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Kallikrein-related peptidase 5 and seasonal influenza viruses, limitations of the experimental models for activating proteases

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  • Kallikrein-related peptidase 5 and seasonal influenza viruses, limitations of the experimental models for activating proteases

    Biol Chem. 2017 Dec 20. pii: /j/bchm.just-accepted/hsz-2017-0340/hsz-2017-0340.xml. doi: 10.1515/hsz-2017-0340. [Epub ahead of print]
    Kallikrein-related peptidase 5 and seasonal influenza viruses, limitations of the experimental models for activating proteases.

    Magnen M1,2, Elsässer BM3, Zbodakova O4, Kasparek P4, Gueugnon F1,2, Petit-Courty A1,2, Sedlacek R4, Goettig P3, Courty Y1,2.
    Author information

    Abstract

    Every year, influenza A virus (IAV) affects and kills many humans worldwide. The viral hemagglutinin (HA) is a critical actor of influenza virus infectivity which needs to be cleaved by host serine proteases to exert its activity. KLK5 has been identified as an activating protease in humans with a preference for the H3N2 IAV subtype. We investigated the origin of this preference using influenza A/Puerto Rico/8/34 (PR8, H1N1) and A/Scotland/20/74 (Scotland, H3N2) viruses. Pretreatment of noninfectious virions with human KLK5 increased infectivity of Scotland IAV in MDCK cells and triggered influenza pneumonia in mice. These effects were not observed with the PR8 IAV. Molecular modelling and in vitro enzymatic studies of peptide substrates and recombinant HAs revealed that the sequences around the cleavage site do not represent the sole determinant of the KLK5 preference for the H3N2 subtype. Using mouse Klk5 and Klk5-deficient mice, we demonstrated in vitro and in vivo that the mouse ortholog protease is not an IAV activating enzyme. This may be explained by unfavorable interactions between H3 HA and mKlk5. Our data highlight the limitations of some approaches used to identify IAV-activating proteases.


    KEYWORDS:

    cleavage; hemagglutinin; molecular modelling

    PMID: 29883316 DOI: 10.1515/hsz-2017-0340
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