title: Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication.
abstract: Members of rhinovirus C (RV-C) species are more likely to cause wheezing illnesses and asthma exacerbations compared with other rhinoviruses. The cellular receptor for these viruses was heretofore unknown. We report here that expression of human cadherin-related family member 3 (CDHR3) enables the cells normally unsusceptible to RV-C infection to support both virus binding and replication. A coding single nucleotide polymorphism (rs6967330, C529Y) was previously linked to greater cell-surface expression of CDHR3 protein, and an increased risk of wheezing illnesses and hospitalizations for childhood asthma. Compared with wild-type CDHR3, cells transfected with the CDHR3-Y529 variant had about 10-fold increases in RV-C binding and progeny yields. We developed a transduced HeLa cell line (HeLa-E8) stably expressing CDHR3-Y529 that supports RV-C propagation in vitro. Modeling of CDHR3 structure identified potential binding sites that could impact the virus surface in regions that are highly conserved among all RV-C types. Our findings identify that the asthma susceptibility gene product CDHR3 mediates RV-C entry into host cells, and suggest that rs6967330 mutation could be a risk factor for RV-C wheezing illnesses.
authors.affiliation: Department of Pediatrics and yabochkov@wisc.edu.
authors.forename: Yury A
authors.initials: YA
authors.lastname: Bochkov
authors.affiliation: Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Kelly
authors.initials: K
authors.lastname: Watters
authors.affiliation: Department of Pediatrics and.
authors.forename: Shamaila
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Department of Pediatrics and.
authors.forename: Theodor F
authors.initials: TF
authors.lastname: Griggs
authors.affiliation: Department of Pediatrics and.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Devries
authors.affiliation: Department of Pediatrics and.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Jackson
authors.affiliation: Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Palmenberg
authors.affiliation: Department of Pediatrics and Department of Medicine, University of Wisconsin-Madison, Madison, WI 53792; and.
authors.forename: James E
authors.initials: JE
authors.lastname: Gern
mesh_terms: D001249:Asthma; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D012229:Rhinovirus / Q000502:physiology*; D012307:Risk Factors; D053586:Virus Internalization; D014779:Virus Replication / Q000502:physiology*
chemical_list: C586717:CDHR3 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D008565:Membrane Proteins
keywords: CDHR3; receptor; rhinovirus C
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