Glucagon-like peptide-1 receptor agonist prevents pulmonary post-acute sequelae of COVID-19 associated with type 2 diabetes 3430

Abstract Description Objective Post-acute sequelae of COVID-19 (PASC) posts a major health burden after SARS-CoV-2 infection. Although type 2 diabetes (T2D) is associated with PASC, the mechanism of T2D-mediated PASC in lung remains elusive. Methods We reanalysed the public dataset of RNA and proteomics from PASC individuals. We then investigated the immune mechanisms underlying T2D-mediated pulmonary fibrosis and evaluated the prophylactic effect of glucagon-like peptide-1 receptor agonist using db/db mouse model. Results We found that people with T2D (PWT2D) exhibited significantly upregulated fibrosis-related genes in monocytes, which correlated positively with pulmonary fibrosis-related biomarkers up to 3 months after acute SARS-CoV-2 infection. Using db/db mice to model human T2D, we found consistently that SARS-CoV-2 infection resulted in upregulation of fibrosis-related genes in lung macrophages and persistent pulmonary fibrosis. Moreover, the macrophage-depletion demonstrated that proinflammatory macrophages in db/db mice were determinants for inducing the pulmonary fibrosis post-infection. Importantly, the anti-T2D GLP-1RA reprogramed macrophage responses to SARS-CoV-2 by normalizing fibrosis-related genes, significantly reducing the pulmonary fibrosis in a glucose-independent manner. Conclusion These findings demonstrated that SARS-CoV-2-induced proinflammatory macrophages are detrimental factors in T2D-mediated PASC, which can be prevented by GLP-1RA. Funding Sources This study was supported by the Hong Kong Research Grants Council Collaborative Research Fund (C7156-20G, C1134-20G and C5110-20G); the Health@InnoHK, Innovation and Technology Commission; the Hong Kong Theme-Based Research Scheme (T11-706/18-N, T11-702/24-N and T12-703/23-N); Wellcome Trust P86433; the Hong Kong Health and Medical Research Fund (COVID1903010-Project 4, COVID190123 and 20190572). Topic Categories Viral Immunology (VIR)