title: The Hemagglutinin of Bat-Associated Influenza Viruses Is Activated by TMPRSS2 for pH-Dependent Entry into Bat but Not Human Cells.
abstract: New World bats have recently been discovered to harbor influenza A virus (FLUAV)-related viruses, termed bat-associated influenza A-like viruses (batFLUAV). The internal proteins of batFLUAV are functional in mammalian cells. In contrast, no biological functionality could be demonstrated for the surface proteins, hemagglutinin (HA)-like (HAL) and neuraminidase (NA)-like (NAL), and these proteins need to be replaced by their human counterparts to allow spread of batFLUAV in human cells. Here, we employed rhabdoviral vectors to study the role of HAL and NAL in viral entry. Vectors pseudotyped with batFLUAV-HAL and -NAL were able to enter bat cells but not cells from other mammalian species. Host cell entry was mediated by HAL and was dependent on prior proteolytic activation of HAL and endosomal low pH. In contrast, sialic acids were dispensable for HAL-driven entry. Finally, the type II transmembrane serine protease TMPRSS2 was able to activate HAL for cell entry indicating that batFLUAV can utilize human proteases for HAL activation. Collectively, these results identify viral and cellular factors governing host cell entry driven by batFLUAV surface proteins. They suggest that the absence of a functional receptor precludes entry of batFLUAV into human cells while other prerequisites for entry, HAL activation and protonation, are met in target cells of human origin.
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Krüger
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: Florian
authors.initials: F
authors.lastname: Wrensch
authors.affiliation: Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Herrler
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pöhlmann
mesh_terms: D000818:Animals; D002685:Chiroptera; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004285:Dogs; D057809:HEK293 Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009980:Influenza A virus / Q000502:physiology*; D061985:Madin Darby Canine Kidney Cells; D012697:Serine Endopeptidases / Q000502:physiology*; D014161:Transduction, Genetic; D014709:Vero Cells; D056189:Viral Tropism; D053586:Virus Internalization
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human