tetano
Editor, Senior Moderator
EMBO Mol Med
. 2021 Nov 26;e14485.
doi: 10.15252/emmm.202114485. Online ahead of print.
SPINK6 inhibits human airway serine proteases and restricts influenza virus activation
Dong Wang[SUP] 1 [/SUP], Cun Li[SUP] 1 [/SUP], Man Chun Chiu[SUP] 1 [/SUP], Yifei Yu[SUP] 1 [/SUP], Xiaojuan Liu[SUP] 1 [/SUP], Xiaoyu Zhao[SUP] 1 [/SUP], Jingjing Huang[SUP] 1 [/SUP], Zhongshan Cheng[SUP] 2 [/SUP], Shuofeng Yuan[SUP] 1 [/SUP], Vincent Poon[SUP] 1 [/SUP], Jian-Piao Cai[SUP] 1 [/SUP], Hin Chu[SUP] 1 3 [/SUP], Jasper Fuk-Woo Chan[SUP] 1 3 4 [/SUP], Kelvin Kai-Wang To[SUP] 1 3 4 [/SUP], Kwok Yung Yuen[SUP] 1 3 4 [/SUP], Jie Zhou[SUP] 1 3 [/SUP]
Affiliations
Abstract
SPINK6 was identified in human skin as a cellular inhibitor of serine proteases of the KLK family. Airway serine proteases are required to cleave hemagglutinin (HA) of influenza A viruses (IAVs) to initiate an infection in the human airway. We hypothesized that SPINK6 may inhibit common airway serine proteases and restrict IAV activation. We demonstrate that SPINK6 specifically suppresses the proteolytic activity of HAT and KLK5, HAT- and KLK5-mediated HA cleavage, and restricts virus maturation and replication. SPINK6 constrains the activation of progeny virions and impairs viral growth; and vice versa, blocking endogenous SPINK6 enhances HA cleavage and viral growth in physiological-relevant human airway organoids where SPINK6 is intrinsically expressed. In IAV-infected mice, SPINK6 significantly suppresses viral growth and improves mouse survival. Notably, individuals carrying the higher SPINK6 expression allele were protected from human H7N9 infection. Collectively, SPINK6 is a novel host inhibitor of serine proteases in the human airway and restricts IAV activation.
Keywords: HA cleavage; SPINK6; airway organoids; influenza virus; virus maturation.
. 2021 Nov 26;e14485.
doi: 10.15252/emmm.202114485. Online ahead of print.
SPINK6 inhibits human airway serine proteases and restricts influenza virus activation
Dong Wang[SUP] 1 [/SUP], Cun Li[SUP] 1 [/SUP], Man Chun Chiu[SUP] 1 [/SUP], Yifei Yu[SUP] 1 [/SUP], Xiaojuan Liu[SUP] 1 [/SUP], Xiaoyu Zhao[SUP] 1 [/SUP], Jingjing Huang[SUP] 1 [/SUP], Zhongshan Cheng[SUP] 2 [/SUP], Shuofeng Yuan[SUP] 1 [/SUP], Vincent Poon[SUP] 1 [/SUP], Jian-Piao Cai[SUP] 1 [/SUP], Hin Chu[SUP] 1 3 [/SUP], Jasper Fuk-Woo Chan[SUP] 1 3 4 [/SUP], Kelvin Kai-Wang To[SUP] 1 3 4 [/SUP], Kwok Yung Yuen[SUP] 1 3 4 [/SUP], Jie Zhou[SUP] 1 3 [/SUP]
Affiliations
- PMID: 34826211
- DOI: 10.15252/emmm.202114485
Abstract
SPINK6 was identified in human skin as a cellular inhibitor of serine proteases of the KLK family. Airway serine proteases are required to cleave hemagglutinin (HA) of influenza A viruses (IAVs) to initiate an infection in the human airway. We hypothesized that SPINK6 may inhibit common airway serine proteases and restrict IAV activation. We demonstrate that SPINK6 specifically suppresses the proteolytic activity of HAT and KLK5, HAT- and KLK5-mediated HA cleavage, and restricts virus maturation and replication. SPINK6 constrains the activation of progeny virions and impairs viral growth; and vice versa, blocking endogenous SPINK6 enhances HA cleavage and viral growth in physiological-relevant human airway organoids where SPINK6 is intrinsically expressed. In IAV-infected mice, SPINK6 significantly suppresses viral growth and improves mouse survival. Notably, individuals carrying the higher SPINK6 expression allele were protected from human H7N9 infection. Collectively, SPINK6 is a novel host inhibitor of serine proteases in the human airway and restricts IAV activation.
Keywords: HA cleavage; SPINK6; airway organoids; influenza virus; virus maturation.