The S1 spike protein of SARS-CoV-2 upregulates the ERK/MAPK signaling pathway in DC-SIGN-expressing THP-1 cells.

Dendritic cells, macrophages, neutophils and other antigen-presenting cells express various C-type lectin receptors that function to recognize the glycans associated with pathogens. DC-SIGN (the Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) binds various pathogens such as HIV gp120, the Ebola glycoprotein, Hemagglutinin, and the dengue virus glycoprotein in addition to the SARS-CoV-2 Spike protein, and also triggers antigen presenting cell endocytosis and immune escape from systemic infections. Many studies on the binding of SARS-CoV-2 spike protein with glycans have been published but the underlying mechanism by which intracellular signaling occurs remains unclear. In this study, we report that the S1 spike protein of SARS-CoV-2 induces the phosphorylation of ERKs in THP-1 cells, a DC-SIGN-expressing human monocytic leukemic cell line. On the other hand, the phosphorylation level of NF-κB remained unchanged under the same conditions. These data suggest that the major cell signaling pathway regulated by S1 spike protein is the ERK pathway, which is superior to the NF-κB pathway in these DC-SIGN-expressing THP-1 cells and may contribute to immune hyperactivation in SARS-CoV-2 infections. Additionally, several glycans such as mannans, mannosylated BSA, the serum amyloid beta protein, and ICAM3 suppressed ERK phosphorylation suggesting that these molecules are target molecules for SARS-CoV-2 infection by suppressing immune hyperactivation that occurs in the ERK signaling pathway.