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The Proceedings of the American Thoracic Society 4:267-270 (2007)
© 2007 The American Thoracic Society
doi: 10.1513/pats.200701-030AW
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Innate Immunity in the Pathogenesis of Virus-induced Asthma Exacerbations

Sebastian L. Johnston1

1 Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and Immunity, Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom

Correspondence and requests for reprints should be addressed to Professor Sebastian L. Johnston, M.D., Ph.D., Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and Immunity and MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, Norfolk Place, London W2 1PG, UK. E-mail: s.johnston{at}imperial.ac.uk

ABSTRACT

The major asthma morbidity, mortality, and health care costs are a result of acute exacerbations. However, exacerbations are only partially responsive to current therapies and new approaches to treatment are needed. The great majority of acute asthma exacerbations are associated with respiratory viral infections and, of viruses implicated, approximately 60% are human rhinoviruses (RVs). The mechanisms of RV-induced asthma exacerbations are poorly understood. We have previously shown that adults with asthma have increased susceptibility to naturally occurring RV infections. Our recent studies have investigated mechanisms of innate host defense against RV infection. First, primary bronchial epithelial cells from subjects with asthma were shown to replicate RV in vitro to several logs, whereas those of normal control subjects were resistant to infection. This resistance was a result of rapid induction of apoptosis and of interferon (IFN)-ß in the normal cells, whereas these responses were deficient in asthmatic cells. These studies were recently extended to a novel family of three related proteins, the IFN-{lambda}s 1–3, production of which was also deficient in vitro and related to asthma exacerbation severity in vivo. These studies identify novel mechanisms for the increased susceptibility of subjects with asthma to RV infection. Further studies are now required to investigate whether administration of IFN-ß or IFN-{lambda} may be beneficial in the treatment of asthma exacerbations, to determine whether similar deficiencies are observed in children and in subjects with nonatopic asthma, and to investigate the mechanisms of deficient IFN production in asthma to help identify better therapeutic strategies for asthma exacerbations.

Key Words: virus infections • asthma • innate immunity

OCCURRENCE AND TREATMENT OF ASTHMA EXACERBATIONS

Asthma prevalence has increased over recent decades, such that approximately 30% of children now report wheeze in the last year (1). The major morbidity, mortality, and health care costs related to asthma are a result of acute exacerbations (2). Inhaled steroids are the mainstay of asthma treatment and their use is associated with reduced risk of exacerbation (3, 4); however, in adults they reduce exacerbation frequency by only approximately 40% even when used in combination with long-acting ß2-agonist therapy (5). In school-age children, prophylactic inhaled steroids were ineffective at reducing exacerbation frequency, duration, or severity (6), and in preschool children, oral steroids were also ineffective (7). Current therapy is thus of limited efficacy and development of more effective therapies is urgently needed. This requires understanding the etiology and mechanisms of asthma exacerbations.

VIRAL ETIOLOGY OF ASTHMA EXACERBATIONS

Respiratory viral infections are detected in the great majority of asthma exacerbations in both children (80–85%) (8, 9) and adults (75–80%) (10, 11); of these, approximately 60% are rhinoviruses (RVs). However, the mechanisms of RV-induced asthma exacerbations are poorly understood.

INCREASED SUSCEPTIBILITY TO RV INFECTION IN ASTHMA

Adults with asthma have increased susceptibility to naturally occurring RV infection in that they have increased severity and duration of lower respiratory symptoms and reductions in lung function when compared with similarly infected normal subjects (12). However, until recently, the mechanism(s) behind this increased susceptibility were not known.

MECHANISMS OF INCREASED SUSCEPTIBILITY TO RV INFECTIONS IN ASTHMA

We have identified novel mechanisms behind this increased susceptibility by showing that atopic adults with asthma have defective innate immune responses to RV infection in vitro (13, 14), which are related to markers of exacerbation severity in vivo (14).

Increased RV Replication in Bronchial Epithelial Cells In Vitro
Using in vitro–cultured primary bronchial epithelial cells (BECs) from atopic subjects with asthma and normal volunteers, we observed that BECs from donors with asthma had a profoundly abnormal response to infection with the major RV group, RV-16, resulting in efficient viral replication leading to cell lysis, whereas, in contrast, cells from healthy control subjects were almost completely resistant to infection and cell lysis was not detected (13), confirming the increased susceptibility to RV infection observed in clinical studies (12).

