A series of hypersensitivities have been proposed to drive chronic inflammatory diseases, including those in the lung. There is hypersensitivity to inhaled irritants and allergens as a cause of asthma, likely due to increased innate and adaptive immune responses and consequent airway inflammation. There is also hypersensitivity to cigarette smoke as a cause of chronic obstructive pulmonary disease (COPD), again likely because of immune-driven airway and alveolar inflammation, damage, and remodeling. We categorize each of these diseases as distinct clinical entities with different genetic abnormalities, histopathology, and treatments. However, there is a nagging possibility that we are missing a secret element of pathobiology that is common to each of these inflammatory airway diseases and perhaps others. In particular, there is an ongoing fascination that each of these diseases, like many other chronic inflammatory disorders, could be triggered by an initial infection that sets off an everlasting chain of immune events. Even more specifically, is there a respiratory virus that comes and goes and leaves the genetically susceptible host with a chronic inflammatory airway disease?

The possible connection between acute viral infection and chronic inflammatory disease has been studied mainly in the context of triggering an aberrant immune response. In fact, in the lung, we now have some of the most definitive experimental evidence for such a virus–disease connection. For example, a single, primary infection with a common type of respiratory virus can leave mice with lifelong chronic obstructive lung disease (COLD) marked by increased airway reactivity and mucus production (1). The immune basis for this virus–disease connection is at least partially understood (2, 3), and the same immune abnormalities are turning up in patients with asthma and COPD as well (4). The final proof-of-concept will only come when a specific immune modulator is applied successfully in humans, and this will likely happen soon. But there is an alternative way of looking at this issue. And that is to consider that individuals with chronic airway disease are also hyper-susceptible to infection and that this susceptibility leads to more severe infection and a greater likelihood of subsequent chronic inflammatory disease. In that regard, there is an emerging but controversial line of evidence that this may be the case, and this possibility is highlighted by an article appearing in this issue of the journal that studies patients (in this case young children) with a third type of chronic inflammatory lung disease, cystic fibrosis (CF)(5). To put this article into perspective, let us consider the evidence to date. The first thing to recognize is that the airway epithelial cell, despite being the primary home to respiratory viruses (and other pathogens), contains a very potent antiviral system based mainly on interferon (IFN) production and subsequent signaling to IFN-stimulated genes (ISGs). An abbreviated scheme for this complex network is diagrammed in Figure 1. If this IFN signaling system is defective, either in mice or man, the host