{"doi":"10.1101/2022.03.18.484956","title":"Human Galectin-9 Potently Enhances SARS-CoV-2 Replication and Inflammation in Airway Epithelial Cells","abstract":"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. Here, we demonstrate that Gal-9 treatment potently enhances SARS-CoV-2 replication in human airway epithelial cells (AECs), including primary AECs in air-liquid interface (ALI) culture. Gal-9-glycan interactions promote SARS-CoV-2 attachment and entry into AECs in an ACE2-dependent manner, enhancing the binding affinity of the viral spike protein to ACE2. Transcriptomic analysis revealed that Gal-9 and SARS-CoV-2 infection synergistically induce 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. Importance COVID-19 continues to have a major global health and economic impact. Identifying host molecular determinants that modulate SARS-CoV-2 infectivity and pathology is a key step in discovering novel therapeutic approaches for COVID-19. Several recent studies have revealed that plasma concentrations of the human β-galactoside-binding protein galectin-9 (Gal-9) are highly elevated in COVID-19 patients. In this study, we investigated the impact of Gal-9 on SARS-CoV-2 pathogenesis ex vivo in airway epithelial cells (AECs), the critical initial targets of SARS-CoV-2 infection. Our findings reveal that Gal-9 potently enhances SARS-CoV-2 replication in AECs, interacting with glycans to enhance the binding between viral particles and entry receptors on the target cell surface. Moreover, we determined that Gal-9 accelerates and exacerbates several virus-induced pro-inflammatory programs in AECs that are established signature characteristics of COVID-19 disease and SARS-CoV-2-induced acute respiratory distress syndrome (ARDS). Our findings suggest that Gal-9 is a promising pharmacological target for COVID-19 therapies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":297497,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":537094,"name":"Mohamed S. Bouzidi","orcid":null,"position":1,"is_corresponding":false},{"id":986092,"name":"Akshay Gala","orcid":null,"position":2,"is_corresponding":false},{"id":336674,"name":"Fred Deiter","orcid":"0000-0003-4454-6489","position":3,"is_corresponding":false},{"id":369381,"name":"Jean-Noël Billaud","orcid":"0000-0002-8924-9069","position":4,"is_corresponding":false},{"id":288835,"name":"Stephen T. Yeung","orcid":"0000-0002-9710-5567","position":5,"is_corresponding":false},{"id":986093,"name":"Prerna Dabral","orcid":null,"position":6,"is_corresponding":false},{"id":985554,"name":"敬 島津","orcid":"0000-0003-0157-2791","position":7,"is_corresponding":false},{"id":250064,"name":"Graham Simmons","orcid":"0000-0002-9615-7023","position":8,"is_corresponding":false},{"id":986094,"name":"Zain Y Dossani","orcid":null,"position":9,"is_corresponding":false},{"id":53006,"name":"Toshiro Niki","orcid":"0000-0003-4531-1331","position":10,"is_corresponding":false},{"id":69472,"name":"Lishomwa C. Ndhlovu","orcid":"0000-0001-5427-4187","position":11,"is_corresponding":false},{"id":311020,"name":"John R. Greenland","orcid":"0000-0003-1422-8367","position":12,"is_corresponding":false},{"id":24132,"name":"Satish K. Pillai","orcid":"0000-0001-8770-7014","position":13,"is_corresponding":false},{"id":250054,"name":"Li Du","orcid":"0000-0001-7700-4868","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T00:31:26.161109Z","pmid":"35378763","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}