Increased Replication Is Independent of Receptor Expression
A similar response was observed when BECs were infected with the minor RV group, RV-1B, which gains entry into cells via the low density lipoprotein (LDL) receptor (15) rather than the intercellular adhesion molecule (ICAM)–1, which is used by the major RV groups, including RV-16 (16). Thus, the abnormal asthmatic BEC response to RV is a function of altered intracellular signaling rather than any difference in ICAM-1 expression and viral entry.

Deficient Viral Induction of Apoptosis in Asthmatic BECs
Having found increased RV replication in asthmatic BECs, we next investigated mechanisms of innate antiviral immunity. Rapid induction of apoptosis of a virus-infected cell is a vital aspect of innate protection, because successful induction of apoptosis will abort infection and allow the infected cell to be phagocytosed without release of inflammatory mediators, whereas in contrast, an infected cell failing to undergo apoptosis will replicate virus and undergo cell death by cell lysis, releasing large amounts of proinflammatory mediators and releasing large numbers of progeny viruses to continue infection of neighboring cells.

We therefore studied apoptotic responses in RV-infected asthmatic and normal BECs, and found early induction of apoptosis to be profoundly impaired in the asthmatic cells (13). We confirmed the importance of apoptosis in host defense against RV infection by inhibiting apoptosis pharmacologically in normal cells and observing that this rendered them as susceptible to RV infection as asthmatic cells.

Deficient Interferon-ß Production in Asthmatic BECs
Type I interferons (IFNs) ({alpha}/ß IFNs) are an important component of the innate immune response, inducing an antiviral state in infected and neighboring cells via induction of apoptosis (17) and in proteins with direct antiviral activity. We therefore analyzed IFN-ß responses to RV infection of asthmatic and normal primary BECs. We studied IFN-ß because it is induced early and is important in inducing both more of itself and IFN-{alpha} through autocrine/paracrine mechanisms. We found asthmatic cells to be profoundly deficient in RV-induced IFN-ß production. Furthermore, there was a highly significant inverse correlation between IFN-ß production and viral load, confirming that IFN-ß responses were linked to RV replication (13).

IFN-ß Signaling Is Intact in Asthmatic BECs
We next showed that exogenous IFN-ß induced apoptosis of RV-infected asthmatic BECs and that it restored the innate antiviral response in asthmatic cells, inhibiting RV replication to levels similar to those observed in normal BECs. This suggests that signaling pathways downstream of the type I IFN receptor, leading to activation of apoptosis and induction of antiviral proteins, are intact.

The Novel Type III IFNs
The 13 {alpha} IFNs and one ß IFN are expressed on chromosome 9 and are classed as type I IFNs because they signal through a common type I IFN receptor and have similar biologic properties in innate host defense. The single class II IFN is IFN-{gamma}, which signals through the IFN-{gamma} receptor and is important in both innate and acquired immunity. A novel class of IFNs has recently been discovered and named type III IFNs. These include IFN-{lambda}1 (also known as IL-29) and IFN-{lambda}2/3 (IL-28A/B), which are expressed on chromosome 19 and signal through a unique IFN-{lambda}–specific receptor (18, 19). The IFN-{lambda}s share significant homology between {lambda}1 and {lambda}2/3 (80%) and between {lambda}2 and {lambda}3 (96%). However, they share only limited (20%) homology with type I IFNs. Similar to type I IFNs, they induce IFN-stimulated genes (ISGs), signal via Jak/STAT (signal transducer and activator of transcription) pathways, and have antiviral activity in vitro (18, 19). However, little is known regarding their role in human diseases.

Deficient Type III IFN Production in Asthmatic BECs
To investigate the role of IFN-{lambda}s in RV-induced asthma, we first investigated their expression and induction in response to RV infection of BEAS2B cells. RV replication induced mRNA expression for IFN-{lambda}1 and IFN-{lambda}2/3, accompanied by IFN-{lambda} protein release assessed by an ELISA cross-reactive for IFN-{lambda}1 and IFN-{lambda}2/3 (14). IFN-{lambda}s also induced ISGs and had direct antiviral activity, suppressing both vRNA production and RV release into supernatants.

Having confirmed that RV induction of IFN-{lambda} occurred in BECs, and that they possessed antiviral properties similar to type I IFNs, we next investigated primary BECs. Similar to IFN-ß, we observed deficient production of the IFN-{lambda}s in atopic asthmatic primary BECs in vitro, and IFN-{lambda} production was strongly related to viral replication in vitro (14).

