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

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.