Asthma is a chronic inflammatory disease of the airways characterized by reversible bronchoconstriction, excessive mucus production, airway hyperresponsiveness, and, in some cases, elevated levels of immunoglobulin E (IgE).
Most patients have mild or moderate asthma, which is well-controlled with standard medications. However, in 5–10% of cases, the disease is severe and poorly responsive to steroid treatment.
Approximately 50% of asthma patients exhibit type 2 inflammatory responses, characterized by eosinophilia and elevated levels of proinflammatory cytokines IL-4, IL-5, and IL-13. However, in patients with severe steroid-resistant asthma, these responses are absent.
Asthma exacerbations are often triggered by allergens, air pollution, active and passive smoking, and viral infections. The four main respiratory viruses that affect children—respiratory syncytial virus (RSV), human metapneumovirus (hMPV), rhinovirus (RV), and human parainfluenza virus (hPIV)—can induce wheezing and increase the risk of pulmonary complications. RSV is associated with bronchiolitis, type 2 inflammation, and allergic sensitization. Up to 80% of asthma exacerbations are linked to respiratory viruses, particularly rhinovirus. In addition to viruses, bacterial infections such as Moraxella catarrhalis, Haemophilus influenzae, and Streptococcus pneumoniae can also exacerbate asthma.
Individuals with asthma and chronic obstructive pulmonary disease (COPD) exhibit weaker immune responses to viral infections, increasing their susceptibility to severe exacerbations. Protection against viruses relies on type I and III interferons (IFNs), but a deficiency of these IFNs in infants may heighten the risk of respiratory infections and future wheezing episodes.
Researchers from UPMC Children’s Hospital in Pittsburgh (USA) investigated the role of type I and III interferons in asthma exacerbations and explored therapeutic and preventive strategies.
Type I and III Interferon Responses in the Lungs
Interferons activate immune defenses against viral infections. Type I interferons (IFN-α and IFN-β) were discovered in 1957, while type III interferons (IFN-λ) were only identified in 2003. Both classes trigger similar antiviral mechanisms, but their effects differ: type I IFNs act systemically, whereas type III IFNs primarily function in mucosal tissues, including the lungs.
Mouse studies have demonstrated that both IFN types are crucial for influenza defense. However, IFN-λ exhibits anti-inflammatory effects and reduces lung tissue damage. Conversely, IFN-λ can impair immune responses against bacterial infections, which is particularly relevant in viral-bacterial coinfections. For instance, during influenza and secondary bacterial infections, type I and III IFNs persistently elevate after influenza infection and may slow bacterial clearance. Similarly, RSV infection with Pseudomonas aeruginosa increases IFN-I and IFN-III production, promoting P. aeruginosa biofilm growth.
Many viruses have evolved mechanisms to suppress interferon signaling by blocking immune receptors and disrupting IFN production, which allows the virus to persist. Type I and III IFN suppression may prolong infections and exacerbate asthma.
Type I and III Interferons in Asthma
Beyond their role in antiviral immunity, type I and III interferons may influence asthma pathogenesis and progression. However, these mechanisms remain less understood. Many studies have focused on IFN-γ as a factor that exacerbates inflammation and reduces steroid responsiveness in severe asthma. However, research also indicates that asthma patients exhibit elevated levels of type I and III IFNs:
- Children with asthma have increased expression of IFN-λ1 and IFN-λ2 in sputum. In adult asthmatics, IFN-λ2 is elevated, while IFN-λ1 remains comparable to levels in healthy individuals.
- IFN-I and IFN-III levels are elevated in sputum from asthmatics with neutrophilic inflammation.
- IFN-α levels in sputum correlate with higher lymphocyte counts in asthma patients.
- ISG activation is evident in mild and severe asthma, independent of viral infections and type 2 inflammation.
Type I and III IFNs restrict Th2 cell differentiation and type 2 cytokine production, which may help suppress allergic inflammation. Similarly, type I IFNs limit the development and activation of Th17 cells.
Dendritic and epithelial cells produce insufficient type I IFNs in patients with severe atopic asthma. Type I IFNs are essential for dendritic cell proliferation and migration during antigen recognition and optimal Th2 cell responses.
Type III IFNs mitigate allergic airway inflammation by reducing eosinophil levels, suppressing type 2 cytokines, and modulating lung dendritic cell and CD4+ T-cell functions.
Viral Infections and Asthma Exacerbations
Viral infections are a primary cause of asthma exacerbations, particularly in children. Up to 85% of asthma exacerbations in children aged 9–11 are associated with viruses such as hMPV and hPIV. Coinfection poses a higher risk of exacerbation than single viral or bacterial infections alone.
