The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells

Yamaya, Mutsuo; Shimotai, Yoshitaka; Hatachi, Yukimasa; Kalonji, Nadine Lusamba; Tando, Yukiko; Kitajima, Yasuo; Matsuo, Kaori; Kubo, Hiroshi; Nagatomi, Ryoichi; Hongō, Seiji; Homma, M.; Nishimura, Hidekazu

doi:10.1016/j.pupt.2015.07.001

Cited by 76 publications

(120 citation statements)

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“…We identified the TMPRSS2 and TMPRSS11D protein at the cell membrane and in the cytoplasm of primary cultures of human tracheal epithelial cells using indirect immunofluorescence assay (Figure 2) [12]. We also detected mRNA encoding TMPRSS2, TMPRSS4 and TMPRSS11D in the cells [12]. Our findings pertaining to the expression of TMPRSS2, TMPRSS4 and TMPRSS11D in primary cultures of human tracheal epithelial cells [12] are consistent with the expression observed in previous reports.…”

Section: The Expression Of Serine Proteases In the Airways And Othersupporting

confidence: 90%

“…We also demonstrated that serine protease inhibitors, including camostat, reduced viral replication and inflammatory cytokine release from the cells [12].…”

Section: Introductionmentioning

confidence: 65%

“…Furthermore, the expression of a trypsin-like protease was identified in rat bronchiolar Clara cells [64]. We identified the TMPRSS2 and TMPRSS11D protein at the cell membrane and in the cytoplasm of primary cultures of human tracheal epithelial cells using indirect immunofluorescence assay (Figure 2) [12]. We also detected mRNA encoding TMPRSS2, TMPRSS4 and TMPRSS11D in the cells [12].…”

Section: The Expression Of Serine Proteases In the Airways And Othermentioning

confidence: 93%

“…TMPRSS2 is expressed in the human nasal and tracheal mucosa, distal airways, and lung [6,12,56,57]. TMPRSS2 is also expressed in the human Caco-2 colon cancer cell line, the human Huh7 hepatocellular carcinoma cell line [58], and swine airway epithelia [59].…”

Section: The Expression Of Serine Proteases In the Airways And Othermentioning

confidence: 99%

“…TMPRSS2 is also expressed in the human Caco-2 colon cancer cell line, the human Huh7 hepatocellular carcinoma cell line [58], and swine airway epithelia [59]. TMPRSS4 is expressed in lung cancer tissue [60], the mouse lung [61] and the human trachea [12], and TMPRSS11D is expressed in human bronchi and tracheae [12,62,63] and in swine airway epithelia [59]. Furthermore, the expression of a trypsin-like protease was identified in rat bronchiolar Clara cells [64].…”

Section: The Expression Of Serine Proteases In the Airways And Othermentioning

confidence: 99%

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Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Inflammation

Yamaya¹,

Shimotai²

2016

Clin Microbiol

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Influenza virus replication and the production of inflammatory cytokines are associated with symptoms, including fever, and exacerbation of bronchial asthma and chronic obstructive pulmonary disease. Proteolytic activation of influenza viruses by serine proteases that are produced by airway epithelial cells is essential for viral entry and replication. Transmembrane protease serine S1 member (TMPRSS) 2, TMPRSS4 and TMPRSS11D have been detected certain cells, including the human alveolar epithelial cell line A549 and the surface epithelial cells of the human nasal mucosa, the trachea, the distal airways, and the lung. Several protease inhibitors, including aprotinin, reduce influenza virus replication. We previously demonstrated the following: (1) TMPRSSs (TMPRSS2, 4, and 11D) are present in primary cultures of human tracheal epithelial cells; (2) serine protease inhibitors, such as camostat and aprotinin, reduce the influenza virus replication and the release of the cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α into cell supernatants; and (3) camostat reduces the cleavage of an influenza virus precursor protein, HA0, into the subunit HA1. These findings suggest that serine proteases expressed by human tracheal epithelial cells induce the proteolytic activation of influenza viruses and that serine protease inhibitors may reduce viral replication and the resultant production of inflammatory cytokines. Thus, serine protease inhibitors are potential candidates for anti-influenza virus drugs.Here, we review the expression of serine proteases, the role of serine proteases in influenza virus activation, and the effects of serine protease inhibitors. In this review, we aim to introduce the effects of serine proteases and their inhibitors on influenza virus infection of human airway epithelial cells by discussing the findings of previous studies performed by our group and other research groups. Furthermore, the clinical features and virulence of influenza virus infection are reviewed to clarify the association of virus replication and cytokine release with disease severity.

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Section: The Expression Of Serine Proteases In the Airways And Othersupporting

confidence: 90%

“…We also demonstrated that serine protease inhibitors, including camostat, reduced viral replication and inflammatory cytokine release from the cells [12].…”

Section: Introductionmentioning

confidence: 65%

Section: The Expression Of Serine Proteases In the Airways And Othermentioning

confidence: 93%

Section: The Expression Of Serine Proteases In the Airways And Othermentioning

confidence: 99%

Section: The Expression Of Serine Proteases In the Airways And Othermentioning

confidence: 99%

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Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Inflammation

Yamaya¹,

Shimotai²

2016

Clin Microbiol

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Smoking and COVID‐19: Similar bronchial ACE2 and TMPRSS2 expression and higher TMPRSS4 expression in current versus never smokers

Voinsky

Genevieve

2020

Drug Development Research

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Uncertainties remain concerning the pathophysiology, epidemiology, and potential therapeutics for COVID‐19. Among unsettled controversies is whether tobacco smoking increases or protects from severe COVID‐19. Several epidemiological studies reported reduced COVID‐19 hospitalizations among smokers, while other studies reported the opposite trend. Some authors assumed that smokers have elevated airway expression of ACE2, the cell recognition site of the SARS‐Cov‐2 spike protein, but this suggestion remains unverified. We therefore performed data mining of two independent NCBI GEO genome‐wide RNA expression files (GSE7894 and GSE994) and report that in both data sets, current smokers and never smokers have, on average, closely similar bronchial epithelial cell mRNA levels of ACE2 , as well as TMPRSS2 , coding for a serine protease priming SARS‐Cov‐2 for cell entry, and ADAM17 , coding for a protease implicated in ACE2 membrane shedding. In contrast, the expression levels of TMPRSS4 , coding for a protease that primes SARS‐CoV‐2 for cell entry similarly to TMPRSS2 , were elevated in bronchial epithelial cells from current smokers compared with never smokers, suggesting that higher bronchial TMPRSS4 levels in smokers might put them at higher SARS‐Cov‐2 infection risk. The effects of smoking on COVID‐19 severity need clarification with larger studies. Additionally, the postulated protective effects of nicotine and nitric oxide, which may presumably reduce the risk of a “cytokine storm” in infected individuals, deserve assessment by controlled clinical trials.

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

Yamaya

Shimotai

Ohkawara

et al. 2020

Journal of Medical Virology

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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.

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The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells

Cited by 76 publications

References 50 publications

Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Inflammation

Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Inflammation

Smoking and COVID‐19: Similar bronchial ACE2 and TMPRSS2 expression and higher TMPRSS4 expression in current versus never smokers

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

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