tetano
Editor, Senior Moderator
Antimicrob Agents Chemother. 2015 Jul 6. pii: AAC.00065-15. [Epub ahead of print]
[h=1]Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin.[/h] Leu CH[SUP]1[/SUP], Yang ML[SUP]2[/SUP], Chung NH[SUP]2[/SUP], Huang YJ[SUP]3[/SUP], Su YC[SUP]3[/SUP], Chen YC[SUP]3[/SUP], Lin CC[SUP]4[/SUP], Shieh GS[SUP]5[/SUP], Chang MY[SUP]6[/SUP], Wang SW[SUP]7[/SUP], Chang Y[SUP]8[/SUP], Chao J[SUP]9[/SUP], Chao L[SUP]9[/SUP], Wu CL[SUP]10[/SUP], Shiau AL[SUP]11[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 lung of mice during influenza infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. By 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 viral load, inflammation, and injury in the lung. Taken together, we identify 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.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26149981 [PubMed - as supplied by publisher]
[h=1]Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin.[/h] Leu CH[SUP]1[/SUP], Yang ML[SUP]2[/SUP], Chung NH[SUP]2[/SUP], Huang YJ[SUP]3[/SUP], Su YC[SUP]3[/SUP], Chen YC[SUP]3[/SUP], Lin CC[SUP]4[/SUP], Shieh GS[SUP]5[/SUP], Chang MY[SUP]6[/SUP], Wang SW[SUP]7[/SUP], Chang Y[SUP]8[/SUP], Chao J[SUP]9[/SUP], Chao L[SUP]9[/SUP], Wu CL[SUP]10[/SUP], Shiau AL[SUP]11[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 lung of mice during influenza infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. By 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 viral load, inflammation, and injury in the lung. Taken together, we identify 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.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26149981 [PubMed - as supplied by publisher]