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

Jessica C de Greef; Bram Slütter; Mary E Anderson; Rebecca Hamlyn; Raul O'Campo Landa; Ellison J McNutt; Yuji Hara; Lecia L Pewe; David Venzke; Kiichiro Matsumura; Fumiaki Saito; John T Harty; Kevin P Campbell

doi:10.1073/pnas.1904493116

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

Journal article

Open access

Peer reviewed

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

Jessica C de Greef, Bram Slütter, Mary E Anderson, Rebecca Hamlyn, Raul O'Campo Landa, Ellison J McNutt, Yuji Hara, Lecia L Pewe, David Venzke, Kiichiro Matsumura, …

Proceedings of the National Academy of Sciences - PNAS, Vol.116(23), pp.11396-11401

06/04/2019

DOI: 10.1073/pnas.1904493116

PMCID: PMC6561248

PMID: 31097590

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Abstract

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.

Cell Line

Basement Membrane - drug effects

Humans

Mice, Inbred C57BL

Inflammation - virology

Basement Membrane - virology

Body Fluids - drug effects

Body Fluids - virology

Glycosylation - drug effects

Influenza A Virus, H1N1 Subtype - drug effects

Dystroglycans - pharmacology

Lung - virology

Animals

Inflammation - drug therapy

Protective Agents - pharmacology

Lung - drug effects

HEK293 Cells

Influenza, Human - virology

Cell Proliferation - drug effects

Mice

Influenza, Human - drug therapy

Viral Load - methods

Orthomyxoviridae Infections - virology

Orthomyxoviridae Infections - drug therapy

Details

Title: Subtitle: Protective role for the N-terminal domain of α-dystroglycan in Influenza A virus proliferation
Creators: Jessica C de Greef - Department of Neurology, The University of Iowa, Iowa City, IA 52242
Bram Slütter - Department of Microbiology and Immunology, The University of Iowa, Iowa City, IA 52242
Mary E Anderson - Department of Neurology, The University of Iowa, Iowa City, IA 52242
Rebecca Hamlyn - Department of Neurology, The University of Iowa, Iowa City, IA 52242
Raul O'Campo Landa - Department of Neurology, The University of Iowa, Iowa City, IA 52242
Ellison J McNutt - Department of Neurology, The University of Iowa, Iowa City, IA 52242
Yuji Hara - Department of Neurology, The University of Iowa, Iowa City, IA 52242
Lecia L Pewe - Department of Microbiology and Immunology, The University of Iowa, Iowa City, IA 52242
David Venzke - Department of Neurology, The University of Iowa, Iowa City, IA 52242
Kiichiro Matsumura - Department of Neurology, Teikyo University School of Medicine, 173-8605 Tokyo, Japan
Fumiaki Saito - Department of Neurology, Teikyo University School of Medicine, 173-8605 Tokyo, Japan
John T Harty - Department of Pathology, The University of Iowa, Iowa City, IA 52242
Kevin P Campbell - Department of Neurology, The University of Iowa, Iowa City, IA 52242
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.116(23), pp.11396-11401
DOI: 10.1073/pnas.1904493116
PMID: 31097590
PMCID: PMC6561248
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: R01 AI114543 / NIAID NIH HHS U54 NS053672 / NINDS NIH HHS R01 AI042767 / NIAID NIH HHS Howard Hughes Medical Institute
Language: English
Date published: 06/04/2019
Academic Unit: Neurology; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute
Record Identifier: 9984068278602771

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