Abstract
BackgroundHuman rhinovirus (HRV) infections are the primary cause of the common cold and are a major trigger for exacerbations of lower airway diseases, such as asthma and chronic obstructive pulmonary diseases. Although human bronchial epithelial cells (HBE) are the natural host for HRV infections, much of our understanding of how HRV replicates and induces host antiviral responses is based on studies using non-airway cell lines (e.g. HeLa cells). The current study examines the replication cycle of HRV, and host cell responses, in highly differentiated cultures of HBE.MethodsHighly differentiated cultures of HBE were exposed to initial infectious doses ranging from 104 to 101 50% tissue culture-infective dose (TCID50) of purified HRV-16, and responses were monitored up to 144 h after infection. Viral genomic RNA and negative strand RNA template levels were monitored, along with levels of type I and II interferons and selected antivirals.ResultsRegardless of initial infectious dose, relatively constant levels of both genomic and negative strand RNA are generated during replication, with negative strand copy numbers being10,000-fold lower than those of genomic strands. Infections were limited to a small percentage of ciliated cells and did not result in any overt signs of epithelial death. Importantly, regardless of infectious dose, HRV-16 infections were cleared by HBE in the absence of immune cells. Levels of type I and type III interferons (IFNs) varied with initial infectious dose, implying that factors other than levels of double-stranded RNA regulate IFN induction, but the time-course of HRV-16 clearance HBE was the same regardless of levels of IFNs produced. Patterns of antiviral viperin and ISG15 expression suggest they may be generated in an IFN-independent manner during HRV-16 infections.ConclusionsThese data challenge a number of aspects of dogma generated from studies in HeLa cells and emphasize the importance of appropriate cell context when studying HRV infections.
Highlights
Human rhinovirus (HRV) infections are responsible for over 50% of common cold-like illnesses [1], and HRV is the most common virus triggering acute exacerbations of asthma and chronic obstructive pulmonary disease [2,3,4].The primary site of HRV infection and replication in both the upper and lower airways is the human airwayMuch of our understanding of how HRV replicates and induces host antiviral responses, is based on studiesWarner et al Respiratory Research (2019) 20:150 using non-airway cell lines (e.g. HeLa cells), or is inferred from studies of other picornaviruses
HRV infection studies in vivo demonstrate that epithelial cells are the natural site of HRV infection and replication [5, 6, 21], and the use of human airway epithelial cell lines [22], and subsequently primary human bronchial epithelial cells (HBE) grown in submersion culture [23, 24], or at air-liquid interface (ALI) [25, 26], have provided important insights into the inflammatory and innate immune responses to HRV infection
Consistent with this, we have previously shown robust induction of IRF1 and interferon regulatory factor (IRF)-7 in HRV-infected human airway epithelial cells [45, 46], and have demonstrated that induction of Interferon stimulated gene of 15 kilodaltons (ISG15) by HRV is dependent upon transcriptional control by IRF-1 [19]
Summary
Human rhinovirus (HRV) infections are responsible for over 50% of common cold-like illnesses [1], and HRV is the most common virus triggering acute exacerbations of asthma and chronic obstructive pulmonary disease [2,3,4].The primary site of HRV infection and replication in both the upper and lower airways is the human airwayMuch of our understanding of how HRV replicates and induces host antiviral responses, is based on studiesWarner et al Respiratory Research (2019) 20:150 using non-airway cell lines (e.g. HeLa cells), or is inferred from studies of other picornaviruses. The viral polyprotein is translated from the positive sense RNA genome and the viral RNA polymerase subsequently generates negative strand copies of the HRV genome. These negative strands serve as templates for replication of positive strand genomes for packaging in the virus capsid [12]. Human rhinovirus (HRV) infections are the primary cause of the common cold and are a major trigger for exacerbations of lower airway diseases, such as asthma and chronic obstructive pulmonary diseases. Human bronchial epithelial cells (HBE) are the natural host for HRV infections, much of our understanding of how HRV replicates and induces host antiviral responses is based on studies using non-airway cell lines (e.g. HeLa cells). Viral genomic RNA and negative strand RNA template levels were monitored, along with levels of type I and II interferons and selected antivirals
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