The Proteolytic Activation of (H3N2) Influenza A Virus Hemagglutinin Is Facilitated by Different Type II Transmembrane Serine Proteases.

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Version: Final published version
Serval ID
serval:BIB_F4A7CA0ED352
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The Proteolytic Activation of (H3N2) Influenza A Virus Hemagglutinin Is Facilitated by Different Type II Transmembrane Serine Proteases.
Journal
Journal of Virology
Author(s)
Kühn N., Bergmann S., Kösterke N., Lambertz R.L., Keppner A., van den Brand J.M., Pöhlmann S., Weiß S., Hummler E., Hatesuer B., Schughart K.
ISSN
1098-5514 (Electronic)
ISSN-L
0022-538X
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
90
Number
9
Pages
4298-4307
Language
english
Abstract
UNLABELLED: Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is necessary for viral activation and infectivity. In humans and mice, members of the type II transmembrane protease family (TTSP), e.g., TMPRSS2, TMPRSS4, and TMPRSS11d (HAT), have been shown to cleave influenza virus HA for viral activation and infectivity in vitro Recently, we reported that inactivation of a single HA-activating protease gene,Tmprss2, in knockout mice inhibits the spread of H1N1 influenza viruses. However, after infection of Tmprss2 knockout mice with an H3N2 influenza virus, only a slight increase in survival was observed, and mice still lost body weight. In this study, we investigated an additional trypsin-like protease, TMPRSS4. Both TMPRSS2 and TMPRSS4 are expressed in the same cell types of the mouse lung. Deletion of Tmprss4 alone in knockout mice does not protect them from body weight loss and death upon infection with H3N2 influenza virus. In contrast,Tmprss2(-/-)Tmprss4(-/-)double-knockout mice showed a remarkably reduced virus spread and lung pathology, in addition to reduced body weight loss and mortality. Thus, our results identified TMPRSS4 as a second host cell protease that, in addition to TMPRSS2, is able to activate the HA of H3N2 influenza virus in vivo
IMPORTANCE: Influenza epidemics and recurring pandemics are responsible for significant global morbidity and mortality. Due to high variability of the virus genome, resistance to available antiviral drugs is frequently observed, and new targets for treatment of influenza are needed. Host cell factors essential for processing of the virus hemagglutinin represent very suitable drug targets because the virus is dependent on these host factors for replication. We reported previously that Tmprss2-deficient mice are protected against H1N1 virus infections, but only marginal protection against H3N2 virus infections was observed. Here we show that deletion of two host protease genes,Tmprss2 and Tmprss4, strongly reduced viral spread as well as lung pathology and resulted in increased survival after H3N2 virus infection. Thus, TMPRSS4 represents another host cell factor that is involved in cleavage activation of H3N2 influenza viruses in vivo.
Keywords
Animals, Bronchi/metabolism, Bronchi/virology, Chemokines/metabolism, Cytokines/metabolism, Disease Models, Animal, Disease Susceptibility, Enzyme Activation, Female, Gene Deletion, Gene Expression, Hemagglutinin Glycoproteins, Influenza Virus/metabolism, Host-Pathogen Interactions, Influenza A Virus, H3N2 Subtype/physiology, Membrane Proteins/genetics, Membrane Proteins/metabolism, Mice, Mice, Knockout, Orthomyxoviridae Infections/genetics, Orthomyxoviridae Infections/immunology, Orthomyxoviridae Infections/</QualifierName> <QualifierName MajorTopicYN="Y" UI="Q000821">, Proteolysis, Pulmonary Alveoli/metabolism, Pulmonary Alveoli/virology, Serine Endopeptidases/genetics, Serine Endopeptidases/metabolism, Viral Load, Virus Replication
Pubmed
Web of science
Open Access
Yes
Create date
16/02/2016 18:49
Last modification date
20/08/2019 17:21
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