Mucin 4 is a cellular biomarker of necrotizing bronchiolitis in influenza A virus infection

Authors: Arruda, Bailey; KANEFSKY, RACHEL - Tufts University; Hau, Samantha; JANZEN, GARRETT - Oak Ridge Institute For Science And Education (ORISE); Anderson, Tavis; Baker, Amy

Submitted to: Microbes and Infection
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/6/2023
Publication Date: 6/7/2023
Citation: Arruda, B.L., Kanefsky, R.A., Hau, S.J., Janzen, G.M., Anderson, T.K., Baker, A.L. 2023. Mucin 4 is a cellular biomarker of necrotizing bronchiolitis in influenza A virus infection. Microbes and Infection. e105169. https://doi.org/10.1016/j.micinf.2023.105169.
DOI: https://doi.org/10.1016/j.micinf.2023.105169

Interpretive Summary: Influenza A virus (IAV) in the human and swine host infects the cells lining the respiratory tract causing these cells to die (necrotizing bronchiolitis). Protecting these surfaces are large glycoproteins called mucins. Mucin 4 (MUC4) is a mucin that consists of an alpha portion that extends from the surface of the cell responsible for surface protection and beta portion within the cell involved in cell signaling to repress cell death and stimulate epithelial growth. This study was designed to determine the expression and potential role of MUC4 during IAV infection. We used immunohistochemistry in combination with a machine learning image analysis algorithm to quantify differential expression of MUC4 in IAV-infected and uninfected lung in a porcine model. MUC4 expression was significantly increased in bronchioles with necrotizing bronchiolitis. Increased expression of MUC4 is likely a regenerative response and with refinement, MUC4 serum concentrations and expression could act as a proxy for disease severity. Understanding the impact of increased expression of MUC4 during IAV infection or other respiratory disease will facilitate control strategies by elucidating mechanisms associated with resistance or enhanced susceptibility to IAV.

Technical Abstract: Influenza A virus (IAV) in the human and swine host infects epithelial cells lining the respiratory tract causing a necrotizing bronchitis and bronchiolitis. These epithelial surfaces are protected by large glycoproteins called mucins. Mucin 4 (MUC4) is a transmembrane mucin that consists of an alpha subunit responsible for surface protection and intracellular beta subunit involved in signal transduction to repress apoptosis and stimulate epithelial proliferation. This study was designed to determine the expression and potential role of MUC4 during IAV infection. We used immunohistochemistry in combination with machine learning image analysis to quantify differential protein expression of MUC4 subunits in IAV-infected and uninfected lung in a porcine model. MUC4 protein basal expression in control animals varied significantly by litter. MUC4 protein expression was significantly increased in bronchioles with necrotizing bronchiolitis compared to histologically normal bronchioles, likely representing a regenerative response to restore mucosal integrity of conducting airways. Understanding the impact of differential MUC4 expression among healthy individuals and during IAV infection will facilitate control strategies by elucidating mechanisms associated with susceptibility to IAV that can be therapeutically or genetically regulated and may be extended to other respiratory diseases.