RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma
Jaisy Arikkatt,
Md Ashik Ullah,
Kirsty Renfree Short,
Vivan Zhang,
Wan Jun Gan,
Zhixuan Loh,
Rhiannon B Werder,
Jennifer Simpson,
Peter D Sly,
Stuart B Mazzone,
Kirsten M Spann,
Manuel AR Ferreira,
John W Upham,
Maria B Sukkar,
Simon Phipps
Affiliations
Jaisy Arikkatt
School of Biomedical Science, University of Queensland, Brisbane, Australia
Md Ashik Ullah
School of Biomedical Science, University of Queensland, Brisbane, Australia; Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, New South Wales, Australia
Kirsty Renfree Short
School of Biomedical Science, University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia
Vivan Zhang
School of Biomedical Science, University of Queensland, Brisbane, Australia
Wan Jun Gan
School of Biomedical Science, University of Queensland, Brisbane, Australia
Zhixuan Loh
School of Biomedical Science, University of Queensland, Brisbane, Australia
Rhiannon B Werder
School of Biomedical Science, University of Queensland, Brisbane, Australia
Jennifer Simpson
School of Biomedical Science, University of Queensland, Brisbane, Australia
Peter D Sly
Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia; Centre for Children's Health Research Children's Health Queensland, The University of Queensland, Brisbane, Australia
Stuart B Mazzone
School of Biomedical Science, University of Queensland, Brisbane, Australia
Kirsten M Spann
Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Australia; School of Biomedical Science, Queensland University of Technology, Brisbane, Australia
Manuel AR Ferreira
QIMR Berghofer Medical Research Institute, Brisbane, Australia
John W Upham
Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia; School of Medicine, The University of Queensland, Princess Alexandra Hospital Brisbane, Brisbane, Australia
Maria B Sukkar
Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, New South Wales, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, Australia
School of Biomedical Science, University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia
Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.
