Kallistatin ameliorates influenza virus pathogenesis by inhibition of kallikrein-related peptidase 1-mediated cleavage of viral hemagglutinin.

Abstract

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 lungs of mice during influenza virus infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. In 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 the viral load, inflammation, and injury in the lung. Taking the data together, we determined 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.

• Authors: Chia-Hsing Leu, Mei-Lin Yang, Nai-Hui Chung, Yen-Jang Huang, Yu-Chu Su, Yi-Cheng Chen, Chia-Cheng Lin, Gia-Shing Shieh, Meng-Ya Chang, Shainn-Wei Wang, Yao Chang, Julie Chao, Lee Chao, Chao-Liang Wu, Ai-Li Shiau
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 9 Pg. 5619-30 (Sep 2015) ISSN: 1098-6596 [Electronic] United States
• PMID: 26149981 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antiviral Agents
• Hemagglutinins, Viral
• Serpins
• kallistatin
• Tissue Kallikreins

Topics

• Animals
• Antiviral Agents (therapeutic use)
• Blotting, Western
• Cell Line
• Dogs
• Enzyme-Linked Immunosorbent Assay
• Hemagglutinins, Viral (metabolism)
• Humans
• Influenza, Human (drug therapy)
• Mice
• Mice, Inbred C57BL
• Reverse Transcriptase Polymerase Chain Reaction
• Serpins (therapeutic use)
• Tissue Kallikreins (metabolism)