TMPRSS2 Activates Hemagglutinin-Esterase Glycoprotein of Influenza C Virus

Influenza C virus (ICV) has only one kind of spike protein, the hemagglutinin-esterase (HE) glycoprotein. HE functions similarly to hemagglutinin (HA) and neuraminidase of the influenza A and B viruses (IAV and IBV, respectively). It has a monobasic site, which is cleaved by some host enzymes. The c...

Full description

Saved in:
Bibliographic Details
Published in:Journal of virology 2021-10, Vol.95 (21), p.e0129621-e0129621
Main Authors: Sato, Ko, Hayashi, Hideki, Shimotai, Yoshitaka, Yamaya, Mutsuo, Hongo, Seiji, Kawakami, Kazuyoshi, Matsuzaki, Yoko, Nishimura, Hidekazu
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antiviral Agents - pharmacology
Benzamidines - pharmacology
Cell Line
Cell Line, Tumor
Cells, Cultured
Dogs
Esters - pharmacology
Gammainfluenzavirus - enzymology
Gammainfluenzavirus - metabolism
Guanidines - pharmacology
Hemagglutinins, Viral - metabolism
Host Microbial Interactions
Humans
Influenza, Human - virology
Madin Darby Canine Kidney Cells
Orthomyxoviridae Infections - virology
Serine Endopeptidases - metabolism
Trypsin - metabolism
Viral Fusion Proteins - metabolism
Viral Proteins - metabolism
Virus-Cell Interactions
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Influenza C virus (ICV) has only one kind of spike protein, the hemagglutinin-esterase (HE) glycoprotein. HE functions similarly to hemagglutinin (HA) and neuraminidase of the influenza A and B viruses (IAV and IBV, respectively). It has a monobasic site, which is cleaved by some host enzymes. The cleavage is essential to activating the virus, but the enzyme or enzymes in the respiratory tract have not been identified. This study investigated whether the host serine proteases, transmembrane protease serine S1 member 2 (TMPRSS2) and human airway trypsin-like protease (HAT), which reportedly cleave HA of IAV/IBV, are involved in HE cleavage. We established TMPRSS2- and HAT-expressing MDCK cells (MDCK-TMPRSS2 and MDCK-HAT). ICV showed multicycle replication with HE cleavage without trypsin in MDCK-TMPRSS2 cells as well as IAV did. The HE cleavage and multicycle replication did not appear in MDCK-HAT cells infected with ICV without trypsin, while HA cleavage and multistep growth of IAV appeared in the cells. Amino acid sequences of the HE cleavage site in 352 ICV strains were completely preserved. Camostat and nafamostat suppressed the growth of ICV and IAV in human nasal surface epithelial (HNE) cells. Therefore, this study revealed that, at least, TMPRSS2 is involved in HE cleavage and suggested that nafamostat could be a candidate for therapeutic drugs for ICV infection. Influenza C virus (ICV) is a pathogen that causes acute respiratory illness, mostly in children, but there are no anti-ICV drugs. ICV has only one kind of spike protein, the hemagglutinin-esterase (HE) glycoprotein on the virion surface, which possesses receptor-binding, receptor-destroying, and membrane fusion activities. The HE cleavage is essential for the virus to be activated, but the enzyme or enzymes in the respiratory tract have not been identified. This study revealed that transmembrane protease serine S1 member 2 (TMPRSS2), and not human airway trypsin-like protease (HAT), is involved in HE cleavage. This is a novel study on the host enzymes involved in HE cleavage, and the result suggests that the host enzymes, such as TMPRSS2, may be a target for therapeutic drugs of ICV infection.
ISSN:0022-538X
1098-5514
DOI:10.1128/jvi.01296-21