Deficient Type III IFN Production in Asthmatic Macrophages
Deficient RV induction of IFN-ß and IFN-{lambda}s in asthmatic BECs suggests a possible cell type–specific defect in IFN production in asthma. We therefore investigated peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages and confirmed that RV induced robust production of IFN-{lambda}s in both. We then studied bronchoalveolar lavage (BAL) cells (~ 90% macrophages) from a newly recruited group of atopic subjects with asthma and normal volunteers and confirmed that RV induction of IFN-{lambda}s occurred in normal cells, but was profoundly deficient in asthmatic BAL cells (14).

Deficient IFN-{lambda} Production In Vitro in Asthma Is Related to Markers of Exacerbation Severity In Vivo
The volunteer subjects with asthma and the normal control volunteers were then experimentally infected with RV-16 in vivo, and IFN-{lambda} production by BAL cells in vitro was significantly related to several markers of asthma exacerbation severity (viral load, clinical symptoms, reductions in lung function, airway hyperresponsiveness, and airway inflammation) in vivo (14).

Deficient IFN Production in Asthma Is Independent of Steroid Treatment
Similar deficient IFN-ß responses were seen in BECs derived from subjects with asthma receiving moderate doses of inhaled steroids and subjects with asthma who had not been treated with inhaled corticosteroids (13, 14); furthermore, exposure of BECs to dexamethasone in vitro had no effect on IFN-ß production or viral replication (13), confirming that these defects are independent of steroid treatment in vitro and in vivo and consistent with the relative ineffectiveness of corticosteroids in virus-induced asthma (6, 7).

Deficient IFN-{alpha} Production in PBMCs from Adults with Asthma
Others have also recently reported deficient IFN-{alpha}2 production from asthmatic PBMCs stimulated with respiratory syncytial virus in vitro, indicating that the IFN deficiency in asthma includes at least one {alpha} IFN subtype and occurs in response to virus types other than RV (20, 21).

MECHANISMS OF INDUCTION OF TYPE I IFNS

The deficiencies in IFN induction in response to viral infection in asthma clearly have profound implications relating to the pathogenesis of virus-induced asthma exacerbations. They also prompt us to try to understand the mechanisms of induction of IFNs in response to respiratory viral infection, and to ask why these deficiencies occur. Toll-like receptor 3 (TLR3) and TLR7/8, double-stranded (ds)RNA-responsive protein kinase (PKR), and RNA helicases, such as retinoic acid inducible gene (RIG)-I and melanoma differentiation associated gene (MDA5), have all been implicated in viral induction of type I IFNs (22).

TLRs activate downstream effectors through numerous adaptors, including MyD88, IL-1 receptor–associated kinase (IRAK)-1/4, Toll/IL-1 receptor domain-containing adaptor-inducing IFN-ß (TRIF), and TNF receptor–associated factor (TRAF)3/6, leading to activation of downstream kinases PI3K and TBK1/IKK{iota}/{epsilon} to activate IFN regulatory factor (IRF)3, IKK{alpha}ß to activate nuclear factor (NF)-{kappa}B, and MAP kinases to activate ATF2/c-Jun (22).

TLR-independent pathways involve RIG-I/MDA5, which are cytoplasmic dsRNA sensing molecules that signal via CARD adaptor-inducing IFN-ß/IFM-ß promotor stimulator 1 (CARDIF/IPS-1), an adaptor molecule that activates downstream molecules TANK binding kinase (TBK)1/I{kappa}B kinase (IKK){iota}/{epsilon} to activate inteferon regulatory factor 3 (IRF3), and IKK{alpha}ß to activate NF-{kappa}B (23). It is not known if RIG-I activates ATF2/c-Jun. In addition to the pattern recognition receptors, it has also been shown that PKR activates NF-{kappa}B (24), leading to type I IFN production in some cell types.

Activation of these pathways culminates in activation of transcription factors required for activation of type I IFN promoters. IRF3, NF-{kappa}B, and ATF2/c-Jun are transcription factors that bind and activate the IFN-ß promoter. IRF3 is constitutively expressed in the cytoplasm and is activated by viral infection through phosphorylation via TBK1/IKK{iota}/{epsilon}. Activation of IRF3 induces nuclear accumulation, homodimerization, and association with transcriptional coactivators like the cAMP responsive element–binding protein, NF-{kappa}B, and ATF2/c-Jun to gain full transcriptional activity (25–27). This results in synthesis of IFN-ß, which acts in an autocrine/paracrine fashion to stimulate the type I IFN receptor and activate the transcription factor STAT1, resulting in up-regulation of ISGs, such as IRF7, TLR3, PKR, and RIG-I, and leading to further type I IFN production, apoptosis, and production of RNases that degrade viral RNA.

