Role of Galectin-3 in Airway Epithelial Barrier Integrity During Influenza A Viral Infection

Abstract

Influenza A virus (IAV) infects the airway and alveolar epithelia in humans, and causes seasonal influenza annually which is a major global health concern, along with COVID-19, besides exhibiting pandemic potential. In severe cases IAV infection causes acute respiratory distress syndrome (ARDS) resulting from increased alveolar permeability due to the disruption of cell-cell tight junctions. The detailed mechanisms involved, however, remain to be fully elucidated. Galectins are β-galactose-binding lectins implicated in diverse cellular functions as well as in pathogen infections, including those from respiratory viruses. In previous studies from our lab on a murine model, IAV infection enhanced galectin-3 (Gal-3) secretion in the bronchoalveolar fluid. In the present study, I investigated in vitro the potential role of the secreted Gal-3 in airway epithelial barrier function during IAV infection. The results thus acquired using the human airway epithelial A549 cells indicate that IAV infection leads to a significant desialylation of the cell surface, exposing the sub-terminal β-galactose ligands, with a concomitant increase in the binding of recombinant galectin-3 (rGal3). I detected potential Gal-3 receptors CD147, integrin-β1 and MUC1 on the surface of A549 cells, and observed an increase in the secretion of matrix metalloproteinases MMP2 and MMP9 after exposure of these cells to rGal3. Furthermore, I observed disruption of the A549 cell surface distribution of tight junction proteins occludin and ZO-1 upon both IAV infection and Gal-3 exposure, as well as significant increase in the monolayer permeability. Using rGal-3, I demonstrated its direct interaction with the A549 cell CD147 as well as integrin-β1 which possibly mediated the above-mentioned cellular effects and validated some of the key findings in A549 cells from this study to the primary small airway epithelial cells (SAECs). In the end by searching for the sequence variants in the Gal-3 encoding genes LGALS3 in two public genetic databases, I found three rare variants that might alter protein function and one that was associated with the phenotypes indicative of a role for Gal-3 in influenza outcome: including influenza vaccine, flu treatment, acute sinusitis, and emphysema.