The sulfolipid Sulfavant A modulates dendritic cell response in a cellular model of inflammation induced by SARS-CoV-2 spike protein

Sulfavant A (SA) is a synthetic glycolipid that activate dendritic cells (DCs) through an unconventional mechanism involving engagement of the triggering receptor expressed on myeloid cells 2 (TREM2). In models of antigen presentation, co-administration of SA elicits a robust T cell response driven by the upregulation of costimulatory signals, in the absence of the classical inflammatory markers. While effective in immunogenic settings, the activity of SA against viral antigens capable of evading antigen-presenting cell recognition and suppressing adaptive effector functions remains unknown. In this study, we investigated the effect of SA on the response of human monocyte-derived DCs (hMoDCs) to the SARS-CoV-2 spike protein. We focused on the secretion of cytokines paradigmatically linked to a productive immune response and on regulation of costimulatory molecules essential for naïve T cells priming and activation. Treatment of hMoDCs with the viral protein in combination with SA promoted their transition from the immature to mature state, while mitigating the spike protein–mediated hyperproduction of pro-inflammatory cytokines IL-6 and TNF-α. The glycolipid also enhanced T cell activation via ICOS/ICOSL and OX40/OX40L interactions leading to downstream polarization towards regulatory T cells (Treg) and follicular helper T cells (Tfh). This mechanism highlights the potential of SA to counteract viral immune evasion and mitigate hyperinflammation, while caution is needed regarding possible dampening of early antiviral responses.