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Cadherin-Related Family Member 3, a Childhood Asthma Susceptibility Gene Product, Mediates Rhinovirus C Binding and Replication

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Cadherin-Related Family Member 3, a Childhood Asthma Susceptibility Gene Product, Mediates Rhinovirus C Binding and Replication Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication Yury A. Bochkova,1, Kelly Wattersb, Shamaila Ashrafa,2, Theodor F. Griggsa, Mark K. Devriesa, Daniel J. Jacksona, Ann C. Palmenbergb,3, and James E. Gerna,c,3 aDepartment of Pediatrics and cDepartment of Medicine, University of Wisconsin–Madison, Madison, WI 53792; and bInstitute for Molecular Virology, University of Wisconsin–Madison, Madison, WI 53706 Edited by Robert A. Lamb, Northwestern University, Evanston, IL, and approved March 17, 2015 (received for review November 5, 2014) Members of rhinovirus C (RV-C) species are more likely to cause been a major obstacle to the study of virus-specific characteristics wheezing illnesses and asthma exacerbations compared with that could lead to effective antiviral strategies for this common other rhinoviruses. The cellular receptor for these viruses was and important respiratory pathogen. We now report that human heretofore unknown. We report here that expression of human cadherin-related family member 3 (CDHR3), a member of the cadherin-related family member 3 (CDHR3) enables the cells cadherin family of transmembrane proteins, mediates RV-C normally unsusceptible to RV-C infection to support both virus entry into host cells, and an asthma-related mutation in this gene binding and replication. A coding single nucleotide polymorphism is associated with enhanced viral binding and increased progeny (rs6967330, C529Y) was previously linked to greater cell-surface yields in vitro. expression of CDHR3 protein, and an increased risk of wheezing illnesses and hospitalizations for childhood asthma. Compared Results with wild-type CDHR3, cells transfected with the CDHR3-Y529 var- In Silico Identification of Candidate RV-C Receptors. To obtain a iant had about 10-fold increases in RV-C binding and progeny working list of potential cellular receptors, we measured gene yields. We developed a transduced HeLa cell line (HeLa-E8) stably expression on microarray chips (Human Gene 1.0 ST Array, expressing CDHR3-Y529 that supports RV-C propagation in vitro. Affymetrix) in two series of experiments involving cells that were Modeling of CDHR3 structure identified potential binding sites either susceptible or not susceptible to RV-C infection (Fig. 1 that could impact the virus surface in regions that are highly con- and Fig. S1). In one experimental series, susceptible cells in- served among all RV-C types. Our findings identify that the asthma cluded whole sinus mucosal tissue specimens (n = 5), epithelial susceptibility gene product CDHR3 mediates RV-C entry into host cell suspension from sinus tissue, and nasal epithelium obtained cells, and suggest that rs6967330 mutation could be a risk factor via brushing, and unsusceptible cells, including monolayers of for RV-C wheezing illnesses. primary undifferentiated epithelial cells and transformed cell lines (n = 5, including HeLa). In a second experimental series, rhinovirus C | CDHR3 | receptor we compared three pairs of undifferentiated (monolayers) and fully differentiated (ALI) sinus epithelial cell cultures. ore than 160 types of rhinoviruses (RVs) are classified into Mthree species (A, B, and C) of enteroviruses in the family Significance picornaviridae. Viruses belonging to the RV-C species were only discovered in 2006 (1, 2), some 50 y after the initial identification The rhinovirus C (RV-C) species was first identified in 2006 and of other RVs (3), because these viruses are not detectable by is a major cause of acute respiratory illnesses in children and – standard tissue-culture techniques (4 7). RV-Cs are of special hospitalizations for exacerbations of asthma. In this study, we clinical interest because they can cause more severe illnesses discovered that expression of human cadherin-related family requiring hospitalization in infants and children compared with member 3 (CDHR3), a transmembrane protein with yet un- the RV-A or RV-B, and are closely associated with acute exac- known biological function, enables RV-C binding and replica- – erbations of asthma (8 10). tion in normally unsusceptible host cells. Intriguingly, we After multiple attempts to grow RV-C in established cell lines found that a coding SNP (rs6967330, C529Y) in CDHR3, pre- were unsuccessful, we described the use of organ culture of hu- viously linked to wheezing illnesses and hospitalizations for man sinus mucosa to propagate a few RV-C clinical isolates in childhood asthma by genetic analysis, also mediates enhanced MICROBIOLOGY vitro (11). Subsequently, we and others documented RV-C RV-C binding and increased progeny yields in vitro. Finally, growth in cultures of epithelial cells isolated from airway tissue using structural modeling, we identified potential binding sites specimens that had then become redifferentiated under air–liquid in CDHR3 domains 1 and 2 interacting