Asthma patients cannot combat respiratory viruses due to impaired type I and III IFN production in the bronchial epithelium. These IFNs play a crucial role in antiviral immunity, but asthmatics exhibit lower IFN levels in bronchial epithelial cells. In mouse models of house dust mite allergy and patients with mild atopic asthma infected with rhinovirus, there is an increased production of IL-33, suppressing type I IFN production.
Mechanisms of Interaction Between Allergic Inflammation and Interferons
- Type I IFNs may suppress innate lymphoid cell type 2 (ILC2) activity, counteracting type 2 inflammation.
- Asthmatics exhibit reduced Toll-like receptor 7 (TLR7) expression, crucial for viral recognition and IFN production.
- Children with atopic asthma display elevated IgE receptor levels on dendritic cells, which correlate with impaired IFN responses to viral infections.
- Influenza infection in mice lacking the type I IFN receptor leads to heightened type 2 inflammation and increased IgE levels.
- Blocking IgE with monoclonal antibodies enhances type I IFN levels during rhinovirus infection.
Asthma is a complex disease involving multiple immune pathways. Considering IFNs as a therapeutic target requires balancing cytokines that drive asthma pathogenesis with those that increase susceptibility to viral infections and exacerbations.
Influenza Infection in Asthma
The relationship between asthma and influenza is more complex than previously thought. It was long believed that asthmatics are not more susceptible to flu than the general population, but data from the 2009 H1N1 pandemic indicated that children with asthma were twice as likely to contract H1N1 influenza compared to other respiratory viruses. However, laboratory studies found no significant differences in the virus’s ability to infect asthmatic and healthy airway cells. Moreover, asthma did not increase H3N2 viral shedding. Thus, asthma’s impact on influenza susceptibility may depend on additional factors, including coexisting viral infections.
Asthma reduces the risk of influenza-related mortality. Historically, it was assumed that asthmatics experience more severe symptoms during influenza. During the 2009 H1N1 pandemic, asthmatics were hospitalized earlier. However, they had a lower mortality rate, potentially due to earlier hospitalization and corticosteroid use. In contrast, corticosteroid treatment in non-asthmatics increased influenza mortality.
Protective Role of Eosinophils. Mouse studies support the lower influenza mortality rate in asthmatics. Mice with allergic airway inflammation cleared the influenza virus more rapidly than healthy controls. Early H1N1 clearance correlated with a stronger IFN-III response and increased lung eosinophil recruitment. Influenza infection upregulated viral sensor genes in eosinophils. Transferring eosinophils into allergic mice reduced viral loads and weight loss. Influenza-exposed eosinophils stimulated CD8+ T-cell activation and proliferation, suggesting a potential antigen-presenting function. Human eosinophils also exhibit antiviral properties, which make them capable of capturing and neutralizing the influenza virus. However, eosinophils from asthma patients have a diminished ability to capture influenza, correlating with disease severity. While mouse studies indicate a direct antiviral role for eosinophils, human data suggest their antiviral function may be impaired in asthma. Thus, reduced influenza severity in asthmatics may involve factors beyond eosinophil activity.
Influenza infection, but not vaccination, can exacerbate asthma. Vaccination does not trigger asthma exacerbations; instead, it reduces their frequency. Studies show that vaccination does not cause asthma exacerbations but, on the contrary, reduces their risk.
Asthma exacerbation during influenza: molecular mechanisms. At the molecular level, influenza exacerbates airway inflammation in asthma, increases mucus production, and induces bronchial hyperresponsiveness—key hallmarks of asthma. This process involves IL-33, a protein that plays a critical role in asthma exacerbations. Blocking the IL-33 receptor alleviates asthma exacerbation symptoms as effectively as corticosteroids. Epidemiological data indicate that influenza triggers asthma exacerbations. However, the precise roles of different immune cells and cytokines in this process require further investigation, particularly in type I and III interferons, which play a central role in influenza defense in healthy individuals. A reduced type I IFN response to viruses in asthmatics may mitigate influenza severity but is likely to enhance type 2 inflammation during influenza-induced asthma exacerbations, as type I IFNs typically suppress this process.
The Role of Bacteria and Fungi in Asthma Exacerbations
Although viral infections are the primary cause of asthma exacerbations, bacterial and fungal infections also contribute to disease severity. Studies indicate that neonates colonized with S. pneumoniae, M. catarrhalis, or H. influenzae have a higher risk of developing airway inflammation and asthma later in life. Sensitization to S. aureus toxins has also been linked to more severe asthma and increased exacerbation frequency.
