Cinnamaldehyde inhibits cytokine storms induced by the ORF3a protein of SARS‐CoV‐2 via ROS‐elimination in activated T cells

Abstract Cytokine storms are the cause of complications in patients with severe COVID‐19, and it becomes the target of therapy. Several natural compounds were selected to screen the inhibitory effect on T‐cell proliferation by Fluorescence‐Activated Cell Sorting (FACS) and cytokine production by enzyme‐linked immunosorbent assay (ELISA). Open reading frame 3a (ORF3a) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) stimulates the specific T‐cell activation model in vivo and in vitro. The coculture system included the macrophage cell line RAW264.7 and splenocytes. Reactive oxygen species (ROS) levels and glycolysis in T cells were evaluated. Cinnamaldehyde effectively inhibits cytokine storms both in vitro and in vivo. It decreased inflammatory cytokine (such as IFN‐γ, TNF‐α, IL‐6, and IL‐2) production by murine peripheral blood cells upon direct stimulation with ConA, after immunization with the MHV‐A59 virus or ORF3a peptide from SARS‐CoV‐2. Cinnamaldehyde restored the percentage of T cells, which was originally decreased in the peripheral blood and splenocytes of ORF3a‐immunized mice. In a coculture system, cinnamaldehyde reduced the secretion of inflammatory cytokines from macrophages in a T‐cell dependent manner. Furthermore, cinnamaldehyde decreased the ROS level in activated T cells, which in turn reduced glycolysis and the activation of T cells. Cinnamaldehyde can be used as a candidate molecule for COVID‐19.