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Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airways

The Journal of biological chemistry, 2020-08, Vol.295 (33), p.11388-11407 [Peer Reviewed Journal]

2020 © 2020 Harbig et al. ;2020 Harbig et al. ;2020 Harbig et al. 2020 Harbig et al. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA120.012635 ;PMID: 32303635

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Title:
Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airways
Author: Harbig, Anne ; Mernberger, Marco ; Bittel, Linda ; Pleschka, Stephan ; Schughart, Klaus ; Steinmetzer, Torsten ; Stiewe, Thorsten ; Nist, Andrea ; Böttcher-Friebertshäuser, Eva
Subjects: airway proteases ; Animals ; Cell Line ; cleavage ; Dogs ; Editors' Picks ; Enzyme Activation - drug effects ; Gene Expression Profiling ; HEK293 Cells ; hemagglutinin ; hepsin ; host-pathogen interactions ; Host-Pathogen Interactions - drug effects ; Humans ; infectious disease ; Influenza A Virus, H3N2 Subtype - drug effects ; Influenza A Virus, H3N2 Subtype - physiology ; Influenza B virus - drug effects ; Influenza B virus - physiology ; influenza virus ; Influenza, Human - drug therapy ; Influenza, Human - enzymology ; Influenza, Human - genetics ; Influenza, Human - virology ; Lung - enzymology ; Lung - metabolism ; Lung - virology ; Madin Darby Canine Kidney Cells ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; mouse ; mouse lung proteases ; Orthomyxoviridae Infections - drug therapy ; Orthomyxoviridae Infections - enzymology ; Orthomyxoviridae Infections - genetics ; Orthomyxoviridae Infections - virology ; Peptide Hydrolases - genetics ; Peptide Hydrolases - metabolism ; prostasin ; protease gene expression ; Protease Inhibitors - pharmacology ; Serine Endopeptidases - genetics ; Serine Endopeptidases - metabolism ; serine protease ; TMPRSS2 ; TMPRSS4 ; trypsin ; trypsin-like protease ; virus ; Virus Activation - drug effects
Is Part Of: The Journal of biological chemistry, 2020-08, Vol.295 (33), p.11388-11407
Description: Cleavage of influenza virus hemagglutinin (HA) by host proteases is essential for virus infectivity. HA of most influenza A and B (IAV/IBV) viruses is cleaved at a monobasic motif by trypsin-like proteases. Previous studies have reported that transmembrane serine protease 2 (TMPRSS2) is essential for activation of H7N9 and H1N1pdm IAV in mice but that H3N2 IAV and IBV activation is independent of TMPRSS2 and carried out by as-yet-undetermined protease(s). Here, to identify additional H3 IAV- and IBV-activating proteases, we used RNA-Seq to investigate the protease repertoire of murine lower airway tissues, primary type II alveolar epithelial cells (AECIIs), and the mouse lung cell line MLE-15. Among 13 candidates identified, TMPRSS4, TMPRSS13, hepsin, and prostasin activated H3 and IBV HA in vitro. IBV activation and replication was reduced in AECIIs from Tmprss2/Tmprss4-deficient mice compared with WT or Tmprss2-deficient mice, indicating that murine TMPRSS4 is involved in IBV activation. Multicycle replication of H3N2 IAV and IBV in AECIIs of Tmprss2/Tmprss4-deficient mice varied in sensitivity to protease inhibitors, indicating that different, but overlapping, sets of murine proteases facilitate H3 and IBV HA cleavages. Interestingly, human hepsin and prostasin orthologs did not activate H3, but they did activate IBV HA in vitro. Our results indicate that TMPRSS4 is an IBV-activating protease in murine AECIIs and suggest that TMPRSS13, hepsin, and prostasin cleave H3 and IBV HA in mice. They further show that hepsin and prostasin orthologs might contribute to the differences observed in TMPRSS2-independent activation of H3 in murine and human airways.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.RA120.012635
PMID: 32303635
Source: MEDLINE
PubMed Central
Alma/SFX Local Collection

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Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airways

2020 © 2020 Harbig et al. ;2020 Harbig et al. ;2020 Harbig et al. 2020 Harbig et al. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA120.012635 ;PMID: 32303635

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