SARS-Cov-2 spike induces intestinal barrier dysfunction through the interaction between CEACAM5 and Galectin-9

Area of Science:

• Gastroenterology
• Immunology
• Virology

Background:

• Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) has immunomodulatory effects and its reduction in COVID-19 patients' feces correlates with gut dysbiosis.
• The specific role of CEACAM5 in gastrointestinal infections, particularly SARS-CoV-2, remains unclear.

Purpose of the Study:

• To investigate the role of CEACAM5 in SARS-CoV-2-induced intestinal inflammation and barrier dysfunction.
• To elucidate the molecular mechanisms underlying CEACAM5's involvement in gut inflammation.

Main Methods:

• Established a mouse model of intestinal inflammation by injecting recombinant SARS-CoV-2 spike-Fc protein.
• Utilized proteomic analysis, KEGG pathway analysis, protein-protein interaction (PPI) network analysis, molecular docking, and co-immunoprecipitation (co-IP) assays.
• Co-cultured Caco-2 cells with CD4+ T cells isolated from healthy donors.

Main Results:

• SARS-CoV-2 spike-Fc stimulation decreased intestinal CEACAM5, tight junction expression, and CD4+ T lymphocytes, while increasing inflammatory factors.
• KEGG analysis highlighted enrichment in COVID-19, tight junction, focal adhesion, adherens junction, and PI3K-Akt signaling pathways.
• Identified an interaction between CEACAM5 and Galectin-9, where reduced CEACAM5 in enterocytes promoted Galectin-9 expression in CD4+ T cells, leading to inflammation and apoptosis via PI3K/AKT/mTOR inhibition and subsequent intestinal barrier dysfunction.

Conclusions:

• CEACAM5 overexpression and Galectin-9 knockdown demonstrate a protective effect against spike-Fc-induced intestinal barrier injury.
• SARS-CoV-2 spike protein induces intestinal barrier dysfunction through the CEACAM5-Galectin-9 interaction.
• These findings identify potential therapeutic targets for treating intestinal barrier dysfunction in severe COVID-19 patients.