Major and minor group rhinoviruses elicit differential signaling and cytokine responses as a function of receptor-mediated signal transduction.

Bryce A Schuler,Megan L Kingdon,David J Hall,Luyuan Li,Vincent R Racaniello,Michael T Schreiber,Dana N Raugi,Michal Mokry,Chelsea Hameister,Cosonya Smith,Susanna Esposito

doi:10.1371/journal.pone.0093897

Bryce A Schuler, Megan L Kingdon + Show 9 more

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https://doi.org/10.1371/journal.pone.0093897

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Journal: PloS one	Publication Date: Apr 15, 2014
Citations: 84	License type: CC BY 4.0

Affiliation: Lawrence University, Royal College of Physicians

Abstract

Major- and minor-group human rhinoviruses (HRV) enter their host by binding to the cell surface molecules ICAM-1 and LDL-R, respectively, which are present on both macrophages and epithelial cells. Although epithelial cells are the primary site of productive HRV infection, previous studies have implicated macrophages in establishing the cytokine dysregulation that occurs during rhinovirus-induced asthma exacerbations. Analysis of the transcriptome of primary human macrophages exposed to major- and minor-group HRV demonstrated differential gene expression. Alterations in gene expression were traced to differential mitochondrial activity and signaling pathway activation between two rhinovirus serotypes, HRV16 (major-group) and HRV1A (minor-group), upon initial HRV binding. Variances in phosphorylation of kinases (p38, JNK, ERK5) and transcription factors (ATF-2, CREB, CEBP-alpha) were observed between the major- and minor-group HRV treatments. Differential activation of signaling pathways led to changes in the production of the asthma-relevant cytokines CCL20, CCL2, and IL-10. This is the first report of genetically similar viruses eliciting dissimilar cytokine release, transcription factor phosphorylation, and MAPK activation from macrophages, suggesting that receptor use is a mechanism for establishing the inflammatory microenvironment in the human airway upon exposure to rhinovirus.

Highlights

Human rhinovirus (HRV) is the etiologic agent responsible for most common cold infections and the majority of asthma exacerbations, in both children [1] and adults [2,3]
HRV16 and HRV1A are phylogenetically closely related, with both belonging to clade-A, and sharing 85% amino acid identity [4,5,39], they bind different receptors, and we have previously demonstrated that these viruses induced different biological outcomes in human primary macrophages [40]
More genes were differentially expressed in HRV16 exposed cells compared to those macrophages exposed to HRV1A (Figure 1A and 1B) and a subset of those genes was chosen for further examination (Table 1)

Summary

Introduction

Human rhinovirus (HRV) is the etiologic agent responsible for most common cold infections and the majority of asthma exacerbations, in both children [1] and adults [2,3]. HRV serotypes are divided into three clades, known as HRV-A, HRV-B, and HRV-C, based upon genetic similarity [4,5,6]. Picornaviruses, including HRV, have an icosahedral capsid measuring approximately 30 nm in diameter and a positive-sense RNA genome of 7.2 kilobases, but they vary in their utilization of host cell-surface receptors to gain entry to cells. Among the HRVA and HRV-B viruses, major-group HRV binds the intercellular adhesion molecule 1 (ICAM-1) receptor [7], whereas minor-group HRV binds the low-density lipoprotein receptor (LDL-R) [8,9]. HRV-C viruses bind an as yet unknown receptor [10]

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