Journal of Stem Cell Research & Therapy

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

4^th International Conference and Exhibition on Cell & Gene Therapy

August 10-12, 2015 London, UK

Chia-Hsing Leu1, Mei-Lin Yang1, Nai-Hui Chung1, Yen-Jang Huang1, Yi-Cheng Chen1, Chia-Cheng Lin2, Gia-Shing Shieh2, Meng-Ya Chang3, Julie Chao4, Lee Chao4, Chao-Liang Wu1 and Ai-Li Shiau1

Posters-Accepted Abstracts: J Stem Cell Res Ther

Abstract:

The influenza virus hemagglutinin (HA) mediates virus binding to cell receptors and promotes the release of viral RNA through
membrane fusion. Proteolytic cleavage of the HA molecule by host cell trypsin-like proteases is required for viral infectivity.
Kallikrein-related peptidase 1 (KLK1) is a widely distributed serine protease. Kallistatin, which is synthesized mainly in the liver and
rapidly secreted into the circulation, is a naturally occurring KLK1 inhibitor. Here we investigated the roles of KLK1 and kallistatin
in influenza virus infection. We show that KLK1 expression was increased whereas kallistatin expression was reduced in the lung of
mice during influenza infection. Furthermore, KLK1 was capable of cleaving H1, H2 and H3 HA molecules with different efficiencies
leading to enhanced viral production. By contrast, kallistatin could inhibit KLK1-mediated HA cleavage and consequently reduce
viral production. Lentivirus-mediated kallistatin gene delivery protected mice against lethal influenza virus challenge and alleviated
lung injury by reducing interleukin (IL)-1β levels and decreasing infiltrating inflammatory cells. Taken together, we identify that
KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting HA cleavage and inflammatory responses. This
study provides a proof of principle for the potential therapeutic application of kallistatin or other KLK1 inhibitors for influenza.