4%), with some mixed infections. In this issue of the Journal of Allergy and Clinical Immunology, Malmström et al14Malmström K. Pitkäranta A. Carpen O. Pelkonen A. Human rhinovirus in bronchial epithelium of infants with recurrent respiratory symptoms.J Allergy Clin Immunol. 2006; 118: 591-596Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar have evaluated the presence of HRV in the lower respiratory tracts of corticosteroid-naive infants age 3 to 26 months with recurrent respiratory symptoms by using in situ hybridization applied to lower airway biopsy specimens. They detected HRV RNA localized to the epithelium in 45% of biopsy specimens associated with abnormal lung function measured as decreased airway conductance in 86% of HRV-positive versus 58% of HRV-negative infants. For ethical reasons, the authors were unable to use healthy control subjects. However, acknowledging this limitation, these unique findings strengthen the potential pathophysiologic role for HRV in infant wheezing and asthma. In a further study of 81 children in Finland who had been hospitalized for wheezing at less than 2 years of age, evaluation during the third year of life revealed asthma in 40% of children, of whom 90% were atopic. In this study early predictors of asthma were atopic dermatitis (OR, 3.5; 95% CI, 1.2-10.1), specific IgE (OR, 3.5; 95% CI, 1.2-10.1), and inhalant allergy (OR, 11.3; 95% CI, 1.9-67.6). The authors also reported that RSV during the wheezing episodes in infancy was relatively rare, but in contrast, HRV infection was common (58%).12Korppi M. Kotaniemi-Syrjanen A. Waris M. Vainionpaa R. Reijonen T.M. Rhinovirus-associated wheezing in infancy: comparison with respiratory syncytial virus bronchiolitis.Pediatr Infect Dis J. 2004; 23: 995-999Crossref PubMed Scopus (138) Google Scholar An important feature of this study was the fact that the infants subjected to bronchoscopy had been symptomatic for a median period of 6 months before airway biopsy and therefore were at special risk of asthma. A recent study by Xatzipsalti et al15Xatzipsalti M. Kyrama S. Tsolia M. Psarras S. Bossios A. Laza-Stanca V. et al.Rhinovirus viraemia in children with respiratory infections.Am J Respir Crit Care Med. 2005; 172: 1037-1040Crossref PubMed Scopus (92) Google Scholar has shown that in hospital admissions for wheezing illness, those infants who had asthma when compared with those without asthma, were at greatest risk of having circulating HRV detected by means of PCR for up to 6 weeks after infection, suggesting that in asthma there is a defect in epithelial barrier function. An association between HRV infection in infancy and the later development of asthma has been reported by Lemanske et al,16Lemanske Jr., R.F. Jackson D.J. Gangnon R.E. Evans M.D. Li Z. Shult P.A. et al.Rhinovirus illnesses during infancy predict subsequent childhood wheezing.J Allergy Clin Immunol. 2005; 116: 571-577Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar who have shown that in a population of 285 children genetically at risk for asthma studied during the first 3 years of life, HRV infection in the first year was the greatest risk factor for persistent wheezing in the third year (OR, 10.0), with 63% of infants who wheezed during RV seasons continuing to wheeze in the third year when compared with only 20% of all other infants (OR, 6.6). Other respiratory viruses, including RSV, also increased the risk of persistent wheezing at age 3 years but to a substantially lesser degree than observed with HRV. The authors suggest symptomatic HRV illness during infancy is likely to be an important risk factor for the development of asthma. Heymann et al17Heymann P.W. Carper H.T. Murphy D.D. Platts-Mills T.A. Patrie J. McLaughlin A.P. et al.Viral infections in relation to age, atopy and season of admission among children hospitalised for wheezing.J Allergy Clin Immunol. 2004; 114 (239-7)Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar came to a similar conclusion that viral infections, especially HRV, were the dominant risk factor for wheezing among children hospitalized before age 3 years, whereas in those aged 3 to 18 years, this was replaced by atopy as the dominant risk factor. A key question arising from these studies is whether atopy and associated allergic inflammation is the cause of asthma or whether some primary abnormality in the airways epithelium, possibly revealed by virus infection, predisposed individuals to express their atopy as asthma. The recent discovery that airway epithelial cells are deficient in their capacity to generate interferon-β (IFN-β) when infected with HRV18Wark P.A. Johnston S.L. Bucchieri F. Powell R. Puddicombe S. Laza-Stanca V. et al.Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus.J Exp Med. 2005; 201: 937-947Crossref PubMed Scopus (971) Google Scholar raises the possibility that a defect in innate immunity might underlie the origins and persistence of asthma. The normal response of the airway epithelium to virus infection is the induction of primary IFNs, such as IFN-β, through activation of the Toll-like receptor 3, which recognizes viral double-stranded RNA, leading to apoptosis that is able to effectively eliminate the infected cell and therefore limit viral replication and release. However, in asthmatic epithelial cells a major defect in this pathway leads to enhanced viral replication and virus-induced cell cytotoxicity. Evidence that this pathway might be relevant to the persistence of asthma, as well as exacerbations, comes from the demonstration that in asthmatic patients HRV can persist up to 6 weeks after infection19Jartti T. Lehtinen P. Vuorinen T. Koskenvuo M. Ruuskanen O. Persistence of rhinovirus and enterovirus RNA after acute respiratory illness in children.J Med Virol. 2004; 72: 695-699Crossref PubMed Scopus (226) Google Scholar, 20Kling S. Donninger H. Williams Z. Vermeulen J. Weinberg E. Lattif K. et al.Persistence of rhinovirus RNA after asthma exacerbation in children.Clin Exp Allergy. 2005; 35: 672-678Crossref PubMed Scopus (112) Google Scholar and that in patients with severe asthma HRV is detectable in airway biopsy specimens between exacerbations.21Crisafi G.M. Billmeyer E.E. Sorkness R.L. Jarjour N.N. Busse W.W. The detection of rhinovirus RNA in severe asthma.Proc Am Thorac Soc. 2006; 3 ([abstract]): A15Google Scholar There is also evidence to suggest that in asthma the coexistence of atopy enhances the clinical effect of HRV infection and both prolongs and enhances airway hyperresponsiveness.22Xepapadaki P. Papadopoulos N.G. Bossios A. Manoussakis E. Manousakas T. Saxoni-Papegeorgiou P. Duration of postviral airway hyperresponsiveness in children with asthma: effect of atopy.J Allergy Clin Immunol. 2005; 116: 299-304Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar The mechanisms through which HRV leads to altered airway function associated with exacerbations is not known for certain, but in addition to the enhanced cell cytotoxicity observed in asthmatic epithelial cells,18Wark P.A. Johnston S.L. Bucchieri F. Powell R. Puddicombe S. Laza-Stanca V. et al.Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus.J Exp Med. 2005; 201: 937-947Crossref PubMed Scopus (971) Google Scholar infection with HRV induces mucin production,23Inoue D. Yamaya M. Kubo H. Sasaki T. Hosoda M. Numassaki M. et al.Mechanisms of mucin production by rhinovirus infection in cultured human airway epithelial cells.Respir Physiol Neurobiol. 2005; (Dec 22 [Epub ahead of print])Google Scholar delays epithelial repair,24Bossios A. Psarras S. Gourgiotis D. Skevaki C.L. Constantopoulos A.G. Saxoni-Papageorgious P. et al.Rhinovirus infection induces cytotoxicity and delays wound healing in bronchial epithelial cells.Respir Res. 2005; 6: 114Crossref PubMed Scopus (69) Google Scholar induces cytokine and chemokine release to recruit secondary effector cells,25Edwards M.R. Johnson M.W. Johnston S.L. Combination therapy: synergistic suppression of virus-induced chemokines in airway epithelial cells.Am J Respir Cell Mol Biol. 2006; 34: 616-624Crossref PubMed Scopus (91) Google Scholar and promotes the production of growth factors.26De Silva D. Dagher H. Ghildyal R. Lindsay M. Li X. Freezer N.J. et al.Vascular endothelial growth factor induction by rhinovirus infection.J Med Virol. 2006; 78: 666-672Crossref PubMed Scopus (26) Google Scholar The inability of the asthmatic airway epithelium to effectively defend the lung against what is normally an innocuous virus raises the possibility of this being part of a broader epithelial defect relevant to asthma pathogenesis. The recent discovery of filaggrin as a key molecule involved in maintaining epithelial integrity and its dysfunction in atopic dermatitis and asthma27Palmer C.N. Irvine A.D. Terron-Kwiatowski A. Zhao Y. Liao H. Lee S.P. et al.Common loss-of-function variants of the epithelial barrier protein filaggrin are a major predisposing factor for atopic dermatitis.Nat Genet. 