Deficient expression or function of any of these signaling intermediates or of transcription factors involved in induction of IFN-ß could potentially explain deficient IFN-ß production in asthma.

MECHANISMS OF INDUCTION OF TYPE III IFNS

Much less is known about regulation of the IFN-{lambda}s; however, it has recently been demonstrated that TLRs 3, 4, 7/8, and 9 mediate viral induction of IFN-{lambda}s, as well as {alpha}/ß IFNs (28). Induction of IFN-{lambda}s via TLRs 7–9 was shown to be mediated by IRAK-4; however, via TLR3 and 4 this was IRAK-4 independent. With the exception of the above information, the signaling intermediates and transcription factors mediating induction of the IFN-{lambda}s by viral infections are unknown.

MECHANISMS OF RV INDUCTION OF TYPE I AND III IFNS IN BECS OR MACROPHAGES

Little of the above information regarding regulation of IFNs relates specifically to RV infection of cells relevant to the respiratory tract. We have previously shown involvement of TLR3, PKR, and NF-{kappa}B in RV-induced signaling in BECs and macrophages (24, 29). There is an urgent need for studies investigating involvement of these pathways in response to RV infection of normal primary BECs and to determine whether any of these pathways are deficient in asthma.

MECHANISMS OF DEFICIENT VIRAL IFN INDUCTION IN ASTHMA

The deficiencies in innate immune responses in subjects with asthma are surprisingly broad and involve deficient responses in two IFN families, involving at least four individual IFN genes/proteins. IFN deficiency has also been observed in different lung cell types, as well as PBMCs and in response to different viral infections.

Given our current state of knowledge, there are at present three leading possible (perhaps nonexclusive) explanations for IFN deficiency in asthma:

  1. Polymorphisms in IFN genes/promoters in subjects with asthma directly impairing IFN production: whereas knowledge regarding IFN deficiency in asthma was restricted to IFN-ß, the existence of polymorphism(s) in the IFN-ß gene represented an attractive possible explanation. However, with deficiency now involving at least four genes in two IFN families on two different chromosomes (18), this explanation seems less likely.
  2. Impairment of mechanism(s) of induction of IFNs common to induction pathways regulating both viral and bacterial induction of both type I and type III IFNs (see above).
  3. Inadequate maturation of type I and III IFN responses due to reduced exposure to infectious disease in early life: little is known regarding the ontogeny of type I and type III IFN responses, but reduced exposure to infectious disease in early life has been implicated in the increasing prevalence of allergies and asthma (30, 31). Related to this, wheezing is much more common in children than in adults (1, 32), and more wheezing in children is related to viral infections (8, 9, 12); thus, the deficiencies we have observed in adult asthma could be even more profound in children and may help to explain the increased incidence of virus-induced wheeze in children.

ROLE FOR IFN THERAPY IN ASTHMA?

Our findings suggest that administration of type I or III IFNs may be a novel approach to treatment or prevention of asthma exacerbations. However, development of IFN therapy for the common cold was halted because therapy was associated with unacceptable side effects as a result of local inflammatory responses (33). Thus, although investigation of the safety of administration of deficient IFNs in asthma is clearly warranted, there is concern that induction of inflammation (especially in an already inflamed airway) may limit clinical development. It is thus imperative to advance our understanding of the mechanisms of deficient IFN production in asthma to identify alternative and possibly better strategies for prevention and/or treatment of asthma exacerbations.

CONCLUSIONS

Studies on the mechanisms of deficient innate immune responses are urgently required to help identify novel targets for development of new and effective therapies for virus-induced exacerbations of asthma for which there is a major unmet clinical need. Studies are also needed to further characterize the subject populations (both adult and children) with deficient IFN production. Studies are also needed to determine whether defective innate immune responses are present at birth, in the early years of childhood, and whether they are related to low exposure to infection in early life. These studies when completed will have profound implications not only for treatment of virus-induced exacerbations of asthma in adults and children but also perhaps for disease pathogenesis, which is strongly associated with respiratory viral infection in early life.

FOOTNOTES

Conflict of Interest Statement: S.L.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form January 29, 2007; accepted in final form February 17, 2007)

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