title: The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies.
abstract: The novel human coronavirus EMC (hCoV-EMC), which recently emerged in Saudi Arabia, is highly pathogenic and could pose a significant threat to public health. The elucidation of hCoV-EMC interactions with host cells is critical to our understanding of the pathogenesis of this virus and to the identification of targets for antiviral intervention. Here we investigated the viral and cellular determinants governing hCoV-EMC entry into host cells. We found that the spike protein of hCoV-EMC (EMC-S) is incorporated into lentiviral particles and mediates transduction of human cell lines derived from different organs, including the lungs, kidneys, and colon, as well as primary human macrophages. Expression of the known coronavirus receptors ACE2, CD13, and CEACAM1 did not facilitate EMC-S-driven transduction, suggesting that hCoV-EMC uses a novel receptor for entry. Directed protease expression and inhibition analyses revealed that TMPRSS2 and endosomal cathepsins activate EMC-S for virus-cell fusion and constitute potential targets for antiviral intervention. Finally, EMC-S-driven transduction was abrogated by serum from an hCoV-EMC-infected patient, indicating that EMC-S-specific neutralizing antibodies can be generated in patients. Collectively, our results indicate that hCoV-EMC uses a novel receptor for protease-activated entry into human cells and might be capable of extrapulmonary spread. In addition, they define TMPRSS2 and cathepsins B and L as potential targets for intervention and suggest that neutralizing antibodies contribute to the control of hCoV-EMC infection.
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gierer
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bertram
authors.forename: Franziska
authors.initials: F
authors.lastname: Kaup
authors.forename: Florian
authors.initials: F
authors.lastname: Wrensch
authors.forename: Adeline
authors.initials: A
authors.lastname: Heurich
authors.forename: Annika
authors.initials: A
authors.lastname: Krämer-Kühl
authors.forename: Kathrin
authors.initials: K
authors.lastname: Welsch
authors.forename: Michael
authors.initials: M
authors.lastname: Winkler
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meyer
authors.forename: Christian
authors.initials: C
authors.lastname: Drosten
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.forename: Thomas
authors.initials: T
authors.lastname: von Hahn
authors.forename: Graham
authors.initials: G
authors.lastname: Simmons
authors.forename: Heike
authors.initials: H
authors.lastname: Hofmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Pöhlmann
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral / Q000097:blood; D002403:Cathepsins / Q000378:metabolism; D017934:Coronavirus / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D018352:Coronavirus Infections / Q000276:immunology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D000085064:Receptors, Coronavirus; D011991:Receptors, Virus / Q000378:metabolism*; D012529:Saudi Arabia; D012697:Serine Endopeptidases / Q000378:metabolism; D064370:Spike Glycoprotein, Coronavirus; D014161:Transduction, Genetic; D014759:Viral Envelope Proteins / Q000276:immunology / Q000378:metabolism*; D056189:Viral Tropism; D053586:Virus Internalization
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D008562:Membrane Glycoproteins; D000085064:Receptors, Coronavirus; D011991:Receptors, Virus; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; D002403:Cathepsins; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human