title: Receptor variation and susceptibility to Middle East respiratory syndrome coronavirus infection.
abstract: The Middle East respiratory syndrome coronavirus (MERS-CoV) recently spread from an animal reservoir to infect humans, causing sporadic severe and frequently fatal respiratory disease. Appropriate public health and control measures will require discovery of the zoonotic MERS coronavirus reservoirs. The relevant animal hosts are liable to be those that offer optimal MERS virus cell entry. Cell entry begins with virus spike (S) protein binding to DPP4 receptors. We constructed chimeric DPP4 receptors that have the virus-binding domains of indigenous Middle Eastern animals and assessed the activities of these receptors in supporting S protein binding and virus entry. Human, camel, and horse receptors were potent and nearly equally effective MERS virus receptors, while goat and bat receptors were considerably less effective. These patterns reflected S protein affinities for the receptors. However, even the low-affinity receptors could hypersensitize cells to infection when an S-cleaving protease(s) was present, indicating that affinity thresholds for virus entry must be considered in the context of host-cell proteolytic environments. These findings suggest that virus receptors and S protein-cleaving proteases combine in a variety of animals to offer efficient virus entry and that several Middle Eastern animals are potential reservoirs for transmitting MERS-CoV to humans.
  
  
  OBJECTIVE
  MERS is a frequently fatal disease that is caused by a zoonotic CoV. The animals transmitting MERS-CoV to humans are not yet known. Infection by MERS-CoV requires receptors and proteases on host cells. We compared the receptors of humans and Middle Eastern animals and found that human, camel, and horse receptors sensitized cells to MERS-CoV infection more robustly than goat and bat receptors. Infection susceptibility correlated with affinities of the receptors for viral spike proteins. We also found that the presence of a cell surface lung protease greatly increases susceptibility to MERS-CoV, particularly in conjunction with low-affinity receptors. This cataloguing of human and animal host cell factors allows one to make inferences on the distribution of MERS-CoV in nature.
authors.affiliation: Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, Illinois, USA.
authors.forename: Arlene
authors.initials: A
authors.lastname: Barlan
authors.forename: Jincun
authors.initials: J
authors.lastname: Zhao
authors.forename: Mayukh K
authors.initials: MK
authors.lastname: Sarkar
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
authors.forename: Stanley
authors.initials: S
authors.lastname: Perlman
authors.forename: Tom
authors.initials: T
authors.lastname: Gallagher
mesh_terms: D000818:Animals; D000829:Animals, Domestic; D000835:Animals, Wild; D017934:Coronavirus / Q000502:physiology*; D014644:Genetic Variation; D006801:Humans; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D000085064:Receptors, Coronavirus; D011991:Receptors, Virus / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D064370:Spike Glycoprotein, Coronavirus / Q000378:metabolism; D053585:Virus Attachment
chemical_list: D000085064:Receptors, Coronavirus; D011991:Receptors, Virus; D011994:Recombinant Proteins; D064370:Spike Glycoprotein, Coronavirus; D010447:Peptide Hydrolases