Protective role for the N-terminal domain of α-dystroglycan in Influenza A virus proliferation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-06, Vol.116 (23), p.11396-11401
• Main Authors: de Greef, Jessica C., Slütter, Bram, Anderson, Mary E., Hamlyn, Rebecca, Landa, Raul O’Campo, McNutt, Ellison J., Hara, Yuji, Pewe, Lecia L., Venzke, David, Matsumura, Kiichiro, Saito, Fumiaki, Harty, John T., Campbell, Kevin P.
• Format: Article
• Language: English
• Subjects: Animals; Basement Membrane - drug effects; Basement Membrane - virology; Biological Sciences; Body fluids; Body Fluids - drug effects; Body Fluids - virology; Cell Line; Cell Proliferation - drug effects; Dystroglycan; Dystroglycans - pharmacology; Furin; Glycosylation; Glycosylation - drug effects; Glycosyltransferase; HEK293 Cells; Hemagglutination inhibition; Humans; Infections; Inflammation - drug therapy; Inflammation - virology; Influenza; Influenza A; Influenza A Virus, H1N1 Subtype - drug effects; Influenza, Human - drug therapy; Influenza, Human - virology; Lung - drug effects; Lung - virology; Lungs; Mice; Mice, Inbred C57BL; Mucin; Neutralization; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - virology; Proprotein convertases; Protective Agents - pharmacology; Viral Load - methods; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1904493116

α-Dystroglycan (α-DG) is a highly glycosylated basement membrane receptor that is cleaved by the proprotein convertase furin, which releases its N-terminal domain (α-DGN). Before cleavage, α-DGN interacts with the glycosyltransferase LARGE1 and initiates functional O-glycosylation of the mucin-like domain of α-DG. Notably, α-DGN has been detected in a wide variety of human bodily fluids, but the physiological significance of secreted α-DGN remains unknown. Here, we show that mice lacking α-DGN exhibit significantly higher viral titers in the lungs after Influenza A virus (IAV) infection (strain A/Puerto Rico/8/1934 H1N1), suggesting an inability to control virus load. Consistent with this, overexpression of α-DGN before infection or intranasal treatment with recombinant α-DGN prior and during infection, significantly reduced IAV titers in the lungs of wild-type mice. Hemagglutination inhibition assays using recombinant α-DGN showed in vitro neutralization of IAV. Collectively, our results support a protective role for α-DGN in IAV proliferation.