FGL-1 plasma levels correlate with markers of inflammation and severe disease during SARS-CoV-2 infection

Background Fibrinogen-like protein 1 (FGL-1), primarily secreted by the liver, modulates immune responses and is upregulated in patients with hepatocellular carcinoma. FGL-1 affects T-cell function by interacting with lymphocyte-activation gene 3 (LAG-3), and blocking this interaction can enhance T-cell activity, making it a potential therapeutic target. In coronavirus disease 2019 (COVID-19), the upregulation of immune checkpoints on T cells, particularly LAG-3, is associated with disease severity. Liver inflammation and damage are well-known features of COVID-19 pathogenesis; however, little is known about FGL-1 expression patterns in COVID-19 and other infectious diseases. Methods In a cohort of 65 patients with COVID-19 and 33 healthy donors, plasma FGL-1 levels were measured, and their correlations with clinical parameters and the course of the disease were evaluated. Additionally, both bulk and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-specific T-cell immune phenotypes, as well as SARS-CoV-2-specific immune responses were comprehensively characterized and measured using multicolor flow cytometry and pMHC multimer technology. Results Plasma FGL-1 levels were elevated in patients with COVID-19 and correlated with IL-6 and disease severity. LAG-3 was significantly upregulated on bulk and COVID-19-specific CD8 + T cells was is co-expressed with T-cell activation markers (CD38, HLA-DR) and inhibitory receptors (PD-1, TIGIT). Conclusion These findings suggest a role for FGL-1 in the pathogenesis of COVID-19, potentially through modulation of T-cell activation and function via LAG-3, and may also be relevant in other hyperinflammatory conditions where immune modulation plays a role.