Host epithelial–viral interactions as cause and cure for asthma

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Research on the pathogenesis of asthma has concentrated on initial stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. Recent evidence indicates that the innate immune cell response to respiratory viruses also contributes to the development of inflammatory airway disease. We further develop this concept by raising the issue that the interaction between host airway epithelial cells and respiratory viruses is another aspect of innate immunity that is also a critical determinant of asthma. We also introduce a rationale for how antiviral performance at the epithelial cell level might be improved to prevent acute infectious illness and chronic inflammatory disease caused by respiratory viruses.

Highlights

► Placing antiviral defense in the context of innate mucosal immunity. ► Understanding how a defect in antiviral defense causes asthma. ► Identifying the precise defect in antiviral defense in asthma. ► Devising a strategy to improve antiviral defense.

Introduction

One of the major tasks facing medical research is to define the pathogenesis of chronic inflammatory diseases. In the case of asthma, the approach to understanding chronic inflammation has implicated a broad array of cell types, cell–cell interactions, and cellular products. One leading scheme for integrating this information is based on the classification of the adaptive immune system, and especially the responses of T helper (Th) cells into T helper type 1 (Th1) cells that mediate delayed-type hypersensitivity reactions and selectively produce interleukin (IL)-2 and interferon (IFN)-γ, and Th2 cells that promote B-cell dependent humoral immunity and selectively produce IL-4, IL-5, and IL-13. Under this scheme, an up-regulated Th2 and perhaps a downregulated Th1 response are thought to drive the development of asthma. The newer contributions of Th17 (IL-17-producing) and Treg (IL-10-producing and TGF-β-producing) subsets of T cells are also proposed to contribute to inflammatory airway disease by skewing the system toward a Th2 response [1, 2].

In general, the Th2 hypothesis is based on observations of the response to allergen challenge in mouse models of asthma and in humans with allergic asthma [3, 4]. However, it has been pointed out that a Th2-biased response does not account for the epidemiological link between respiratory viral infection and the subsequent development of asthma [5]. Indeed, the broader issue of the relationship between acute viral infection and chronic inflammatory disease remains uncertain. In an effort to understand this issue, we identified the likely steps leading from viral infection to inflammatory disease using respiratory viral infection and asthma as a template for this process (as outlined in Figure 1). Here, we review three major advances that lead to a substantial revision of this virus-disease connection. First, we develop the experimental and clinical evidence that the link between acute infection and chronic disease of the airway unexpectedly depends on immune cells of the innate rather than the adaptive immune system; second, we extend this concept to the airway epithelial cell and the proposal that high-level viral replication at this cellular site is required to trigger the innate immune cell activation that in turn drives asthma; and third, we introduce strategies that could improve antiviral defense at the airway epithelial cell level and thereby help to prevent acute infectious illness and chronic asthmatic disease. We conclude by showing how these advances provide for a new virus-disease paradigm.

Section snippets

Introducing the innate immune cells for chronic postviral disease

One of the initial objectives for understanding the role of respiratory viruses in the pathogenesis of asthma was to define the immune program for postviral disease. This goal required a high-fidelity experimental model of postviral asthma in humans, where respiratory syncytial virus (RSV) is implicated. However, we recognized (and confirmed) the shortcomings of using RSV for an experimental model in mice [6], and therefore substituted the corresponding mouse paramyxovirus, Sendai virus (SeV).

Moving upstream to the airway epithelial cell

Despite being the primary home to respiratory viruses (or perhaps because of it), airway epithelial cells contain a potent antiviral system based mainly on IFN production and subsequent expression of IFN-stimulated genes (ISGs). An abbreviated scheme for this complex IFN-based network features a master regulator known as STAT1 (as diagrammed in Figure 3). If this network is genetically defective (e.g., due to STAT1 deficiency) in mice or man, the host often succumbs to lethal viral infection [21

Improving innate immunity

Taken together, there appears to be a direct relationship between viral level and both the severity of acute illness and the likelihood of chronic disease in experimental models and in humans with asthma. Moreover, the capacity of the host to control viral level appears to be deficient in asthma, perhaps at the level of IFN production and/or signaling in airway epithelial cells and likely in immune cells in the airway as well. Even if some of these tenets turn out to be wrong, there still

Conclusion

Here we summarize new work on the pathogenesis of asthma to support three breakthrough issues: firstly, respiratory viral infections drive long-term activation of an innate immune cell response and in turn chronic obstructive lung disease in an experimental model that resembles virus-induced asthma in humans; secondly, this type of innate immune response depends on the severity of acute infection and in turn the tissue levels of virus, so that proper control of virus by airway epithelial cells

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

Our research on this topic is supported by grants from the National Institutes of Health (National Heart, Lung, and Blood Institute and National Institute of Allergy and Infectious Diseases).

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