Abstract
BackgroundThe Rhinovirus C (RV-C), first identified in 2006, produce high symptom burdens in children and asthmatics, however, their primary target host cell in the airways remains unknown. Our primary hypotheses were that RV-C target ciliated airway epithelial cells (AECs), and that cell specificity is determined by restricted and high expression of the only known RV-C cell-entry factor, cadherin related family member 3 (CDHR3).MethodsRV-C15 (C15) infection in differentiated human bronchial epithelial cell (HBEC) cultures was assessed using immunofluorescent and time-lapse epifluorescent imaging. Morphology of C15-infected differentiated AECs was assessed by immunohistochemistry.ResultsC15 produced a scattered pattern of infection, and infected cells were shed from the epithelium. The percentage of cells infected with C15 varied from 1.4 to 14.7% depending on cell culture conditions. Infected cells had increased staining for markers of ciliated cells (acetylated-alpha-tubulin [aat], p < 0.001) but not markers of goblet cells (wheat germ agglutinin or Muc5AC, p = ns). CDHR3 expression was increased on ciliated epithelial cells, but not other epithelial cells (p < 0.01). C15 infection caused a 27.4% reduction of ciliated cells expressing CDHR3 (p < 0.01). During differentiation of AECs, CDHR3 expression progressively increased and correlated with both RV-C binding and replication.ConclusionsThe RV-C only replicate in ciliated AECs in vitro, leading to infected cell shedding. CDHR3 expression positively correlates with RV-C binding and replication, and is largely confined to ciliated AECs. Our data imply that factors regulating differentiation and CDHR3 production may be important determinants of RV-C illness severity.
Highlights
The Rhinovirus C (RV-C), first identified in 2006, produce high symptom burdens in children and asthmatics, their primary target host cell in the airways remains unknown
RV-B14 replication and expression of the major group RV receptor ICAM-1 have been identified in non-ciliated cells derived from the palatine tonsils, and high levels of RV-A16 (A16) replication were noted in cultures with mucus cell metaplasia, which can occur in asthma or chronic obstructive pulmonary disease (COPD) [31, 32, 34]
RV-C15 infection of HBEC-air–liquid interface (ALI) cultures result in diffuse, apical shedding of intact cells To visualize RV-C-infected cells, human bronchial epithelial cells (HBECs) were differentiated in vitro at an air-liquid interface (ALI) for 30–50 days, and inoculated with RV-C15 (C15)
Summary
The Rhinovirus C (RV-C), first identified in 2006, produce high symptom burdens in children and asthmatics, their primary target host cell in the airways remains unknown. Our primary hypotheses were that RV-C target ciliated airway epithelial cells (AECs), and that cell specificity is determined by restricted and high expression of the only known RV-C cell-entry factor, cadherin related family member 3 (CDHR3). RV-B14 replication and expression of the major group RV receptor ICAM-1 have been identified in non-ciliated cells derived from the palatine tonsils, and high levels of RV-A16 (A16) replication were noted in cultures with mucus cell metaplasia, which can occur in asthma or COPD [31, 32, 34]. The specific host cell for the RV-C remains unknown [37, 38]
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