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Published ahead of print 6 March 2013, doi: 10.1128/JVI.00128-13 JVI.00128-13
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
Stefanie Gierer1,
Stephanie Bertram1,
Franziska Kaup1,
Florian Wrensch1,
Adeline Heurich1,
Annika Kr?mer-K?hl1,
Kathrin Welsch1,
Michael Winkler1,
Benjamin Meyer2,
Christian Drosten2,
Ulf Dittmer3,
Thomas von Hahn4,5,
Graham Simmons6,
Heike Hofmann1 and
Stefan P?hlmann1,*
+ Author Affiliations
1Infection Biology Unit, German Primate Center, G?ttingen, Germany
2Institute for Virology, University Medical Center, Bonn, German
3Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
4Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
5Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
6Blood Systems Research Institute, San Francisco, California
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 viral pathogenesis 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 lung, kidney and colon, as well as primary human macrophages. Expression of 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.
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
Stefanie Gierer1,
Stephanie Bertram1,
Franziska Kaup1,
Florian Wrensch1,
Adeline Heurich1,
Annika Kr?mer-K?hl1,
Kathrin Welsch1,
Michael Winkler1,
Benjamin Meyer2,
Christian Drosten2,
Ulf Dittmer3,
Thomas von Hahn4,5,
Graham Simmons6,
Heike Hofmann1 and
Stefan P?hlmann1,*
+ Author Affiliations
1Infection Biology Unit, German Primate Center, G?ttingen, Germany
2Institute for Virology, University Medical Center, Bonn, German
3Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
4Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
5Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
6Blood Systems Research Institute, San Francisco, California
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 viral pathogenesis 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 lung, kidney and colon, as well as primary human macrophages. Expression of 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.
