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Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2018.00091

Enterokinase enhances Influenza A virus infection by activating trypsinogen in human cell lines

 Hideki Hayashi1*,  Yoshinao Kubo1,  Mai Izumida1, Etsuhisa Takahashi2,  Hiroshi Kido2,  Ko Sato3, Mutsuo Yamaya4, Hidekazu Nishimura3, Kou Nakayama1 and Toshifumi Matsuyama1
  • 1Nagasaki University, Japan
  • 2Tokushima University, Japan
  • 3Sendai Medical Center, Japan
  • 4Tohoku University, Japan

Cleavage and activation of hemagglutinin (HA) by trypsin-like proteases in influenza A virus (IAV) are essential prerequisites for its successful infection and spread. In host cells, some transmembrane serine proteases such as TMPRSS2, TMPRSS4 and HAT, along with plasmin in the bloodstream, have been reported to cleave the HA precursor (HA0) molecule into its active forms, HA1 and HA2. Some trypsinogens can also enhance IAV proliferation in some cell types (e.g., rat cardiomyoblasts). However, the precise activation mechanism for this process is unclear, because the expression level of the physiological activator of the trypsinogens, the TMPRSS15 enterokinase, is expected to be very low in such cells, with the exception of duodenal cells. Here, we show that at least two variant enterokinases are expressed in various human cell lines, including A549 lung-derived cells. The exogenous expression of these enterokinases was able to enhance the proliferation of IAV in 293T human kidney cells, but the proliferation was reduced by knocking down the endogenous enterokinase in A549 cells. The enterokinase was able to enhance HA processing in the cells, which activated trypsinogen in vitro and in the IAV-infected cells also. Therefore, we conclude that enterokinase plays a role in IAV infection and proliferation by activating trypsinogen to process viral HA in human cell lines.

Keywords: Enterokinase, Influenza A virus, Hemagglutinin processing, transmembrane serine protease, genome structure and function

Received: 17 Nov 2017; Accepted: 07 Mar 2018.

Edited by:

Samuel K. Campos, University of Arizona, United States

Reviewed by:

Makoto Takeda, National Institute of Infectious Diseases (NIID), Japan
Teneema Kuriakose, St. Jude Children's Research Hospital, United States  

Copyright: © 2018 Hayashi, Kubo, Izumida, Takahashi, Kido, Sato, Yamaya, Nishimura, Nakayama and Matsuyama. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Hideki Hayashi, Nagasaki University, Nagasaki, Japan,