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

Project Summary
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.

Grant Number: 1R21AI190446-01
NIH Institute/Center: NIH
Principal Investigator: Katherine Cahill