with viral capsid surface interface (ALI) conditions (12, 13). Notably, only fully differ- regions that are highly conserved among RV-C types. entiated ALI cultures supported RV-C replication, whereas undifferentiated airway epithelial cell monolayers did not. RV-C Author contributions: Y.A.B., A.C.P., and J.E.G. designed research; Y.A.B., K.W., S.A., can only be produced using reverse genetics, as the full-length T.F.G., M.K.D., and A.C.P. performed research; Y.A.B., K.W., D.J.J., A.C.P., and J.E.G. ana- viral RNA transcripts synthesized in vitro are infectious when lyzed data; and Y.A.B., A.C.P., and J.E.G. wrote the paper. transfected into human cell lines (for example, HeLa, WisL, and The authors declare no conflict of interest. HEK293T) normally not susceptible to viral infection (11). This article is a PNAS Direct Submission. With these tools, it was possible to show that the RV-C re- Data deposition: The data reported in this paper have been deposited in the Gene Ex- ceptor is distinct from the intercellular adhesion molecule 1 pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE61396). (ICAM-1) and low-density lipoprotein receptor (LDLR) family 1To whom correspondence should be addressed. Email: [email protected]. members used by the other species of RV (14, 15). However, the 2Present address: ATCC Microbiology Systems, Manassas, VA 20110. existing RV-C culture systems have relatively low throughput 3A.C.P. and J.E.G. contributed equally to this work. and are labor intensive. Failure to identify the cellular receptor This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. and the inability to propagate RV-C in convenient cell lines has 1073/pnas.1421178112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1421178112 PNAS | April 28, 2015 | vol. 112 | no. 17 | 5485–5490 Downloaded by guest on September 24, 2021 A Gene Ontology terms and second experiments, respectively. We then performed ad- Plasma membrane Receptor ditional filtering steps to narrow the candidate gene lists on the n = 66 genes n = 65 genes basis of available Gene Ontology information (membrane lo- calization, receptor activity) and expression levels of the known rhinovirus receptor genes (Fig. 1A and Table S1). We identified a total of 12 common genes (represented by 14 probe sets) Exp Common Exp Exp Common Exp encoding proteins localized to plasma membrane or with pre- #1 n = 25 #2 #2 n = 23 #1 dicted or functionally demonstrated receptor activity, including members of the human MHC class II, stomatin, guanine nucle- otide-binding, type I cytokine, and atypical chemokine receptor Expression level: and cadherin protein families (Fig. 1B). RV-C susceptible > 7 log2 > RV-C unsusceptible Plasma membrane Receptor CDHR3 Expression in HeLa Cells Enables RV-C Binding and Replication. n = 38 genes n = 26 genes We next selected a subset of candidate genes [interleukin 5 re- ceptor, alpha (IL5RA); chemokine (C-C motif) receptor-like 1 (CCRL1); cadherin-related family member 3 (CDHR3); low den- sity lipoprotein receptor class A domain containing 1 (LDLRAD1); Exp Common Exp Exp Common Exp calponin homology domain containing 2 (CHDC2); membrane- #1 n = 11 #2 12 genes #1 n = 11 #2 14 probe sets spanning 4-domains, subfamily A, member 8 (MS4A8)] for func- tional validation (Fig. 1B and Fig. S2). We transfected HeLa cells with plasmid DNAs encoding the identified genes under control of the CMV promoter. The cells were then exposed to a reporter 3 Common 3 virus (RV-C15-GFP) engineered to express GFP during replication n = 8 (Fig. 2A) to facilitate the analysis. This reporter virus replicated well in susceptible ALI cultures of airway epithelial cells (Fig. S3). We repeatedly detected some GFP expression only in cells trans- fected with CDHR3-expressing cDNA (Fig. 2B). B log2 expression To confirm that this result was not unique to the GFP-expressing virus, we then infected CDHR3-expressing HeLa cells with wild- +3.7 +13.4 type RV-C15. Relative to untransfected control cells, we again observed enhanced virus binding and evidence of vigorous rep- n n RV-C unsusceptible ( = 8) RV-C susceptible ( = 10) lication (about 2-log increase in RV-C RNA compared with in- STOML3 put) (Fig. 2C). Therefore, transfection-induced expression of DNAAF1 CDHR3 was sufficient to convert HeLa cells normally unsusceptible KLHL6 to RV-C infection into targets that supported virus binding and CCRL1 subsequent replication. CERKL → ENPP3 Mutation in CDHR3 (Cys529 Tyr) Increases RV-C Binding and Progeny IL5RA Yields. CDHR3 is a related member of the cadherin family of transmembrane proteins. Typically, cadherins are involved in PROM1 homologous cell adhesion processes that are important for epi- CDHR3 thelial polarity, cell–cell interactions, and tissue differentiation HLA-DRA (16–18). Four alleles of CDHR3 gene are described, of which HLA-DRA one representing a single nucleotide polymorphism (G→A) that HLA-DRA converts residue cysteine to tyrosine at position 529 (Cys529→ RGS22 Tyr, rs6967330), was recently linked with a much greater risk of GNA14 asthma hospitalizations and severe exacerbations in young chil- dren in a genome-wide association study (19).
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