Respiratory syncytial virus infection does not increase allergen-induced type 2 cytokine production, yet increases airway hyperresponsiveness in mice

Abstract

Severe respiratory syncytial virus (RSV)-induced disease is associated with childhood asthma and atopy. We combined murine models of allergen-sensitization and RSV infection to explore the interaction of allergic and virus-induced airway inflammation and its impact on airway hyperresponsiveness (AHR). We found that RSV infection during ova-sensitization (OVA/RSV) increased and prolonged AHR compared to mice only RSV-infected (RSV) or ova-sensitized (OVA). AHR is known to be associated with an increase in Type 2 cytokines (IL-4, IL-5, and IL-13) in allergen-sensitized mice. Therefore, we hypothesized that RSV-induced enhancement of AHR was a result of potentiating the Type 2 cytokine profile promoted by ova-sensitization. Surprisingly, we found that Type 2 cytokines induced by ova-sensitization were not increased by RSV infection despite the increase in AHR, and in some cases were diminished. RNAse protection assay revealed no difference in IL-4 and IL-5 mRNA levels between the OVA and OVA/RSV groups, and IL-13 mRNA was significantly decreased in the OVA/RSV mice compared to the OVA group. Flow cytometric analysis of Type 2 cytokines demonstrated the same frequency of IL-4 and IL-5 production in lung-derived T lymphocytes from the OVA/RSV and OVA groups. Direct cytokine ELISA measurements of lung supernatant showed the level of IL-13 was significantly decreased in the OVA/RSV group compared to OVA mice, while there was no difference in either IL-4 or IL-5 between these two groups. These data indicate that the enhanced and prolonged AHR caused by the interaction of allergic airway inflammation and virus-induced immune responses is a complex process that can not be explained simply by augmented production of Type 2 cytokines.

TNF-α and Macrophages Are Critical for Respiratory Syncytial Virus–Induced Exacerbations in a Mouse Model of Allergic Airways Disease

“…Further, RSV infection during the OVA challenge phase resulted in increased AHR, eosinophil numbers, and enhanced expression of IL-4 and IL-5 in the lung (24). By contrast, RSV infection with A2 strain induced AHR in mice with allergic airways disease without inducing Th2 cytokines, but rather through increased IL-17A levels (25,26). Finally, RSV infection after OVA challenge in the absence of adjuvant sensitization also increased AHR and induced high levels of IL-4 and IL-5 and the accumulation of eosinophils and neutrophils into the airways (20).…”

Progress in Defining the Role of RSV in Allergy and Asthma: From Clinical Observations to Animal Models

“…with OVA in alum and subsequently aerosolized with OVA on days 2 2 through 6 post RSV infection found no increase in lung IL-4, IL-5 or IL-13 mRNA expression despite greater airway hyperresponsiveness (Peebles et al, 2001). There is an explanation for both results.…”

“…Moreover, other reports have shown that allergens and environmental pollutant exposure can alter the outcome of RSV infection (Gurkan et al, 2000;Makela et al, 2003). In murine models, researchers have demonstrated increased airway hyperresponsiveness when allergen is administered before infection to achieve sensitization and then challenge exposure is performed during infection (Peebles et al, 2001). This phenomenon has been demonstrated not only in the mouse but also in bovine models of RSV infection.…”

“…A variety of different extraneous antigens have been employed to demonstrate this effect. These antigens include: cockroach allergen, ragweed, carbon black, Micropolyspora faeni (currently known as Saccharopolyspora rectivirgula), ovalbumin (OVA), and Dermatophagoides farinae (Df) (Leibovitz et al, 1988;Gershwin and Giri, 1990, 1992, Gershwin et al, 1994Lukacs et al, 2001;Peebles et al, 2001;Foster et al, 2003;Lambert et al, 2003).…”

Animal Models of Respiratory Syncytial Virus Pathogenesis and Vaccine Development: Opportunities and Future Directions

“…In autopsy lung tissues from fatal HRSV disease cases, epithelial damage and mechanical airway obstruction are implicated as key features of HRSV pathogenesis (Johnson et al, 2007;Welliver et al, 2007). Although laboratory animal models of HRSV pathogenesis have been widely used to determine pathogenic mechanisms of HRSV infection, the commonly used lab strains of HRSV do not cause airway epithelial cell desquamation, airway mucus production, or lung dysfunction in mice (Moore et al, 2009a;Peebles et al, 2001). However, some strains of HRSV (e.g.…”