Lamb, D; Yew-Booth, L; Farhadi, N; Hulland, K; Janies, J; Mori, H; Parker, NS; Philip, J; Rodrigues, D; Taylor, B; Evans, S; Bright, H
RATIONALE
Respiratory syncytial virus (RSV) infection is associated with clinical exacerbations of asthma. We have assessed the effect of RSV on airway inflammation and airways hyperresponsiveness (AHR) elicited by chronic house dust mite (HDM) challenge in mice.
METHODS
In 2, 4-week HDM-challenge studies, BALB/c mice were dosed intranasally 5 days/week with 25μg HDM. At the end of the third week, groups of animals were infected with either a single dose of live RSV (2x10^6 FFU), UV-inactivated RSV (UV-RSV), or 75μg of the TLR3 agonist, poly(I:C), or 3 consecutive doses of RSV (6x10^5 FFU), UV-RSV or 25μg poly(I:C). In a separate 3-week HDM-challenge study, mice were challenged with 3 consecutive daily doses of RSV (6x10^5 FFU) either 1 week before HDM challenge, immediately before HDM challenge, or one week into the HDM challenge period. Exhaled nitric oxide (eNO) and methacholine-induced enhanced pause (Penh, a breathing parameter associated with AHR) were assessed throughout the study. Terminal bronchoalveolar lavage (BAL) was performed for leucocyte profiling and lungs homogenised for cytokine assay. Satellite animals were terminated 3 days post-viral challenge to determine viral titres which were consistent between studies, with both the single high RSV and 3x low dose RSV groups yielding similar titres.
RESULTS
eNO was significantly elevated only in animals challenged concomitantly with both live virus and HDM. Baseline Penh was elevated in both HDM- and RSV-challenged animals, indicating a degree of airways obstruction. No additive effect was observed in the HDM-RSV challenged animals. Whilst HDM-treated animals demonstrated increased methacholine-induced Penh compared with control animals, there was no evidence of increased AHR in any animals co-challenged with RSV, UV-RSV or poly(I:C). High- and low-dose RSV, high-dose UV-RSV and high-dose poly(I:C) partially inhibited HDM-elicited eosinophilia when concomitantly dosed with HDM, compared with HDM alone. Low-dose RSV completely inhibited eosinophilia when dosed before HDM challenge. Neither low-dose UV-RSV or poly(I:C) modulated eosinophilia). There was no change in BAL neutrophils or lymphocytes. High-dose RSV alone elicited a strong IFN-g response which was attenuated in RSV-HDM treated animals. Low-dose RSV and poly(I:C) augmented HDM-elicited KC, IL-1b & IL-10 responses. However, RSV did not inhibit HDM-elicited Th2 cytokines, despite the reduction in eosinophilia.
CONCLUSION
In summary, HDM-mediated AHR was not exacerbated by any co-challenge. However, live RSV attenuated HDM-elicited airway eosinophilia, and both live RSV and poly(I:C) augmented specific cytokines in this model.
