Galectin-9 protects humanized-ACE2 immunocompetent mice from SARS-CoV-2 infection

Abstract

SARS-CoV-2 remains a global health crisis even with effective vaccines and the availability of FDA approved therapies. Efforts to understand the complex disease pathology and develop effective strategies to limit mortality and morbidity are needed. Recent studies reveal circulating Galectin-9 (gal-9), a soluble beta-galactoside binding lectin with immunoregulatory properties, are elevated in SARS-CoV-2 infected individuals with moderate to severe disease. Moreover, in silico studies demonstrate gal-9 can potentially competitively bind the ACE2 receptor on susceptible host cells. Here, we determined whether early introduction of exogenous gal-9 following SARS-CoV-2 infection in humanized ACE2 transgenic mice (K18-hACE2) may reduce disease severity. Mice were infected and treated with a single dose of a human recombinant form of gal-9 (rh-gal-9) and monitored for morbidity. Subgroups of mice were humanely euthanized at 2- and 5- days post infection (dpi) for viral levels by plaque assay, immune changes measures by flow cytometry, and soluble mediators by protein analysis from lung tissue and bronchoalveolar Lavage fluid (BALF). Mice treated with rh-gal-9 during acute infection had improved survival compared to PBS treated controls. At 5 dpi, rh-gal-9 treated mice had enhanced viral clearance in the BALF, but not in the lung parenchyma. Increased T and dendritic cells and decreased neutrophil frequencies in the lung at 5 dpi were observed, whereas BALF had elevated levels of type-I interferons and proinflammatory cytokines. These results suggest a role for rh-gal-9 in limiting acute COVID-19. Further studies are required to determine the optimal design of gal-9 treatment to effectively ameliorate COVID-19 disease.

A unique maternal and placental galectin signature upon SARS-CoV-2 infection suggests galectin-1 as a key alarmin at the maternal–fetal interface

“…Levels of gal-3 and gal-9 were reported to be upregulated only in patients with severe disease ( 40 , 41 ), raising the possibility that circulating gal-3 or gal-9 can be valuable biomarkers for severe pneumonia in patients with COVID-19 ( 44 , 45 ). Interestingly, exogenous gal-9 administration during acute SARS-CoV-2 infection has been reported to increase the survival rate inducing a robust innate and adaptive immune response in mice ( 46 ). More recently, an inhaled gal-3 inhibitor has been tested as a potential therapy for COVID-19 pneumonitis ( 47 ).…”

Immune Regulation Patterns in Response to Environmental Pollutant Chromate Exposure-Related Genetic Damage: A Cross-Sectional Study Applying Machine Learning Methods

“…LAG-3 can block the exhaustion of T and B cells and even enhance the activity and proportion of CD8+ T cells. 55,56 Consistent with the fact that positive immune response activation often coexists with negative immune response regulation activation, 57 the negative immune regulation pattern (EFA Factor 2, represented by galectin-9, 58,59 TGF-β, 60,61 and PD-L2 62,63 ) was also observed to be activated.…”

Plasma N-Cleaved Galectin-9 Is a Surrogate Marker for Determining the Severity of COVID-19 and Monitoring the Therapeutic Effects of Tocilizumab

“…Plasma Gal-9 shows positive correlations with proinflammatory mediators, especially IL-6, IP-10, and CRP, and a negative correlation with an anti-inflammatory cytokine, transforming growth factor-β (TGF-β), in COVID-19 patients [ 15 ]. Moreover, exogenous Gal-9 diminishes SARS-CoV-2 infection and replication in a mouse model [ 38 ]. Mice treated with Gal-9 exhibit increased survival rates potentiating cytokine and chemokine productions in bronchoalveolar lavage fluid and inducing effector T cell and DC responses in lung tissues.…”