Individuals with asthma are at greater risk of severe pneumococcal infections compared to healthy individuals. Research on mice has demonstrated that administration of IFN-α enhances macrophage and neutrophil activation, promoting more efficient pathogen clearance and reducing pulmonary inflammation. However, asthmatics exhibit a weakened IFN response, impairing their defense against both viral and bacterial infections that can precipitate asthma exacerbations, which highlights the necessity of investigating novel IFN-based therapies.
Bacteria such as M. catarrhalis and H. influenzae can induce wheezing and increase the likelihood of asthma development. Studies suggest that children with airway colonization by these microbes experience persistent wheezing, elevated eosinophil counts, and higher IgE levels, all indicative of airway inflammation. Moreover, H. influenzae can destabilize the respiratory microbiome, heightening the risk of recurrent respiratory infections. These bacteria trigger robust inflammatory responses by activating the immune system, exacerbating asthma symptoms. H. influenzae promotes the secretion of pro-inflammatory cytokines IL-8, TNFα, and IFN-γ, whereas M. catarrhalis induces IL-6, TNFα, IFN-γ, and IL-17 production. Targeted therapies using anti-IL-6 and anti-TNFα antibodies have been effective in preventing M. catarrhalis-induced asthma exacerbations. However, the role of IFNs in this process remains unclear, as M. catarrhalis can suppress immune responses, significantly reducing IFN-β, IFN-λ, and IL-8 production.
Bacteria can exacerbate asthma, particularly in the context of viral-bacterial coinfections, which are common during influenza. However, asthma may provide some protection against severe coinfections. Mouse studies have shown that allergic airway inflammation enhances bacterial clearance and increases survival rates following influenza and S. pneumoniae coinfections compared to non-allergic mice. This protective effect is associated with elevated TGFβ levels, a key immunoregulatory protein often elevated in asthmatic patients. Since type I and III IFNs are central to bacterial susceptibility during influenza, their regulation in individuals with asthma warrants further investigation.
The fungal pathogen Aspergillus fumigatus can cause infections in both immunocompromised and immunocompetent individuals. Even when it merely colonizes the airways of asthmatics, A. fumigatus increases the risk of exacerbations. The fungus can invade lung tissue in severe cases, leading to invasive aspergillosis. The immune response against A. fumigatus relies on type I and III IFNs, which activate immune cells. Monocytes initiate IFN-I production, facilitating optimal IFN-λ signaling. IFN-λ acts directly on neutrophils, enhancing their antifungal activity and promoting pathogen clearance. Given these properties, IFNs are being explored as potential antifungal therapies, though further research is needed.
Clinical Applications of Type I and III Interferons in Asthma Treatment
Inhaled corticosteroids (ICS) are widely used to treat asthma and COPD, yet they are often ineffective in patients with severe non-type 2 asthma. Moreover, ICS suppresses IFN production, increasing susceptibility to respiratory infections and pneumonia. Consequently, type I and III IFNs may offer therapeutic benefits in asthma management.
Type I and III IFNs have demonstrated efficacy in controlling asthma:
- In mouse models of allergic airway inflammation, intranasal administration of IFN-λ1, IFN-λ2, and IFN-λ3 reduced eosinophilic airway inflammation and inhibited lung IL-4, IL-5, and IL-13 production.
- IFN-α, when combined with corticosteroids, improved lung function and reduced airway hyperresponsiveness in patients with poorly controlled asthma.
- IFN-β has been shown to reduce airway hyperreactivity in murine models of asthma.
- In the context of asthma exacerbations, IFN-β administered at the onset of cold symptoms improved peak expiratory flow and asthma control scores in patients with severe asthma. Another study found that IFN-β treatment in asthmatic patients infected with rhinovirus led to modest improvements in morning peak expiratory flow recovery.
IFN-γ and Severe Steroid-Resistant Asthma
CD4+ T cells producing IFN-γ are more prevalent in patients with severe asthma airways. IFN-γ enhances CXCL10 production and reduces SLPI levels, promoting airway hyperresponsiveness and steroid resistance in severe asthma.
Conclusion
Type I and III IFNs play a crucial role in protecting the lungs from viral, bacterial, and fungal infections. Given that infections are a primary cause of asthma exacerbations, a deeper understanding of IFN-mediated immune responses may be key to developing novel asthma prevention and treatment strategies.
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Reference
Insights Into Type I and III Interferons in Asthma and Exacerbations
