Mechanisms by which Glp-1 and Gip receptor signaling enhance airway epithelial barrier function

Respiratory viral infections are a key risk factor for asthma development in early life and the major trigger of asthma exacerbations across the lifespan. Impaired airway epithelium responses to viral infections are hallmarks of asthma and worsened by comorbid obesity. The rationale for the proposed research is that developing new therapeutic approaches for reducing viral-induced asthma exacerbations is critical for reducing asthma-related morbidity. The overall objective in this proposal is to establish proof-of-concept that dual glucagon-like peptide-1 receptor (GLP1R)/glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling improve airway epithelial cell barrier function and anti-viral immune responses to respiratory syncytial viral (RSV) and improve clinical outcomes in patients with asthma. Our novel preliminary data in differentiated human bronchial epithelial cells showed that a GLP1R agonist, a GIP agonist, or the dual GLP1R/GIPR agonist, tirzepatide (Trz), preserved airway epithelial barrier function, reduced RSV viral load, and increased IFNB expression. Based on these data, our central hypothesis is that GLP1R and GIPR agonists decrease RSV-induced airway inflammation by increasing airway epithelial cell barrier function. We will capitalize on samples and clinical data available from patients with asthma initiating Trz therapy as part of standard care for management of obesity in distinct, but highly integrated specific aims. In aim 1, we will define how Trz increases airway epithelial barrier function and anti-viral response leading to reduced RSV infectivity and cytokine expression. We will differentiate nasal airway epithelial cells (NAECs) from donors with asthma prior to starting Trz therapy and overnight treat NAECs with a GLP1R agonist, a GIPR agonist, or Trz followed by RSV 01/2-20 infection. We will determine if Trz treatment (Aim 1a) increases airway epithelial cell tight junction barrier function and (Aim 1b) decreases viral load and increases interferons and/or anti-viral pathways. In aim 2, we utilize NAECs differentiated before and after Trz therapy and respiratory symptom scores collected at both time points to determine the effect of dual GLP-1R/GIPR signaling synergism on airway barrier function in patients with asthma pre- and post-Trz therapy. We will determine if Trz therapy (Aim 2a) increases NAEC barrier function and (Aim 2b) improves respiratory symptoms in patients with asthma. This fully human approach is innovative because no study has posited that GLP1R and/or GIPR signaling pathways directly regulate airway epithelial barrier function or enhance IFN responses to limit respiratory viral infections. This proposal is significant because it develops new therapeutic approaches for reducing viral-induced asthma exacerbations, critical for reducing asthma-related morbidity. This study will inform the mechanistic rationale and sample size estimates required to repurpose Trz to prevent respiratory viral infection-induced exacerbations in asthma and potentially other chronic respiratory diseases exacerbated by viral infections. Project Number: 1R21AI190446-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Katherine Cahill (+1 co-PI) | Institution: VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TN | Award Amount: $481,249 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 RCCS-B (03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19044601