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Major and Minor Group Human Rhinovirus Response in Human Macrophages

ABSTRACT: Major- and minor-group rhinoviruses 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. Even though major- and minor-group rhinoviruses are nearly genetically identical, these viruses do not replicate with equal success in monocyte-lineage cell lines. In human primary macrophages, differential mitochondrial activity and signaling pathway activation was observed between major- and minor-group rhinovirus upon initial HRV binding, indicating discordant receptor-dependent response to these rhinovirus types. As well, 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. The difference between major- and minor- group HRV activation of signaling pathways was confirmed through RNA-sequencing and observation of differential 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. These results suggest that receptor dependence plays a role in establishing the inflammatory microenvironment initiated in part by monocytic-lineage cells in the human airway upon exposure to rhinovirus.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55271 | GEO | 2014/03/14

SECONDARY ACCESSION(S): PRJNA239024

REPOSITORIES: GEO

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Major and Minor Group Human Rhinovirus Response in Human Macrophages

Project description:Major- and minor-group rhinoviruses 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. Even though major- and minor-group rhinoviruses are nearly genetically identical, these viruses do not replicate with equal success in monocyte-lineage cell lines. In human primary macrophages, differential mitochondrial activity and signaling pathway activation was observed between major- and minor-group rhinovirus upon initial HRV binding, indicating discordant receptor-dependent response to these rhinovirus types. As well, 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. The difference between major- and minor- group HRV activation of signaling pathways was confirmed through RNA-sequencing and observation of differential 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. These results suggest that receptor dependence plays a role in establishing the inflammatory microenvironment initiated in part by monocytic-lineage cells in the human airway upon exposure to rhinovirus. RNA sequencing of monocyte-derived macrophages after mock infection or infection by HRV16 or HRV1A

2014-03-14 | E-GEOD-55271 | biostudies-arrayexpress

Transcription profiling of human bronchial epithelial cells from normal and asthmatic individuals to investigate rhinovirus-induced modulation of gene expression

Project description:Human Rhinovirus (HRV) infection can trigger exacerbations of asthma. Understanding of the mechanisms provoking airway inflammation and remodeling in asthma, as well as the pathogenic mechanisms of HRV infection and its association with asthma exacerbations, may offer significant opportunities for improved disease management. Genome-wide expression analysis of HRV type 1A-infected primary bronchial epithelial (PBE) cells from normal and asthmatic donors was performed to determine whether asthma is associated with a unique pattern of gene expression after HRV infection in vitro. Experiment Overall Design: Frozen stocks of human PBE cells obtained from the bronchial brushings of six normal and five asthmatic individuals were grown in vitro in Bronchial Epithelial Growth Media (BEGM, Lonza). Subconfluent monolayers of PBE cells were infected with purified and concentrated minor group HRV serotype 1A at multiplicity of infection of 10 plaque forming units (pfu) per cell or mock-infected with growth media alone. Cells were lysed 16 hours post infection (p.i.) and isolated total RNAs were analyzed using the Human Genome U133 Plus 2.0 GeneChip arrays (Affymetrix, Santa Clara, CA).

2008-11-13 | E-GEOD-13396 | biostudies-arrayexpress

IL-33 induces an antiviral signature in mast cells but enhances their permissiveness for human rhinovirus infection

Project description:Mast cells (MCs) are classically associated with allergic asthma but their role in antiviral immunity is unclear. Human rhinoviruses (HRVs) are a major cause of asthma exacerbations and can infect and replicate within MCs. The primary site of HRV infection is the airway epithelium and MCs localise to this site with increasing asthma severity. The asthma susceptibility gene, IL-33, encodes an epithelial-derived cytokine released following HRV infection but its impact on MC antiviral responses has yet to be determined. In this study we investigated the global response of LAD2 MCs to IL-33 stimulation using RNA sequencing and identified genes involved in antiviral immunity. In spite of this, IL-33 treatment increased permissiveness of MCs to HRV16 infection which, from the RNA-Seq data, we attributed to upregulation of ICAM1. Flow cytometric analysis confirmed an IL-33-dependent increase in ICAM1 surface expression as well as LDLR, the receptors used by major and minor group HRVs for cellular entry. Neutralisation of ICAM1 reduced the IL-33-dependent enhancement in HRV16 replication and release in both LAD2 MCs and cord blood derived MCs. These findings demonstrate that although IL-33 induces an antiviral signature in MCs, it also upregulates the receptors for HRV entry to enhance infection. This highlights the potential for a gene-environment interaction involving IL33 and HRV in MCs to contribute to virus-induced asthma exacerbations.

2022-11-01 | GSE216269 | GEO

Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma

2008-11-01 | GSE13396 | GEO

Distinct peripheral blood mononuclear cells transcriptional modules in the response to human respiratory syncytial virus or human rhinovirus in hospitalized infants with bronchiolitis

Project description:Human respiratory syncytial virus (HRSV) is the main cause of bronchiolitis during the first year of life, but other viruses such as rhinovirus also occur and are clinically indistinguishable. In hospitalized infants with bronchiolitis, the analysis of the peripheral blood mononuclear cells (PBMC) gene expression might be useful for identification the etiologies caused by HRSV and human rhinovirus (HRV) and to the development of future tests, as well as to elucidate the pathogenic mechanisms triggered by different viral agents and new therapeutic possibilities. In this study, we conducted a comparative global gene expression analysis of infants with acute viral bronchiolitis infected by HRSV (HRSV group) or HRV (HRV group).

