title: DESC1 and MSPL activate influenza A viruses and emerging coronaviruses for host cell entry.
abstract: The type II transmembrane serine protease (TTSP) TMPRSS2 cleaves and activates the influenza virus and coronavirus surface proteins. Expression of TMPRSS2 is essential for the spread and pathogenesis of H1N1 influenza viruses in mice. In contrast, H3N2 viruses are less dependent on TMPRSS2 for viral amplification, suggesting that these viruses might employ other TTSPs for their activation. Here, we analyzed TTSPs, reported to be expressed in the respiratory system, for the ability to activate influenza viruses and coronaviruses. We found that MSPL and, to a lesser degree, DESC1 are expressed in human lung tissue and cleave and activate the spike proteins of the Middle East respiratory syndrome and severe acute respiratory syndrome coronaviruses for cell-cell and virus-cell fusion. In addition, we show that these proteases support the spread of all influenza virus subtypes previously pandemic in humans. In sum, we identified two host cell proteases that could promote the amplification of influenza viruses and emerging coronaviruses in humans and might constitute targets for antiviral intervention. Importance: Activation of influenza viruses by host cell proteases is essential for viral infectivity and the enzymes responsible are potential targets for antiviral intervention. The present study demonstrates that two cellular serine proteases, DESC1 and MSPL, activate influenza viruses and emerging coronaviruses in cell culture and, because of their expression in human lung tissue, might promote viral spread in the infected host. Antiviral strategies aiming to prevent viral activation might thus need to encompass inhibitors targeting MSPL and DESC1.
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Zmora
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Paulina
authors.initials: P
authors.lastname: Blazejewska
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Anna-Sophie
authors.initials: AS
authors.lastname: Moldenhauer
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Welsch
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Nehlmeier
authors.affiliation: Molecular Cardiology, Nephrology, and Hypertension, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Institute for Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Schneider
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany spoehlmann@dpz.eu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pöhlmann
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bertram
mesh_terms: D000818:Animals; D017934:Coronavirus / Q000502:physiology*; D004285:Dogs; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D061985:Madin Darby Canine Kidney Cells; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000502:physiology*; D014775:Virus Activation / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D012697:Serine Endopeptidases; C524420:TMPRSS11E protein, human; C429035:TMPRSS13 protein, human