The effects of neuraminidase inhibitors on the release of oseltamivir-sensitive and oseltamivir-resistant influenza viruses from primary cultures of human tracheal epithelium

Yamaya, Mutsuo; Nadine, Lusamba; Kubo, Hiroshi; Saito, Ko; Saito, Reiko; Nishimura, Hidekazu

doi:10.1002/jmv.23974

Cited by 5 publications

(9 citation statements)

References 34 publications

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“…In this report, we found that the NA segment of H9N2 AIV modulated the immune function of DCs by adjusting miR-155 and miR-674 expression. NA, an envelope glycoprotein on the surface of the influenza virus, catalyses the cleavage of sialic acids on glycoproteins from virus-infected cells and enables virus release [18, 19]. Studies have demonstrated that low NA enzyme activity renders virus release from infected cells inefficient and leaves progeny viruses gathered on the cell surface [19, 20].…”

Section: Discussionmentioning

confidence: 99%

“…NA, an envelope glycoprotein on the surface of the influenza virus, catalyses the cleavage of sialic acids on glycoproteins from virus-infected cells and enables virus release [18, 19]. Studies have demonstrated that low NA enzyme activity renders virus release from infected cells inefficient and leaves progeny viruses gathered on the cell surface [19, 20]. DCs represent a central element in the generation and maintenance of immune responses [21].…”

Section: Discussionmentioning

confidence: 99%

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MiR674 inhibits the neuraminidase-stimulated immune response on dendritic cells via down-regulated Mbnl3

et al. 2016

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Neuraminidase (NA), a structural protein of the H9N2 avian influenza virus (H9N2 AIV), can facilitate viral invasion of the upper airway by cleaving the sialic acid moieties on mucin. Dendritic cells (DCs) are major antigen-presenting cells whose immune functions, such as presenting antigens and activating lymphocytes, can be regulated by microRNAs. Here, we studied the molecular mechanism of miRNA-induced repression of immune responses in mouse DCs. First, we screened for and verified the miRNAs induced by NA. Then, we showed that, consistent with the H9N2 virus treatment, the viral NA up-regulated the expression of miR-155, miR-674, and miR-499 in DCs; however, unlike H9N2 virus treatment, the presence of NA was associated with reduced expression of miR-181b1. Our results suggest that NA significantly increased DC surface markers CD80 and MHCII and enhanced the ability of activating lymphocytes and secreting cytokines compared with HA, NP and M2. Meanwhile, we found that miR-674 and miR-155 over-expression increased all surface markers of DC. Nevertheless, by inhibiting the expression of miR-674 and miR-155, NA lost the ability to promote DC maturation. Furthermore, we predicted and demonstrated that Pgm2l1, Aldh18a1, Camk1d, and Mbnl3 were the target genes of miR-674. Among them, Mbnl3 interference strongly blocked the mature DCs. Collectively, our data shed new light on the roles of and mechanisms involved in the repression of DCs by miRNAs, which may contribute to efforts to develop a prophylaxis for the influenza virus.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MiR674 inhibits the neuraminidase-stimulated immune response on dendritic cells via down-regulated Mbnl3

et al. 2016

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“…Oseltamivir-resistant influenza A (H1N1) virus infection has been reported, and this type of seasonal influenza has caused severe disease in immuno-compromised patients [26]. In a previous study, Oseltamivir did not reduce inflammatory cytokine production by airway epithelial cells after infection with seasonal influenza viruses with an Oseltamivir-resistant genotype [27]. Moreover, Oseltamivir did not reduce viral titers or viral RNA levels.…”

Section: Clinical Features Of Influenza Virus Infection and Antiinflumentioning

confidence: 97%

“…Moreover, Oseltamivir did not reduce viral titers or viral RNA levels. The 50% inhibitory concentration (IC 50 ) of Oseltamivir for neuraminidase activity in the Oseltamivir-resistant seasonal virus was 300-fold higher than that observed for the pandemic influenza virus [27]. According to a report by Shobugawa et al, oral intake of Oseltamivir is feasible for children younger than 5 years old, whereas Zanamivir inhalation is prescribed for children ≥ 5 years old [28].…”

Section: Clinical Features Of Influenza Virus Infection and Antiinflumentioning

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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Effects of high temperature on pandemic and seasonal human influenza viral replication and infection-induced damage in primary human tracheal epithelial cell cultures

Yamaya

Nishimura

Kalonji

et al. 2019

Heliyon

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High temperature reduces influenza viral replication; however, the treatment of fevers is thought to be necessary to improve patients' conditions. We examined the effects of high temperature on viral replication and infection-induced damage to human tracheal epithelial cells. Cell viability and dome formation were reduced, the number of detached cells was increased and lactate dehydrogenase (LDH) levels tended to be increased from 72 h to 120 h in uninfected cells cultured at 40 °C. Long-term (72 h and/or 120 h) exposure to high temperatures (39 °C and/or 40 °C) decreased RNA levels and/or viral titers of eight influenza virus strains. Cell viability and dome formation were reduced, and the number of detached cells and LDH levels were increased to a similar extent after infection with the A/H1N1 pdm 2009 virus at 37 °C and 40 °C. High temperature increased the endosomal pH, where the viral RNA enters the cytoplasm, in uninfected cells. High temperature reduced the production of IL-6, which mediate viral replication processes, and IL-1β and IL-8 in uninfected and infected cells. Based on these findings, high temperature may cause similar levels of airway cell damage after infection to cells exposed normal temperatures, although high temperature reduces viral replication by affecting the function of acidic endosomes and inhibiting IL-6-mediated processes.

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The effects of neuraminidase inhibitors on the release of oseltamivir-sensitive and oseltamivir-resistant influenza viruses from primary cultures of human tracheal epithelium

Cited by 5 publications

References 34 publications

MiR674 inhibits the neuraminidase-stimulated immune response on dendritic cells via down-regulated Mbnl3

MiR674 inhibits the neuraminidase-stimulated immune response on dendritic cells via down-regulated Mbnl3

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

Effects of high temperature on pandemic and seasonal human influenza viral replication and infection-induced damage in primary human tracheal epithelial cell cultures

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