Human Galectin-9 Potently Enhances SARS-CoV-2 Replication and Inflammation in Airway Epithelial Cells

Overview

Journal J Mol Cell Biol

Publisher Oxford University Press

Specialty Molecular Biology

Date 2023 May 1

PMID 37127426

Authors

Li Du

Mohamed S Bouzidi

Akshay Gala

Fred Deiter

Jean-Noel Billaud

Stephen T Yeung

Prerna Dabral

Jing Jin

Graham Simmons

Zain Y Dossani

Toshiro Niki

Lishomwa C Ndhlovu

John R Greenland

Satish K Pillai

Affiliations

Soon will be listed here.

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.

Citing Articles

Plasma galectin-9 levels correlate with blood monocyte turnover and predict simian/human immunodeficiency virus disease progression.

Zablocki-Thomas L, Ardeshir A, Takahashi N, White K, Sumer C, Wallis Z Transl Med Commun. 2025; 9(1.

PMID: 39822268 PMC: 11737433. DOI: 10.1186/s41231-023-00160-w.

TIM3 in COVID-19; A potential hallmark?.

Zamani M, Sacha P Heliyon. 2025; 10(23):e40386.

PMID: 39759854 PMC: 11700678. DOI: 10.1016/j.heliyon.2024.e40386.

Exploring the role of galectin-9 and artemin as biomarkers in long COVID with chronic fatigue syndrome: links to inflammation and cognitive function.

Elahi S, Rezaeifar M, Osman M, Shahbaz S Front Immunol. 2024; 15:1443363.

PMID: 39386210 PMC: 11461188. DOI: 10.3389/fimmu.2024.1443363.

A viral assembly inhibitor blocks SARS-CoV-2 replication in airway epithelial cells.

Du L, Deiter F, Bouzidi M, Billaud J, Simmons G, Dabral P Commun Biol. 2024; 7(1):486.

PMID: 38649430 PMC: 11035691. DOI: 10.1038/s42003-024-06130-8.

The Role of Cytokines and Molecular Pathways in Lung Fibrosis Following SARS-CoV-2 Infection: A Physiopathologic (Re)view.

Lazar M, Sandulescu M, Barbu E, Chitu-Tisu C, Andreescu D, Anton A Biomedicines. 2024; 12(3).

PMID: 38540252 PMC: 10968428. DOI: 10.3390/biomedicines12030639.

References

Patel H, Ashton N, Dobson R, Andersson L, Yilmaz A, Blennow K . Proteomic blood profiling in mild, severe and critical COVID-19 patients. Sci Rep. 2021; 11(1):6357. PMC: 7973581. DOI: 10.1038/s41598-021-85877-0. View

Djidrovski I, Georgiou M, Hughes G, Patterson E, Casas-Sanchez A, Pennington S . SARS-CoV-2 infects an upper airway model derived from induced pluripotent stem cells. Stem Cells. 2021; 39(10):1310-1321. PMC: 8441770. DOI: 10.1002/stem.3422. View

Bi S, Hong P, Lee B, Baum L . Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011; 108(26):10650-5. PMC: 3127870. DOI: 10.1073/pnas.1017954108. View

Elbein A, Tropea J, Mitchell M, Kaushal G . Kifunensine, a potent inhibitor of the glycoprotein processing mannosidase I. J Biol Chem. 1990; 265(26):15599-605. View

Mulay A, Konda B, Garcia Jr G, Yao C, Beil S, Villalba J . SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery. Cell Rep. 2021; 35(5):109055. PMC: 8043574. DOI: 10.1016/j.celrep.2021.109055. View

Hu B, Guo H, Zhou P, Shi Z . Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2020; 19(3):141-154. PMC: 7537588. DOI: 10.1038/s41579-020-00459-7. View

Abdel-Mohsen M, Chavez L, Tandon R, Chew G, Deng X, Danesh A . Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation. PLoS Pathog. 2016; 12(6):e1005677. PMC: 4890776. DOI: 10.1371/journal.ppat.1005677. View

Sehrawat S, Reddy P, Rajasagi N, Suryawanshi A, Hirashima M, Rouse B . Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response. PLoS Pathog. 2010; 6(5):e1000882. PMC: 2865527. DOI: 10.1371/journal.ppat.1000882. View

Iwasaki-Hozumi H, Chagan-Yasutan H, Ashino Y, Hattori T . Blood Levels of Galectin-9, an Immuno-Regulating Molecule, Reflect the Severity for the Acute and Chronic Infectious Diseases. Biomolecules. 2021; 11(3). PMC: 7998537. DOI: 10.3390/biom11030430. View

10.

Pacha O, Sallman M, Evans S . COVID-19: a case for inhibiting IL-17?. Nat Rev Immunol. 2020; 20(6):345-346. PMC: 7194244. DOI: 10.1038/s41577-020-0328-z. View

11.

Subramaniyan B, Larabee J, Bodas M, Moore A, Burgett A, Myers D . Characterization of the SARS-CoV-2 Host Response in Primary Human Airway Epithelial Cells from Aged Individuals. Viruses. 2021; 13(8). PMC: 8402710. DOI: 10.3390/v13081603. View

12.

Nobumoto A, Oomizu S, Arikawa T, Katoh S, Nagahara K, Miyake M . Galectin-9 expands unique macrophages exhibiting plasmacytoid dendritic cell-like phenotypes that activate NK cells in tumor-bearing mice. Clin Immunol. 2008; 130(3):322-30. DOI: 10.1016/j.clim.2008.09.014. View

13.

Kadowaki T, Morishita A, Niki T, Hara J, Sato M, Tani J . Galectin-9 prolongs the survival of septic mice by expanding Tim-3-expressing natural killer T cells and PDCA-1+ CD11c+ macrophages. Crit Care. 2013; 17(6):R284. PMC: 4056346. DOI: 10.1186/cc13147. View

14.

Baum L, Garner O, Schaefer K, Lee B . Microbe-Host Interactions are Positively and Negatively Regulated by Galectin-Glycan Interactions. Front Immunol. 2014; 5:284. PMC: 4061488. DOI: 10.3389/fimmu.2014.00284. View

15.

Yang R, Sun L, Li C, Wang Y, Yao J, Li H . Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun. 2021; 12(1):832. PMC: 7864927. DOI: 10.1038/s41467-021-21099-2. View

16.

Matsumoto N, Katoh S, Yanagi S, Arimura Y, Tokojima M, Ueno M . A possible role of galectin-9 in the pulmonary fibrosis of patients with interstitial pneumonia. Lung. 2013; 191(2):191-8. DOI: 10.1007/s00408-012-9446-0. View

17.

Mahallawi W, Khabour O, Zhang Q, Makhdoum H, Suliman B . MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine. 2018; 104:8-13. PMC: 7129230. DOI: 10.1016/j.cyto.2018.01.025. View

18.

De Biasi S, Meschiari M, Gibellini L, Bellinazzi C, Borella R, Fidanza L . Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia. Nat Commun. 2020; 11(1):3434. PMC: 7338513. DOI: 10.1038/s41467-020-17292-4. View

19.

Anderson A, Anderson D, Bregoli L, Hastings W, Kassam N, Lei C . Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science. 2007; 318(5853):1141-3. DOI: 10.1126/science.1148536. View

20.

Giovannone N, Liang J, Antonopoulos A, Geddes Sweeney J, King S, Pochebit S . Galectin-9 suppresses B cell receptor signaling and is regulated by I-branching of N-glycans. Nat Commun. 2018; 9(1):3287. PMC: 6098069. DOI: 10.1038/s41467-018-05770-9. View