title: The Proteolytic Activation of (H3N2) Influenza A Virus Hemagglutinin Is Facilitated by Different Type II Transmembrane Serine Proteases.
abstract: Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is necessary for viral activation and infectivity. In humans and mice, members of the type II transmembrane protease family (TTSP), e.g., TMPRSS2, TMPRSS4, and TMPRSS11d (HAT), have been shown to cleave influenza virus HA for viral activation and infectivity in vitro Recently, we reported that inactivation of a single HA-activating protease gene,Tmprss2, in knockout mice inhibits the spread of H1N1 influenza viruses. However, after infection of Tmprss2 knockout mice with an H3N2 influenza virus, only a slight increase in survival was observed, and mice still lost body weight. In this study, we investigated an additional trypsin-like protease, TMPRSS4. Both TMPRSS2 and TMPRSS4 are expressed in the same cell types of the mouse lung. Deletion of Tmprss4 alone in knockout mice does not protect them from body weight loss and death upon infection with H3N2 influenza virus. In contrast,Tmprss2(-/-)Tmprss4(-/-)double-knockout mice showed a remarkably reduced virus spread and lung pathology, in addition to reduced body weight loss and mortality. Thus, our results identified TMPRSS4 as a second host cell protease that, in addition to TMPRSS2, is able to activate the HA of H3N2 influenza virus in vivo
  
  
  OBJECTIVE
  Influenza epidemics and recurring pandemics are responsible for significant global morbidity and mortality. Due to high variability of the virus genome, resistance to available antiviral drugs is frequently observed, and new targets for treatment of influenza are needed. Host cell factors essential for processing of the virus hemagglutinin represent very suitable drug targets because the virus is dependent on these host factors for replication. We reported previously that Tmprss2-deficient mice are protected against H1N1 virus infections, but only marginal protection against H3N2 virus infections was observed. Here we show that deletion of two host protease genes,Tmprss2 and Tmprss4, strongly reduced viral spread as well as lung pathology and resulted in increased survival after H3N2 virus infection. Thus, TMPRSS4 represents another host cell factor that is involved in cleavage activation of H3N2 influenza viruses in vivo.
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, and University of Veterinary Medicine Hannover, Braunschweig, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Kühn
authors.affiliation: Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Silke
authors.initials: S
authors.lastname: Bergmann
authors.affiliation: Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Kösterke
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, and University of Veterinary Medicine Hannover, Braunschweig, Germany.
authors.forename: Ruth L O
authors.initials: RLO
authors.lastname: Lambertz
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Keppner
authors.affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Judith M A
authors.initials: JMA
authors.lastname: van den Brand
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Stefan
authors.identifier: http://orcid.org/0000-0001-6086-9136
authors.initials: S
authors.lastname: Pöhlmann
authors.affiliation: Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiß
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, and University of Veterinary Medicine Hannover, Braunschweig, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hatesuer
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, and University of Veterinary Medicine Hannover, Braunschweig, Germany klaus.schughart@helmholtz-hzi.de.|Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schughart
mesh_terms: D000818:Animals; D001980:Bronchi / Q000378:metabolism / Q000821:virology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004789:Enzyme Activation; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D053122:Influenza A Virus, H3N2 Subtype / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000821:virology*; D059748:Proteolysis; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000821:virology; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load; D014779:Virus Replication
chemical_list: D018925:Chemokines; D016207:Cytokines; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008565:Membrane Proteins; D012697:Serine Endopeptidases