TMPRSS2 Is an Activating Protease for Respiratory Parainfluenza Viruses

Abe, Masako; Tahara, Maino; Sakai, Kouji; Yamaguchi, Hiromi; Kanou, Kazuhiko; Shirato, Kunio; Kawase, Miyuki; Noda, Masahiro; Kimura, Hirokazu; Matsuyama, Shutoku; Fukuhara, Hideo; Mizuta, Katsumi; Maenaka, Katsumi; Ami, Yasushi; Esumi, Mariko; Kato, Atsushi; Takeda, Makoto

doi:10.1128/jvi.01490-13

Cited by 65 publications

(57 citation statements)

References 32 publications

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“…TMPRSS2 proteolytically activates a wide range of viral envelope proteins (14,16,25,(28)(29)(30)(31)(32)(33)(34)(35) and has been shown to be critical for the in vivo activation of influenza viruses (36)(37)(38). Therefore, it will be interesting to examine the efficacy of nafamostat against viruses other than MERS-CoV.…”

Section: Discussionmentioning

confidence: 99%

Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay

Yamamoto

Matsuyama

et al. 2016

Antimicrob Agents Chemother

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329

301

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e Middle East respiratory syndrome (MERS) is an emerging infectious disease associated with a relatively high mortality rate of approximately 40%. MERS is caused by MERS coronavirus (MERS-CoV) infection, and no specific drugs or vaccines are currently available to prevent MERS-CoV infection. MERS-CoV is an enveloped virus, and its envelope protein (S protein) mediates membrane fusion at the plasma membrane or endosomal membrane. Multiple proteolysis by host proteases, such as furin, transmembrane protease serine 2 (TMPRSS2), and cathepsins, causes the S protein to become fusion competent. TMPRSS2, which is localized to the plasma membrane, is a serine protease responsible for the proteolysis of S in the post-receptor-binding stage. Here, we developed a cell-based fusion assay for S in a TMPRSS2-dependent manner using cell lines expressing Renilla luciferase (RL)-based split reporter proteins. S was stably expressed in the effector cells, and the corresponding receptor for S, CD26, was stably coexpressed with TMPRSS2 in the target cells. Membrane fusion between these effector and target cells was quantitatively measured by determining the RL activity. The assay was optimized for a 384-well format, and nafamostat, a serine protease inhibitor, was identified as a potent inhibitor of S-mediated membrane fusion in a screening of about 1,000 drugs approved for use by the U.S. Food and Drug Administration. Nafamostat also blocked MERS-CoV infection in vitro. Our assay has the potential to facilitate the discovery of new inhibitors of membrane fusion of MERS-CoV as well as other viruses that rely on the activity of TMPRSS2.

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Section: Discussionmentioning

confidence: 99%

Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay

Yamamoto

Matsuyama

et al. 2016

Antimicrob Agents Chemother

Self Cite

329

301

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“…Further studies will be necessary to determine whether the KLK1-to-kallistatin ratio might serve as an early biomarker for acute influenza virus infection. Since proteolytic activation is also essential for the infectious cycle of some viruses besides influenza virus, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and respiratory parainfluenza virus (64,65), whether KLK1 and kallistatin have impacts on infection by these viruses warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin

Leu

Yang

Chung

et al. 2015

Antimicrob Agents Chemother

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i Proteolytic cleavage of the hemagglutinin (HA) of influenza virus by host trypsin-like proteases is required for viral infectivity. Some serine proteases are capable of cleaving influenza virus HA, whereas some serine protease inhibitors (serpins) inhibit the HA cleavage in various cell types. Kallikrein-related peptidase 1 (KLK1, also known as tissue kallikrein) is a widely distributed serine protease. Kallistatin, a serpin synthesized mainly in the liver and rapidly secreted into the circulation, forms complexes with KLK1 and inhibits its activity. Here, we investigated the roles of KLK1 and kallistatin in influenza virus infection. We show that the levels of KLK1 increased, whereas those of kallistatin decreased, in the lungs of mice during influenza virus infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. In contrast, kallistatin inhibited KLK1-mediated HA cleavage and reduced viral production. Cells transduced with the kallistatin gene secreted kallistatin extracellularly, which rendered them more resistant to influenza virus infection. Furthermore, lentivirus-mediated kallistatin gene delivery protected mice against lethal influenza virus challenge by reducing the viral load, inflammation, and injury in the lung. Taking the data together, we determined that KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting the cleavage of the HA peptide and inflammatory responses. This study provides a proof of principle for the potential therapeutic application of kallistatin or other KLK1 inhibitors for influenza. Since proteolytic activation also enhances the infectivity of some other viruses, kallistatin and other kallikrein inhibitors may be explored as antiviral agents against these viruses.

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“…TMPRSS2 was shown to activate the fusion proteins of some paramyxoviruses (i.e. metapneumovirus [58], trypsin-dependent parainfluenza subtypes and Sendai virus [59]). Likewise, for some human coronaviruses including the deadly SARS and MERS variants [8,60,61,62 ], TMPRSS2 cleavage activates the viral spike (S)-protein at the cell surface enabling cathepsin-independent host cell entry [63,64].…”

Section: Potential For Safe and Broad Spectrum Antiviral Therapymentioning

confidence: 99%

Airway proteases: an emerging drug target for influenza and other respiratory virus infections

Laporte

Naesens

2017

Current Opinion in Virology

106

101

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To enter into airway epithelial cells, influenza, parainfluenza- and coronaviruses rely on host cell proteases for activation of the viral protein involved in membrane fusion. One protease, transmembrane protease serine 2 (TMPRSS2) was recently proven to be crucial for hemagglutinin cleavage of some human influenza viruses. Since the catalytic sites of the diverse serine proteases linked to influenza, parainfluenza- and coronavirus activation are structurally similar, active site inhibitors of these airway proteases could have broad therapeutic applicability against multiple respiratory viruses. Alternatively, superior selectivity could be achieved with allosteric inhibitors of TMPRSS2 or another critical protease. Though still in its infancy, airway protease inhibition represents an attractive host-cell targeting approach to combat respiratory viruses such as influenza.

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TMPRSS2 Is an Activating Protease for Respiratory Parainfluenza Viruses

Cited by 65 publications

References 32 publications

Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay

Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay

Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin

Airway proteases: an emerging drug target for influenza and other respiratory virus infections

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