Preventing human influenza and coronaviral mono or coinfection by blocking virus-induced sialylation

Influenza A viruses (IAVs) and endemic coronaviruses (eCoVs) are common etiologic agents for seasonal respiratory infections. The human H1N1 of IAV and coronavirus OC43 (HCoV-OC43) can result in hospitalization, acute respiratory distress syndrome (ARDS), and even death, particularly in immunocompromised individuals. They infect the epithelium of the respiratory tract by interacting with host cell sialic acid (Sia)- linked receptors whose synthesis is catalyzed by sialyltransferases (STs). Viral coinfection is challenging to treat because of the need to target specific components of two or more distinct pathogens. Emerging drug and vaccine resistance due to the high mutation rate of viral genomes further complicates the treatment and prevention of viral infection. Sialylation mediated by STs may be a potential drug target for treating viral diseases. ST is an attractive target because it could be effective before identifying the pathogen that has occurred, providing a novel direction for overcoming drug resistance and achieving a broad-spectrum antiviral effect. We developed an H1N1 and OC43 mono or coinfection model using 14 days post-plating (14 PP) human primary small airway epithelial cells (HSAEC) grown on transwell inserts at an air-fluid interface (ALI), mimicking in vivo cellular dynamics. Using this model, we have observed that mono or coinfection with OC43 and H1N1 results in increased sialic acid levels and synergistic viral infection. We showed for the first time that H1N1 and OC43 mono- and coinfection in HSAEC caused increased expression and activity of STs, which can be blocked by pan-STs inhibitor (3Fax-Peracetyl Neu5Ac) with no host cell toxicity.