Viral induction of a chronic asthma phenotype and genetic segregation from the acute response

Abstract

Paramyxoviral infections cause most of the acute lower respiratory tract illness in infants and young children and predispose to the development of chronic wheezing, but the relationship between these short-and long-term viral effects are uncertain. Here we show that a single paramyxoviral infection of mice (C57BL6/J strain) not only produces acute bronchiolitis, but also triggers a chronic response with airway hyperreactivity and goblet cell hyperplasia lasting at least a year after complete viral clearance. During the acute response to virus, same-strain ICAM-1-null mice are protected from airway inflammation and hyperreactivity despite similar viral infection rates, but the chronic response proceeds despite ICAM-1 deficiency. Neither response is influenced by IFN-γ deficiency, but the chronic response is at least partially prevented by glucocorticoid treatment. In contrast to viral infection, allergen challenge caused only short-term expression of asthma phenotypes. Thus, paramyxoviruses cause both acute airway inflammation/hyperreactivity and chronic airway remodeling/hyperreactivity phenotypes (the latter by a hit-and-run strategy, since viral effects persist after clearance). These two phenotypes can be segregated by their dependence on the ICAM-1 gene and so depend on distinct controls that appear critical for the development of lifelong airway diseases such as asthma. Conflict of interest:No conflict of interest has been declared. Nonstandard abbreviations used: Sendai virus (SeV); 50% egg infectious dose (EID50); periodic acid-Schiff (PAS); enhanced pause (Penh); ovalbumin (Ova).newly described yet invariant feature of asthma: an intrinsic abnormality in cellular programming of the airway epithelium toward an anti-viral Th1 response (26). In particular, airway epithelial cells are specially programmed with anti-viral networks, and the behavior of these cells in asthma resembles a persistent antiviral response (27)(28)(29)(30)(31). It is also not certain how the Th2 hypothesis reconciles its insights into the allergic response -a short-term response -with the development of a lifelong disease.In that context, a relationship between viral infection and the development of chronic inflammatory disease has been proposed for diverse clinical syndromes, but the mechanistic basis for this relationship is still uncertain. Relevant to asthma, paramyxoviral infections are the leading cause of lower respiratory tract illness in infants and young children (32,33), and children with clinically significant viral bronchiolitis appear to be marked for the subsequent development of a chronic wheezing illness that is independent of allergy (34). Presumably paramyxoviral infection triggers an abnormal host response, since paramyxoviruses (and other respiratory RNA viruses) are not thought to persist in airway tissue as an ongoing stimulus of chronic respiratory disease (35). In either case (i.e., with or without viral persistence), the role of specific host factors in the development of acute or chronic wheezing or lifelo...

Arginases I and II in lungs of ovalbumin-sensitized mice exposed to ovalbumin: Sources and consequences

“…The occurrence of arginase II constitutively in airway epithelial cells is reasonable if we consider another important role for arginase in the cell, catalysis of the synthesis of proline and glutamate, which play an important role in protein biosynthesis. Since we know that there is airway epithelial cell hyperplasia and proliferation in the ovalbumin model, it is reasonable to assume that there is an obligatory need for baseline levels of arginase in the airway epithelium (Li et al, 2001;2002) and that this role is played by arginase II in the mouse.…”

“…Mice were certified as chronic respiratory disease free by the supplier, and were routinely screened for health status by serology and histology by our veterinary animal resources facility. There were no paramyxoviral, or other viral pathogens, present in these animals that might themselves provoke chronic airway inflammation (Walter et al, 2002;Schwarze et al, 1997). Animals were maintained in a HEPA-filtered laminar flow cage rack with a 12-hour light/dark cycle and allowed free access to food (Purina Rodent Chow) and water.…”

Functional single nucleotide polymorphisms of theCCL5gene and nonemphysematous phenotype in COPD patients

“…In general, late-onset asthma is not strongly associated with specific allergen sensitisation. Rather, infections, including respiratory viruses, may be more likely to be involved in the pathophysiology of late-onset asthma through host response mechanisms [3]. Viral infections are associated with most exacerbations of asthma and chronic obstructive pulmonary disease (COPD) [4][5][6][7][8], and the most prominent aspect of the epithelial immune response towards viral respiratory infections consists of the production and release of CCL5 [9][10][11][12].…”

Étude d'association entre certains gènes candidats et l'asthme dans une cohorte familiale originaire du Saguenay-Lac-Saint-Jean :

“…(citons à titre d'exemple PIL-4, l'IL-5 ou l'IL-13) et une diminution de produits Thl (I'IFN-Y ou FIL-12) (Walter et al, 2002 Wjst, 2002). Les études de jumeaux et les analyses de ségrégation sont deux approches utilisées pour mesurer la contribution relative des gènes et de l'environnement dans la susceptibilité à l'asthme (Sandford et al, 1996).…”