Journal Article

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection

Shahbaz, Shima, MacIntyre, Erika, Xu, Lai, Bozorgmehr, Najmeh, Perez Rosero, Eliana, Osman, Mohammed, O’Neil, Conar R., Mashhouri, Siavash, Elahi, Shokrollah, Kutsogiannis, Demetrios J., Sligl, Wendy

2021

Overview

The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. In this study, we observed massive elevation of plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls (HCs). By using the receiver operating characteristic (ROC) curve, we found that a baseline of 2,042 pg/ml plasma Gal-9 can differentiate SARS-CoV-2-infected from noninfected individuals with high specificity/sensitivity (95%). Analysis of 30 cytokines and chemokines detected a positive correlation of the plasma Gal-9 with C-reactive protein (CRP) and proinflammatory cytokines/chemokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IP-10, MIP-1α, and MCP-1 but an inverse correlation with transforming growth factor β (TGF-β) in COVID-19 patients. In agreement, we found enhanced production of IL-6 and TNF-α by monocytes and NK cells of COVID-19 patients once treated with the recombinant human Gal-9 in vitro . Also, we observed that although the cell-membrane expression of Gal-9 on monocytes does not change in COVID-19 patients, those with higher Gal-9 expression exhibit an activated phenotype. Furthermore, we noted significant downregulation of surface Gal-9 in neutrophils from COVID-19 patients compared to HCs. Our further investigations indicated that immune activation following SARS-CoV-2 infection results in Gal-9 shedding from neutrophils. The strong correlation of Gal-9 with proinflammatory mediators suggests that inhibition of Gal-9 may severe as a therapeutic approach in COVID-19 infection. Besides, the plasma Gal-9 measurement may be used as a surrogate diagnostic biomarker in COVID-19 patients. IMPORTANCE The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. We observed substantial elevation of the plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls. Gal-9 is an abundant protein in many immune and nonimmune cells. We found that Gal-9 detection assay can differentiate SARS-CoV-2-infected from noninfected individuals with a specificity/sensitivity of 95%. Importantly, we found a positive correlation of the plasma Gal-9 with a wide range of proinflammatory biomarkers in COVID-19 patients. In agreement, we found enhanced expression and production of such proinflammatory molecules by immune cells of COVID-19 patients once treated with Gal-9 in vitro . Our results propose Gal-9 as an important contributing factor in cytokine release syndrome; therefore, Gal-9 inhibition may serve as a beneficial therapeutic approach by suppressing the hyperimmune activation in COVID-19 patients.

• Publisher: American Society for Microbiology
• Subject: Adult / Age Factors / Aged / Aged, 80 and over / Biomarkers / Biomarkers - blood / C-reactive protein / Chemokines / COVID-19 / COVID-19 - blood / COVID-19 - diagnosis / Cytokine Release Syndrome - blood / Cytokine Release Syndrome - physiopathology / Cytokine storm / Dengue fever / Female / Females / Galectin-9 / Galectins - blood / Healthy Volunteers / HIV / Human immunodeficiency virus / Humans / Immune response / Inflammation / Interleukin 6 / IP-10 protein / Leukocytes (neutrophilic) / Male / Middle Aged / Monocyte chemoattractant protein 1 / Monocytes / Mortality / Neutrophils / Outbreaks / Patients / Phenotypes / Plasma / Research Article / ROC Curve / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Sex Factors / Signal transduction / Transforming growth factor-b / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Tumors / Viral infections