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Aging and many age-related health conditions are associated with skeletal muscle loss. Furthermore, older adults are more susceptible to severe respiratory infections, which can in turn lead to muscle wasting. The mechanisms by which respiratory viral infection can impact skeletal muscle in older adults are not well understood. We determined the effects of acute infection with respiratory syncytial virus (RSV) on the lung and skeletal muscle of aged mice. RSV infection caused more severe disease in aged mice with enhanced weight loss, reduced feeding, higher viral load, and greater airway inflammation. Aged but not young mice showed decreased leg muscle weight at the peak of illness and decreased size of leg muscle fibers. Aged mice increased muscle-specific expression of atrophy-promoting enzymes (Atrogin-1 and MuRF-1) and failed to increase the rate of muscle protein synthesis during RSV infection. In aged mice, the changes in Atrogin-1 and MuRF-1 gene expression in skeletal muscle correlated with IL-6 levels in the lungs. These findings indicate that RSV infection of aged mice provides a model for studying the diverse adverse systemic consequences of respiratory viral infections on health and wellbeing in older adults., (© 2024. The Author(s).)

Background: Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33 ox ) is thought to limit its activity. We investigated whether IL-33 ox has functional activities that are independent of ST2 in the airway epithelium., Methods: In vitro epithelial damage assays and three-dimensional, air-liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33 ox . Transcriptomic changes occurring in healthy ALI cultures treated with IL-33 ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis., Results: We demonstrate that IL-33 ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro . IL-33 ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33 ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33 ox were enriched in airway epithelia from patients with severe COPD., Conclusions: Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and muco-obstructive features in COPD., Competing Interests: Conflict of interest: S. Strickson, V.A. Negri, Y. Ohne, T. Ottosson, R.B. Dodd, C.C. Huntington, T. Baker, J. Li, K.E. Stephenson, A.J. O'Connor, J.S. Sagawe, H. Killick, D.G. Rees, S. Koch, Y. Wang, M. Ghaedi, S. Saumyaa, G.P. Sims, I.C. Scott, X. Romero Ros and E.S. Cohen are employees of AstraZeneca and may hold stock or stock options in AstraZeneca. K.F. Houslay, T. Moore, E. Gubbins, R. Kolbeck and A.A. Humbles are former employees of AstraZeneca and may hold stock or stock options in AstraZeneca. C. Sanden has nothing to disclose. J.S. Erjefält is a founder and board member of Medetect AB., (Copyright ©The authors 2023.)