Basal Cells of Differentiated Bronchial Epithelium Are More Susceptible to Rhinovirus Infection

Jakieła, Bogdan; Brockman-Schneider, Rebecca; Amineva, S. P.; Lee, Wai-Ming; Gern, James E.

doi:10.1165/rcmb.2007-0050oc

Cited by 152 publications

(140 citation statements)

References 46 publications

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“…However, a recent study reported that various types of differentiated bronchial epithelial cells differ in their susceptibility to RV infection (46). Whereas cells at the superficial layer were relatively resistant to RV infection, basal cells were more sensitive.…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Decreases Innate Responses of Epithelial Cells to Rhinovirus Infection

Eddleston¹,

Lee²,

Doerner³

et al. 2011

Am J Respir Cell Mol Biol

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Exposure to cigarette smoke is associated with a significant increase in the risk for respiratory viral infections. The airway epithelium is the primary target for both cigarette smoke and respiratory viral infection. We investigated the effects of cigarette smoke on the response of airway epithelial cells to rhinovirus infection. We found that pre-exposure of BEAS-2B cells or primary normal human bronchial epithelial cells (NHBEs) to cigarette smoke extract (CSE) reduced the induction of mRNA of the chemokines CXCL10 and CCL5 by either the viral mimic polyinosine-polycytidylic acid (Poly I:C) or human rhinovirus 16 (HRV-16) infection. The HRV-16-induced release of CXCL10 and CCL5 was also significantly suppressed by CSE. Activation of the IFN mediator STAT-1 and the activation of JNK by poly I:C and HRV-16 were partially suppressed by pre-exposure to CSE. In contrast, the poly I:C-induced and HRV-16-induced phosphorylation of ERK1/2 was unaffected by CSE. HRV-16-stimulated IFN-b mRNA was also significantly reduced by CSE. Because suppression of the IFN response to viral infection was associated with increased viral production, we assessed HRV-16 RNA concentrations. Exposure to CSE resulted in an increase in HRV-16 RNA at 48 hours after the infection of BEAS-2B cells. These data demonstrate that exposure to CSE alters the response of airway epithelial cells to HRV infection, leading to decreased activation of the IFN-STAT-1 and SAP-JNK pathways, the suppression of CXCL10 and CCL5 production, and increased viral RNA. A diminished, early epithelial-initiated antiviral response to rhinovirus infection could contribute to the increased susceptibility of subjects to prolonged respiratory viral infections after exposure to cigarette smoke.

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Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Decreases Innate Responses of Epithelial Cells to Rhinovirus Infection

Eddleston¹,

Lee²,

Doerner³

et al. 2011

Am J Respir Cell Mol Biol

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“…This may be because of their differential susceptibility to RV infection. Previously, basal undifferentiated airway epithelial cells have been shown to be more susceptible to RV than are suprabasal mucociliary-differentiated cells (15). This difference was attributed to higher expression of intercellular adhesion molecule (ICAM)-1, a receptor for major group RV in basal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…RV has also been shown to delay wound closure in nonpolarizedundifferentiated bronchial epithelial cells (14). Furthermore, basal/undifferentiated cells, which are readily accessible after airway epithelial injury and during regeneration, are more susceptible to RV infection than are the suprabasal/differentiated cells (15). On the basis of the facts that RV readily infects basal epithelial cells (which are abundant in injured airway epithelium or epithelium showing basal cell hyperplasia) and causes delay in wound closure, we hypothesized that RV may interfere with the cell repolarization and normal renewal of injured/regenerating airway epithelial cells, leading to structurally and functionally abnormal airway epithelium.…”

