Red Pitahaya Betacyanins Selectively Upregulate Proinflammatory Cytokines In Vitro During Influenza A Virus Infection

Among the four influenza types, Influenza A virus (IAV) is responsible for annual epidemics and pandemics, causing the most severe illnesses, resulting in patient hospitalizations or death. With IAV threatening the next global influenza pandemic, it is a race against time to search for antiviral drugs. Betacyanins are reddish-violet, unique water-soluble nitrogen-containing pigments that have previously been reported to possess antiviral effects against IAV. The objectives of this study were to study interactions between betacyanins and key inflammatory markers, such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and suppressor of cytokine signaling 3 (SOCS3), in IAV-infected A549 cells. Betacyanins were first extracted from red pitahaya, quantified, and characterized. A549 cells were infected with IAV and then treated with betacyanins. Quantitative PCR was performed to study the change in expression levels of IL-1β, IL-6, TNF-α, and SOCS3. Molecular docking was performed to study any interactions between betacyanins and IL-1β, IL-6, TNF-α, SOCS3, and their respective receptors, namely, IL-1R1, IL-6R, and TNFR1. Betacyanins modulated IL-1β, IL-6, and TNF-α uniquely after up to 72 h. Specifically, both IL-1β and IL-6 were significantly downregulated after 48 and 72 h, and TNF-α was significantly downregulated after 48 h. Additionally, SOCS3, a host factor that IAV hijacks and induces to promote its own survival, was downregulated after 48 and 72 h. In silico analysis showed that betacyanins such as phyllocactin, hylocerenin, betanin, and isobetanin formed binding interactions and hydrogen bonds with IL-1β, IL-6, TNF-α, SOCS3, IL-1R1, IL-6R, and TNFR1. This study suggests that novel interactions between betacyanins and inflammatory cytokines might contribute to the antiviral effects of betacyanins, leading to the survival of the host cell. Future studies into the immunological aspects of the cell and overall cellular health are recommended.