2019-03-19 | GSE124124 | GEO

Homo sapiens

Project description:Major and Minor Group Human Rhinovirus Response in Human Macrophages

| PRJNA239024 | ENA

Phenotypic responses of differentiated asthmatic human airway epithelial cultures to rhinovirus

Project description:We report the application of RNA sequencing technology for high-throughput profiling of gene expression responses to human rhinovirus infection at 24 hours in air-liquid interface human airway epithelial cell cultures derived from 6 asthmatic and 6 non-asthmatic donors. RNA-seq analysis identified sets of genes associated with asthma specific viral responses. These genes are related to inflammatory pathways, epithelial remodeling and cilium assembly and function, including those described previously (e.g. CCL5, CXCL10 and CX3CL1), and novel ones that were identified for the first time in this study (e.g. CCRL1, CDHR3). We concluded that air liquid interface cultured human airway epithelial cells challenged with live HRV are a useful in vitro model for the study of rhinovirus induced asthma exacerbation, given that our findings are consistent with clinical data sets. Furthermore, our data suggest that abnormal airway epithelial structure and inflammatory signaling are important contributors to viral induced asthma exacerbation. Differentiated air-liquid interface cultured human airway epithelial cell mRNA profiles from 6 asthmatic and 6 non-asthmatic donors after 24 hour treatment with either HRV or vehicle control were generated by deep sequencing, using Illumina HiSeq 2000.

2015-03-01 | E-GEOD-61141 | biostudies-arrayexpress

Whole Blood Transcriptional Profiling Differentiates Between Asymptomatic and Symptomatic Human Rhinovirus Detection in Children

Project description:Human rhinoviruses (HRV) are among the most common causes of respiratory infections in humans but can be frequently detected also in asymptomatic subjects. We evaluated the value of gene expression profiles to differentiate asymptomatic detection from symptomatic HRV infection in children.

2016-01-14 | GSE67059 | GEO

Critical role of pDC in regulating gene expression and innate immune responses to human rhinovirus

Project description:Human rhinoviruses (HRV) are usually innocuous viruses; however, they can trigger serious consequences in certain individuals, especially in the setting of deficient interferon (IFN) synthesis. Plasmacytoid dendritic cells (pDC) are key IFN producing cells, though we know little about the mechanisms by which pDC regulate HRV-induced immune responses. Herein we used gene expression microarrays to examine HRV-induced mRNA in blood mononuclear cells from healthy people, in combination with pDC depletion to assess whether observed expression patterns were pDC dependent. As expected, pDC depletion led to a major reduction in HRV-induced IFN-α release, and this was associated with profound differences in gene expression between intact PBMC and pDC depleted PBMC. pDC depletion led to major changes in upstream regulators, with 70-80% of the HRV activated genes appearing to be pDC dependent. PCR validation experiments confirmed changes seen in the microarrays, specifically the extent to which the following differentially expressed genes were highly pDC dependent: the transcription factor IRF7, both IL-27 chains (IL-27 and EBI3), the alpha chain of the IL-15 receptor (IL-15RA) and the IFN stimulated gene IFI27. IL-6, IFN-γ and IL-27 protein synthesis were also highly pDC dependent. Supplementing pDC-depleted cultures with either recombinant IFN-γ, IL-15, IL-27 or IL-6 was able to restore the IFN-α response, thereby compensating for the absence of pDC. Though pDC comprise only a minority population of migratory leukocytes, our findings highlight the extent to which these cells are able to exert a profound effect on the immune response to HRV.

2017-06-10 | GSE99858 | GEO

PGC-1alpha mediates a metabolic host defense response in human airway epithelium during rhinovirus infections

Project description:Human rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. Although viral induced epithelial damage mediates inflammation, the molecular mechanisms responsible for airway epithelial damage and dysfunction remain undefined. Using experimental HRV infection studies in humans and highly differentiated human bronchial epithelial cells grown at air-liquid interface (ALI), we examined the links between viral host defense, cellular metabolism, and epithelial barrier function. We observed that early HRV-C15 infection induced a transitory barrier-protective metabolic state characterized by glycolysis that ultimately becomes exhausted as the infection progresses and leads to cellular damage. Pharmacological promotion of glycolysis induced ROS-dependent upregulation of the mitochondrial metabolic regulator, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), thereby restoring epithelial barrier function, improving viral defense, and attenuating disease pathology. Therefore, PGC-1alpha regulates a metabolic pathway essential to host defense that can be therapeutically targeted to rescue airway epithelial barrier dysfunction and potentially prevent severe respiratory complications or secondary bacterial infections.

2021-04-30 | PXD024591 | Pride

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