Glucagon-like peptide-1 receptor signaling attenuates RSV-induced type 2 responses and immunopathology
Glucagon-like peptide-1 receptor (GLP-1R) agonists are a well-accepted and safe treatment for Type II diabetes. Recent evidence suggests that GLP-1R signaling also has anti- inflammatory effects. Severe acute bronchiolitis can be caused by infection with respiratory syncytial virus (RSV) and is characterized by significant immunopathology including mucus production and airway dysfunction. We determined the effect of GLP-1R signaling on RSV-induced type 2 immune responses and immunopathology. To test this, BALB/c mice were infected with RSV strain 12/12-6 or mock preparation and treated with GLP-1R agonist or vehicle. GLP-1R agonist treatment attenuated airway inflammation, airway responsiveness, and airway mucus in RSV 12/12-6-infected mice. The GLP-1R agonist decreased total lung IL- 13 and IL-33 protein expression, with concurrent decreases in IL-13+ group 2 innate lymphoid cells (ILC2), CD4+ type 2 helper T cells, and basophils as well as IL-33+ epithelial cells. GLP-1R agonist treatment prevented airway inflammation, and did not increase viral load or decrease anti-viral interferon and antibody production during secondary RSV infection. A Phenome-wide association study (PheWAS) was performed to assess the association between GLP-1R signaling and human disease. The PheWAS identified a statistically significant link between GLP-1R signaling and acute bronchiolitis. Taken together, these data suggest that GLP-1R signaling protects against type 2-mediated immunopathology during RSV infection and that GLP-1R signaling is associated with acute bronchiolitis in humans. GLP-1R agonists, drugs that are currently FDA-approved for type 2 diabetes, are the first known agents to inhibit IL-33 protein expression and may represent a novel treatment strategy for RSV bronchiolitis.