title: Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 Is an Important Surface Attachment Factor That Facilitates Entry of Middle East Respiratory Syndrome Coronavirus.
abstract: The spike proteins of coronaviruses are capable of binding to a wide range of cellular targets, which contributes to the broad species tropism of coronaviruses. Previous reports have demonstrated that Middle East respiratory syndrome coronavirus (MERS-CoV) predominantly utilizes dipeptidyl peptidase 4 (DPP4) for cell entry. However, additional cellular binding targets of the MERS-CoV spike protein that may augment MERS-CoV infection have not been further explored. In the current study, using the virus overlay protein binding assay (VOPBA), we identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a novel cell surface binding target of MERS-CoV. CEACAM5 coimmunoprecipitated with the spike protein of MERS-CoV in both overexpressed and endogenous settings. Disrupting the interaction between CEACAM5 and MERS-CoV spike with anti-CEACAM5 antibody, recombinant CEACAM5 protein, or small interfering RNA (siRNA) knockdown of CEACAM5 significantly inhibited the entry of MERS-CoV. Recombinant expression of CEACAM5 did not render nonpermissive baby hamster kidney (BHK21) cells susceptible to MERS-CoV infection. Instead, CEACAM5 overexpression significantly enhanced the attachment of MERS-CoV to the BHK21 cells. More importantly, the entry of MERS-CoV was increased when CEACAM5 was overexpressed in permissive cells, which suggested that CEACAM5 could facilitate MERS-CoV entry in conjunction with DPP4 despite not being able to support MERS-CoV entry independently. Taken together, the results of our study identified CEACAM5 as a novel cell surface binding target of MERS-CoV that facilitates MERS-CoV infection by augmenting the attachment of the virus to the host cell surface.
  
  
  
  Infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) is associated with the highest mortality rate among all known human-pathogenic coronaviruses. Currently, there are no approved vaccines or therapeutics against MERS-CoV infection. The identification of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a novel cell surface binding target of MERS-CoV advanced our knowledge on the cell binding biology of MERS-CoV. Importantly, CEACAM5 could potentiate the entry of MERS-CoV by functioning as an attachment factor. In this regard, CEACAM5 could serve as a novel target, in addition to dipeptidyl peptidase-4 (DPP4), in the development of antiviral strategies for MERS-CoV.
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong Special Administrative Region, China Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Che-Man
authors.initials: CM
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong Special Administrative Region, China Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Hin
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Bosco Ho-Yin
authors.initials: BH
authors.lastname: Wong
authors.affiliation: Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong Special Administrative Region, China Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Sze Pui
authors.initials: SP
authors.lastname: Leung
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong Special Administrative Region, China Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong Special Administrative Region, China Carol Yu Centre for Infection, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Jasper Fuk-Woo
authors.initials: JF
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong Special Administrative Region, China Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Man-Lung
authors.initials: ML
authors.lastname: Yeung
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yan
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Guangwen
authors.initials: G
authors.lastname: Lu
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: George Fu
authors.initials: GF
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong Special Administrative Region, China Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong Special Administrative Region, China Carol Yu Centre for Infection, University of Hong Kong, Hong Kong Special Administrative Region, China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China kyyuen@hku.hk.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
mesh_terms: D000818:Animals; D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D002460:Cell Line; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D065207:Middle East Respiratory Syndrome Coronavirus / Q000502:physiology*; D011991:Receptors, Virus / Q000378:metabolism*; D053585:Virus Attachment; D053586:Virus Internalization
chemical_list: C527875:CEACAM5 protein, human; D002272:Carcinoembryonic Antigen; D058851:GPI-Linked Proteins; D011991:Receptors, Virus