tetano
Editor, Senior Moderator
J Med Virol
. 2020 Nov 28.
doi: 10.1002/jmv.26700. Online ahead of print.
The clinically used serine protease inhibitor nafamostat reduces influenza virus replication and cytokine production in human airway epithelial cells and viral replication in mice
Mutsuo Yamaya[SUP] 1 2 [/SUP], Yoshitaka Shimotai[SUP] 3 [/SUP], Ayako Ohkawara[SUP] 4 [/SUP], Enkhbold Bazarragchaa[SUP] 4 [/SUP], Masatoshi Okamatsu[SUP] 4 [/SUP], Yoshihiro Sakoda[SUP] 4 5 [/SUP], Hiroshi Kida[SUP] 5 6 [/SUP], Hidekazu Nishimura[SUP] 1 [/SUP]
Affiliations
Abstract
The effects of the clinically used protease inhibitor nafamostat on influenza virus replication have not been well studied. Primary human tracheal (HTE) and nasal (HNE) epithelial cells were pretreated with nafamostat and infected with the 2009 pandemic [A/Sendai-H/108/2009/(H1N1) pdm09] or seasonal [A/New York/55/2004(H3N2)] influenza virus. Pretreatment with nafamostat reduced the titers of the pandemic and seasonal influenza viruses and the secretion of inflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, in the supernatants of the cells infected with the pandemic influenza virus. HTE and HNE cells exhibited mRNA and/or protein expression of transmembrane protease serine 2 (TMPRSS2), TMPRSS4 and TMPRSS11D. Pretreatment with nafamostat reduced cleavage of the precursor protein HA0 of the pandemic influenza virus into subunit HA1 in HTE cells and reduced the number of acidic endosomes in HTE and HNE cells where influenza virus RNA enters the cytoplasm. Additionally, nafamostat (30 mg/kg/day, intraperitoneal administration) reduced the levels of the pandemic influenza virus [A/Hyogo/YS/2011 (H1N1) pdm09] in mouse lung washes. These findings suggest that nafamostat may inhibit influenza virus replication in human airway epithelial cells and mouse lungs and reduce infection-induced airway inflammation by modulating cytokine production. This article is protected by copyright. All rights reserved.
Keywords: antiviral agents; cell cultures; cytokines; influenza virus; protease inhibitor; respiratory tract.
. 2020 Nov 28.
doi: 10.1002/jmv.26700. Online ahead of print.
The clinically used serine protease inhibitor nafamostat reduces influenza virus replication and cytokine production in human airway epithelial cells and viral replication in mice
Mutsuo Yamaya[SUP] 1 2 [/SUP], Yoshitaka Shimotai[SUP] 3 [/SUP], Ayako Ohkawara[SUP] 4 [/SUP], Enkhbold Bazarragchaa[SUP] 4 [/SUP], Masatoshi Okamatsu[SUP] 4 [/SUP], Yoshihiro Sakoda[SUP] 4 5 [/SUP], Hiroshi Kida[SUP] 5 6 [/SUP], Hidekazu Nishimura[SUP] 1 [/SUP]
Affiliations
- PMID: 33247612
- DOI: 10.1002/jmv.26700
Abstract
The effects of the clinically used protease inhibitor nafamostat on influenza virus replication have not been well studied. Primary human tracheal (HTE) and nasal (HNE) epithelial cells were pretreated with nafamostat and infected with the 2009 pandemic [A/Sendai-H/108/2009/(H1N1) pdm09] or seasonal [A/New York/55/2004(H3N2)] influenza virus. Pretreatment with nafamostat reduced the titers of the pandemic and seasonal influenza viruses and the secretion of inflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, in the supernatants of the cells infected with the pandemic influenza virus. HTE and HNE cells exhibited mRNA and/or protein expression of transmembrane protease serine 2 (TMPRSS2), TMPRSS4 and TMPRSS11D. Pretreatment with nafamostat reduced cleavage of the precursor protein HA0 of the pandemic influenza virus into subunit HA1 in HTE cells and reduced the number of acidic endosomes in HTE and HNE cells where influenza virus RNA enters the cytoplasm. Additionally, nafamostat (30 mg/kg/day, intraperitoneal administration) reduced the levels of the pandemic influenza virus [A/Hyogo/YS/2011 (H1N1) pdm09] in mouse lung washes. These findings suggest that nafamostat may inhibit influenza virus replication in human airway epithelial cells and mouse lungs and reduce infection-induced airway inflammation by modulating cytokine production. This article is protected by copyright. All rights reserved.
Keywords: antiviral agents; cell cultures; cytokines; influenza virus; protease inhibitor; respiratory tract.