MUCIN-MEDIATED AND INTERFERON-DRIVEN DEFENSE MECHANISMS AGAINST INFLUENZA VIRUS INFECTION IN HUMAN AIRWAY EPITHELIUM

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2022

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Abstract

The human airway epithelium represents the primary site of infection for many respiratory viruses, including influenza A virus (IAV). To safeguard this tissue and maintain the functionality of the lung, humans possess a two-layer, extracellular, mucus barrier composed predominantly of individual proteins termed mucins. Additionally, underlying epithelial cells produce interferons upon virus detection that promote the establishment of a local antiviral state through autocrine and paracrine signaling. However, despite these protective measures, IAV continues to cause significant annual morbidity and mortality across the globe. Therefore, we sought to further investigate how specific mucin molecules interact with IAV, and how interferon drives intrinsic antiviral defense in the context of a human airway epithelial (HAE) culture system. By utilizing fluorescently-labeled influenza virus particles we further elucidate the adhesive interactions between mucus and influenza virus while also detailing, for the first time, real-time IAV diffusivity within patient-derived mucus samples. These results reveal that the polymeric structure of mucus greatly influences the mobility of IAV within human secreted mucus. Additionally, we investigate the interaction between influenza virus and tethered mucin 1 (MUC1), finding that MUC1 expression is enhanced by virus-driven inflammation and interferon signaling. Moreover, by establishing a genetically-tractable airway epithelial model, we detail the protective role MUC1 plays in preventing the initial establishment and spread of influenza virus in HAE. Specifically, we find that the loss of MUC1 significantly enhances IAV uptake and spread. Finally, we observe that the directionality of IFN exposure at airway epithelial surfaces impacts the magnitude of protection against IAV and SARS-CoV-2. We then detail the cellular composition of our HAE culture system and define a shared IFN response profile across all HAE component cell types as well as cell type-specific interferon stimulated genes. Together our work provides novel insight into the innate and intrinsic anti-viral properties of the human airway epithelium.

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