Human galectin-9 potently enhances SARS-CoV-2 replication and inflammation in airway epithelial cells

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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a β-galactoside-binding lectin involved in immune regulation and viral immunopathogenesis, were reported to be elevated in the setting of severe COVID-19 disease. However, the impact of Gal-9 on SARS-CoV-2 infection and immunopathology remained to be elucidated. In this study, we demonstrate that Gal-9 treatment potently enhances SARS-CoV-2 replication in human airway epithelial cells (AECs), including immortalized AECs and primary AECs cultured at the air–liquid interface. Gal-9–glycan interactions promote SARS-CoV-2 attachment and entry into AECs in an angiotensin-converting enzyme 2 (ACE2)-dependent manner, enhancing the binding of the viral spike protein to ACE2. Transcriptomic analysis revealed that Gal-9 and SARS-CoV-2 infection synergistically induced the expression of key pro-inflammatory programs in AECs, including the IL-6, IL-8, IL-17, EIF2, and TNFα signaling pathways. Our findings suggest that manipulation of Gal-9 should be explored as a therapeutic strategy for SARS-CoV-2 infection.

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  1. SciScore for 10.1101/2022.03.18.484956: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsField Sample Permit: All the studies involving live viruses were conducted in the Vitalant Research Institute BSL-3 under approved safety protocols.
    Sex as a biological variablenot detected.
    RandomizationImage Analysis: To measure the frequency of infected cells, randomly-selected areas were imaged.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line AuthenticationContamination: All cells had been previously tested for mycoplasma contamination and incubated at 37°C in a humidified atmosphere with 5% CO2.

    Table 2: Resources

    Antibodies
    SentencesResources
    Cells were then incubated with a primary antibody (monoclonal rabbit anti-SARS-CoV-2 nucleocapsid antibody (GeneTex, GTX135357)) in 1 X PBS …