Glucagon-like peptide 1 receptor signaling attenuates respiratory syncytial virus-induced type 2 responses and immunopathology

Abstract

GLP-1R signaling, an emerging anti-inflammatory therapeutic 59 target, 60 attenuated type 2-associated immunopathology in mice infected with a strain of RSV that was 61 isolated from a hospitalized infant with severe lower respiratory tract infection and bronchiolitis.

Figure 1. GLP-1R agonist decreases RSV-induced type 2 responses and immunopathology

(A) ELISA for IL-13 in whole lung homogenate (right lung only). (B) Total number of IL-13⁺ ILC2, (C) Th2 cells, and (D) basophils. (E) Representative IL-13 expression measured by flow cytometry in ILC2. (F) Representative PAS-stained section of mucus-containing airways in the lungs (40x magnification); arrowhead denotes intraluminal mucus strand. (G) Quantification of airway mucus from the experiment in A. (H) Airway responsiveness and (I) BAL cell counts. Data plotted as mean + SEM. n = 3–6 mice per group representative of 3 (A) or 2 (B–G & I) independent experiments. n = 6–12 mice per group combined from 2 independent experiments (H). *p < 0.05, **p < 0.01, ***p < 0.001 by one-way (B & E–H) or two-way (C–D) ANOVA. BL = baseline.

Figure 2. GLP-1R signaling decreases IL-33, does not increase viral titer or decrease IFN-γ production, and associates with acute bronchiolitis in humans

(A) Total number of IL-33⁺ epithelial cells, (B) MFI of IL-33 expression in epithelial cells, (C) representative IL-33 expression measured by flow cytometry in epithelial cells, and (D) ELISA for IL-33 in whole lung homogenate (left lung only). (E) Lung mRNA RSV M protein expression normalized to GAPDH. (F) ELISA for IFN-γ in whole lung homogenate (right lung only). (G) Phenome-wide association study (PheWAS) plot for THADA rs7578597 using logistic regression assuming an additive genetic model adjusted for age, sex, study site, and the first 3 principal components. rs7578597 associated with acute bronchiolitis (OR = 1.24, P = 6.3 × 10⁻³). Data plotted as mean + SEM. n = 3–6 mice per group representative of 2 independent experiments (A–F). *p < 0.05, **p < 0.01, ***p < 0.001 by one-way (A–B, D, & F) or two-way (E) ANOVA. NS = not significant.