Roles of kallikrein-related peptidase 1 kallistatin and vascular endothelial growth factor in influenza virus infection

摘要

Influenza virus infection is a common contagious respiratory illness in human Influenza virus usually induces inflammatory responses Sometimes it results in serious respiratory failure and tissue injury Influenza virus undergoes antigenic variation enabling the virus to evade the immune response of the host and to confer resistance of currently available anti-influenza drugs which target viral M2 protein or neuraminidase Considerable efforts are still being made to develop novel antiviral drugs for influenza virus Proteolytic cleavage of the hemagglutinin (HA) by host trypsin-like proteases is required for influenza virus infection Kallikrein-related peptidase 1 (KLK1 also known as tissue kallikrein) is a widely distributed serine protease in human tissues Kallistatin a serine protease inhibitors synthesized mainly in the liver and rapidly secreted into the blood circulation forms complexes with KLK1 and inhibits its activity In the first part we investigated the roles of KLK1 and kallistatin in influenza virus infection We showed that KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting the cleavage of the HA peptide and inflammatory responses We observed unbalance of KLK1 and kallistatin expression in the lung of mice during influenza infection KLK1 cleaved HA molecules of influenza virus and consequently enhanced viral production By contrast kallistatin reduced HA cleavage and reduced viral production by inhibiting KLK1 ability Cells transduced with the kallistatin gene secreted kallistatin extracellularly which rendered them more resistant to influenza virus infection Furthermore mice with kallistatin gene delivery had less mortality by reducing viral load inflammation and injury in the lung In the second part we studied the role of vascular endothelial growth factor (VEGF) in influenza virus pathogenesis We found that VEGF production was attenuated by influenza virus infection Influenza virus infection decreased VEGF expression in mouse primary lung fibroblasts and normal bronchial epithelial cells (NL-20 cells) but not in type I interferon (IFN) deficient cells (Vero cells) Moreover we showed that Poly(I:C) and IFN-? inhibited VEGF production in NL-20 cells When we exogenously added VEGF protein or endogenously overexpressed VEGF gene in NL-20 cells VEGF increase did not influence influenza virus infection and production However mice pretreated with lentiviral vectors encoding VEGF (LV-VEGF) had less monocyte chemoattractant protein-1 (MCP-1) and more tumor necrosis factor-? (TNF-?) production in bronchoalveolar lavage fluid compared with mice pretreated with lentiviral vectors encoding green fluorescent protein (LV-GFP) during influenza infection Collectively we provide a novel insight in antiviral immune response and a new approach in therapy of influenza virus infection

獎項日期	2015 7月 31
原文	English
監督員	Chao-Liang Wu (Supervisor)