2006; 38: 441-446Crossref PubMed Scopus (2216) Google Scholar adds support to the view that diseases such as eczema and asthma are disorders of the epithelium rather than primarily being diseases of the adaptive immune response. A high proportion of the novel genes identified by positional cloning in asthma are epithelial in origin (eg, ESE3, DPP10, HLA-G, GPRA, PCDH-1, and filaggrin). A reduced ability of the airway epithelium to defend itself against multiple environmental insults could help explain why so many different environmental factors are risk factors for the development of asthma (eg, domestic chemicals, environmental tobacco smoke, outdoor and indoor air pollutants, allergens, and viruses). In addition to an impaired innate response to virus infection, asthmatic airway epithelial cells cultured and differentiated on an air-liquid interface exhibit reduced transepithelial electrical resistance that, when compared with normal epithelial cells, decreases further on exposure to irritants, such as tobacco smoke extract.28Puddicombe S.M. Xiao C. Haynes R. Martin S.A. Holgate S.T. Davies D.E. Epithelial barrier integrity is impaired in cultured bronchial epithelial cells (BECs) differentiated in vitro.Proc Am Thorac Soc. 2006; 3 ([abstract]): A424Crossref PubMed Scopus (135) Google Scholar This decrease in transepithelial electrical resistance is explained by deficient formation of tight junctions and organizations of their constituent proteins that include occludin, ZO1, and the claudins. Such a fundamental barrier defect would serve to facilitate the passage of inhaled environmental materials from the surface into the airway wall, thereby augmenting inflammatory process in the airway wall. Thus, by interacting with environmental insults, such as virus infections and pollutants, the airways in asthma might be reacting as a chronic wound in which defective epithelial repair delays healing and maintains inflammation.29Holgate S.T. Davies D.E. Lackie P.M. Wilson S.J. Puddicombe S.M. Lordan J.L. 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Epidermal growth factor enemas with oral mesalamine for mild to moderate left-sided ulcerative colitis proctitis.N Engl J Med. 2003; 349: 350-357Crossref PubMed Scopus (276) Google Scholar to accelerate mucosal healing and keratinocyte growth factor to protect the oral mucosa from ulceration (mucositis) during cancer chemotherapy.36Finch P.W. Rubin J.S. Keratinocyte growth factor/fibroblast growth factor 7, a homeostatic factor with therapeutic potential for epithelial protection and repair.Adv Cancer Res. 2004; 91: 69-136Crossref PubMed Scopus (190) Google Scholar One therapy currently being investigated in asthma is synthetic surfactant, inhalation of which has been shown to protect against allergen-induced bronchoconstriction,37Babu K.S. Woodcock D.A. Smith S.E. Staniforth J.N. Holgate S.T. Conway J.H. Inhaled synthetic surfactant abolishes the early allergen-induced response in asthma.Eur Respir J. 2003; 21: 1046-1049Crossref PubMed Scopus (52) Google Scholar possibly by acting as a barrier because endogenous surfactant production is also deficient in asthma.38Wright S.M. Hockey P.M. Enhorning G. Strong P. Reid K.B. Holgate S.T. et al.Altered airway surfactant phospholipids composition and reduced lung function in asthma.J Appl Physiol. 2000; 89: 1283-1292Crossref PubMed Scopus (117) Google Scholar Finally, with the population continuing to age, it should not be forgotten that HRV infection is a major cause of lower airway problems in the elderly,39Hicks L.A. Shepard C.W. Britz P.H. Erdmann D.D. Fischer M. Flannery B.L. et al.Two outbreaks of severe respiratory disease in nursing homes associated with rhinovirus.J Am Geriatr Soc. 2006; 54: 284-289Crossref PubMed Scopus (61) Google Scholar, 40Louie J.K. Yagi S. Nelson F.A. Kieng D. Glaser C.A. Rosenberg J. et al.Rhinovirus outbreak in a long term core facility for elderly persons associated with unusually high mortality.Clin Infect Dis. 2005; 41: 262-265Crossref PubMed Scopus (87) Google Scholar especially in those with chronic obstructive pulmonary disease.41Wilkinson T.M. Hurst J.R. Perera W.R. Wilks M. Donaldson G.C. Wedzicha J.A. Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations.Chest. 2006; 129: 317-324Crossref PubMed Scopus (246) Google Scholar The recent discovery that the airway epithelial cells of patients with chronic obstructive pulmonary disease and smokers also deficient in IFN-β production and are even more sensitive to the cytotoxic effects of HRVs42Bucchieri F. Wark P. Foo S.W. Ribbene A. Djukanobvic R. Holgate S.T. et al.Bronchial epithelial cells from smokers have a poor innate immune response to infection with rhinovirus.Proc Am Thorac Soc. 2006; 3 ([abstract]): A842Google Scholar raises the possibility that with smoking or aging, the IFN-β pathway is compromised, thereby increasing the risk of severe, acute lower airway infection. Although generally a benign virus, HRV is teaching us that both in the origins and exacerbations of asthma, as well as in the elderly and those who smoke, altered innate immunity increases the risk of significant common lung diseases. Asthma is a complex disorder that in many cases involves allergic pathways, but increasingly, research is steering us away from simply thinking of the disorder solely in terms of allergic inflammatory mechanisms and redirecting us to the target organ, which is likely to be the prime origin of disease susceptibility.