Section: Clinical Relevancementioning

confidence: 99%

Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium

Faris¹,

Ganesan²,

Chattoraj³

et al. 2016

Am J Respir Cell Mol Biol

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Rhinovirus (RV), which causes exacerbation in patients with chronic airway diseases, readily infects injured airway epithelium and has been reported to delay wound closure. In this study, we examined the effects of RV on cell repolarization and differentiation in a model of injured/regenerating airway epithelium (polarized, undifferentiated cells). RV causes only a transient barrier disruption in a model of normal (mucociliary-differentiated) airway epithelium. However, in the injury/regeneration model, RV prolongs barrier dysfunction and alters the differentiation of cells. The prolonged barrier dysfunction caused by RV was not a result of excessive cell death but was instead associated with epithelial-to-mesenchymal transition (EMT)-like features, such as reduced expression of the apicolateral junction and polarity complex proteins, E-cadherin, occludin, ZO-1, claudins 1 and 4, and Crumbs3 and increased expression of vimentin, a mesenchymal cell marker. The expression of Snail, a transcriptional repressor of tight and adherence junctions, was also up-regulated in RV-infected injured/regenerating airway epithelium, and inhibition of Snail reversed RV-induced EMT-like features. In addition, compared with sham-infected cells, the RV-infected injured/regenerating airway epithelium showed more goblet cells and fewer ciliated cells. Inhibition of epithelial growth factor receptor promoted repolarization of cells by inhibiting Snail and enhancing expression of E-cadherin, occludin, and Crumbs3 proteins, reduced the number of goblet cells, and increased the number of ciliated cells. Together, these results suggest that RV not only disrupts barrier function, but also interferes with normal renewal of injured/regenerating airway epithelium by inducing EMT-like features and subsequent goblet cell hyperplasia.Keywords: barrier function; epithelial-to-mesenchymal transition; Crumbs polarity complex; epithelial growth factor receptor; goblet cell hyperplasia Clinical RelevanceTo the best of our knowledge, this is the first study to demonstrate that rhinovirus delays cell repolarization in a model of injured/regenerating, but not normal, airway epithelium by inducing epithelial-to-mesenchymal transition-like features. Furthermore, rhinovirus reduces ciliated cell differentiation and promotes goblet-cell differentiation and mucin gene expression. These changes depended partially on persistent EGFR activation induced by rhinovirus. Such changes during regeneration can lead to airway epithelium with impaired barrier and mucociliary clearance functions.Airway epithelium that lines the respiratory tract acts as a physical barrier between the external environment and the lung and plays an important role in maintaining tissue homeostasis. Paracellular permeability of airway epithelium is maintained through the co-operation of two functionally distinct structural components: tight and adherence junctions located in the apicolateral membranes. Tight junctions regulate the transport of solutes and ions across airway epithelium...

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“…Viral infections could damage the barrier function of the airway epithelium, leading to enhanced absorption of allergens and/or irritants across the airway wall and enhanced inflammation (98). Conversely, intact epithelial layers are difficult to infect with HRV in vitro, and replication is enhanced by damaging the epithelium or by removing the top layer of cells (41,68). These findings suggest that allergens and pollutants that damage airway epithelium could increase susceptibility to infection and/or lead to more-severe infections (Fig.…”

Section: Risk Factors For More-severe Hrv Illnessesmentioning

confidence: 99%

The ABCs of Rhinoviruses, Wheezing, and Asthma

Gern

2010

J Virol

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Human rhinoviruses (HRVs) were discovered as common cold pathogens over 50 years ago. Recent advances in molecular viral diagnostics have led to an appreciation of their role in more-significant respiratory illnesses, including bronchiolitis in infancy, childhood pneumonia, and acute exacerbations of chronic respiratory diseases such as asthma, chronic obstructive lung disease, and cystic fibrosis. Until a few years ago, only two groups of HRVs (A and B) had been recognized. However, full and partial sequencing of HRVs led to the discovery of a third species of HRV (HRV-C) that has distinct structural and biologic features. Risk factors and pathogenic mechanisms for more-severe HRV infections are being defined, and yet fundamental questions persist about mechanisms relating this common pathogen to allergic diseases and asthma. The close relationship between HRV infections and asthma suggests that antiviral treatments could have a major impact on the morbidity associated with this chronic respiratory disease.Virology and clinical textbooks and virtually all web-based information sources generally describe human rhinoviruses (HRVs) as the most frequent cause of the common cold. In this light, HRVs are important pathogens because common colds are so widespread and annoying, and from an economic perspective, supplying symptomatic-relief medications is a huge industry. A 2003 study estimated that expenditures on common cold medications in the United States exceeded 4 billion dollars, including 1.1 billion dollars spent on inappropriate prescriptions for antibiotics (18). Finding a cure for the common cold has been a much-publicized goal ever since HRVs were first discovered in the 1950s and 1960s. The basic biology of the replication cycle was soon described, and most HRVs were found to replicate best at 33°to 35°C (88, 99), which is consistent with their role as upper airway pathogens. HRVs were found to have tremendous diversity, and approximately 100 serotypes in two groups (A and B) had been identified by 1990, when it was presumed that all, or nearly all, HRVs had been identified. These HRVs were found to bind to one of two main receptors: ICAM-1 (major group) (30) and the low-density-lipoprotein receptor (most of the minor group) (35). Despite advances in understanding HRV genetics and the picornavirus replication cycle, efforts toward developing specific antivirals have fallen short due to modest efficacy, side effects, drug interactions, and economic considerations (16). Consequently, enthusiasm for pursuing a common cold cure has waned, and the pharmaceutical industry has refocused attention on viruses that cause more-significant illnesses. This failure is a bit embarrassing. As summarized by White and Fenner, "In this era of organ transplantation, genetic engineering, and other dramatic demonstrations of the wonders of medical science, the man in the street perceives a certain irony in the inability of modern medicine to make the slightest impact on that most trivial of all human ailments, the common cold" ...

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Basal Cells of Differentiated Bronchial Epithelium Are More Susceptible to Rhinovirus Infection

Cited by 152 publications

References 46 publications

Cigarette Smoke Decreases Innate Responses of Epithelial Cells to Rhinovirus Infection

Cigarette Smoke Decreases Innate Responses of Epithelial Cells to Rhinovirus Infection

Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium

The ABCs of Rhinoviruses, Wheezing, and Asthma

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