The clinically used serine protease inhibitor nafamostat reduces influenza virus replication and cytokine production in human airway epithelial cells and viral replication in mice.

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.

• Authors: Mutsuo Yamaya, Yoshitaka Shimotai, Ayako Ohkawara, Enkhbold Bazarragchaa, Masatoshi Okamatsu, Yoshihiro Sakoda, Hiroshi Kida, Hidekazu Nishimura
• Journal: Journal of medical virology (J Med Virol) Vol. 93 Issue 6 Pg. 3484-3495 (06 2021) ISSN: 1096-9071 [Electronic] United States
• PMID: 33247612 (Publication Type: Journal Article)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Benzamidines
• Cytokines
• Guanidines
• Serine Proteinase Inhibitors
• nafamostat

Topics

• Animals
• Benzamidines (pharmacology, therapeutic use)
• Cells, Cultured
• Cytokines (analysis, immunology)
• Epithelial Cells (drug effects, virology)
• Female
• Guanidines (pharmacology, therapeutic use)
• Humans
• Lung (drug effects, virology)
• Male
• Mice
• Mice, Inbred BALB C
• Nose (cytology)
• Serine Proteinase Inhibitors (pharmacology, therapeutic use)
• Trachea (cytology)
• Virus Replication (drug effects)