scholarly journals A Meta-Analysis of Multiple Whole Blood Gene Expression Data Unveils a Diagnostic Host-Response Transcript Signature for Respiratory Syncytial Virus

2020 ◽  
Vol 21 (5) ◽  
pp. 1831 ◽  
Author(s):  
Ruth Barral-Arca ◽  
Alberto Gómez-Carballa ◽  
Miriam Cebey-López ◽  
Xabier Bello ◽  
Federico Martinón-Torres ◽  
...  
Keyword(s):  
Gene Expression ◽  
Respiratory Syncytial Virus ◽  
Drug Targets ◽  
Cohort Analysis ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Healthy Controls ◽  
Infection Pattern ◽  
Rsv Infection ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is one of the major causes of acute lower respiratory tract infection worldwide. The absence of a commercial vaccine and the limited success of current therapeutic strategies against RSV make further research necessary. We used a multi-cohort analysis approach to investigate host transcriptomic biomarkers and shed further light on the molecular mechanism underlying RSV-host interactions. We meta-analyzed seven transcriptome microarray studies from the public Gene Expression Omnibus (GEO) repository containing a total of 922 samples, including RSV, healthy controls, coronaviruses, enteroviruses, influenzas, rhinoviruses, and coinfections, from both adult and pediatric patients. We identified > 1500 genes differentially expressed when comparing the transcriptomes of RSV-infected patients against healthy controls. Functional enrichment analysis showed several pathways significantly altered, including immunologic response mediated by RSV infection, pattern recognition receptors, cell cycle, and olfactory signaling. In addition, we identified a minimal 17-transcript host signature specific for RSV infection by comparing transcriptomic profiles against other respiratory viruses. These multi-genic signatures might help to investigate future drug targets against RSV infection.

scholarly journals Gene Expression of Nucleic Acid-Sensing Pattern Recognition Receptors in Children Hospitalized for Respiratory Syncytial Virus-Associated Acute Bronchiolitis

2009 ◽  
Vol 16 (6) ◽  
pp. 816-823 ◽  
Author(s):  
Carolina Scagnolari ◽  
Fabio Midulla ◽  
Alessandra Pierangeli ◽  
Corrado Moretti ◽  
Enea Bonci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pattern Recognition ◽  
Viral Load ◽  
Respiratory Syncytial Virus ◽  
Pattern Recognition Receptors ◽  
Mrna Levels ◽  
Acute Bronchiolitis ◽  
Expression Levels ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT Given the critical role of pattern recognition receptors (PRRs) in acid nucleic recognition in the initiation of innate immunity and the orchestration of adaptive immunity, the aim of this study was to determine whether any heterogeneity of PRR expression in the airway tracts of infants with respiratory syncytial virus (RSV) infection might explain the broad clinical spectrum of RSV-associated bronchiolitis in infants. For this purpose, the levels of melanoma differentiation-associated protein-5 (MDA-5), retinoic acid inducible gene-1 (RIG-1), and Toll-like receptor 3 (TLR-3), TLR-7, TLR-8, and TLR-9 mRNAs were evaluated, using TaqMan quantitative reverse transcription-PCR, in cells from nasopharyngeal washes collected from 157 infants suffering from acute bronchiolitis whether or not they were associated with respiratory viruses. High interindividual variability was observed in both virus-positive and -negative infants; however, the relative gene expression levels of MDA-5, RIG-1, TLR-7, and TLR-8 were significantly higher in the virus-infected group, whereas the expression levels of TLR-3 and TLR-9 were not significantly different. The differences in the gene expression of MDA-5, RIG-1, TLR-7, and TLR-8 were more evident in infants with RSV infection than in those with bocavirus or rhinovirus infection. In RSV-infected infants, PRR-mRNA levels also were analyzed in relation to interferon protein levels, viral load, clinical severity, days of hospitalization, age, and body weight. A significant positive correlation was observed only between RSV viral load and RIG-1 mRNA levels. These findings provide the first direct evidence that, in infants with respiratory virus-associated bronchiolitis, especially RSV, there are substantial changes in PRR gene expression; this likely is an important determinant of the clinical outcome of bronchiolitis.

scholarly journals Differential Histopathology and Chemokine Gene Expression in Lung Tissues following Respiratory Syncytial Virus (RSV) Challenge of Formalin-Inactivated RSV- or BBG2Na-Immunized Mice

2001 ◽  
Vol 75 (24) ◽  
pp. 12421-12430 ◽  
Author(s):  
Ultan F. Power ◽  
Thierry Huss ◽  
Vincent Michaud ◽  
Hélène Plotnicky-Gilquin ◽  
Jean-Yves Bonnefoy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Respiratory Syncytial Virus ◽  
Mouse Model ◽  
Subunit Vaccine ◽  
Late Time ◽  
Chemokine Gene ◽  
Time Points ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Chemokine Gene Expression

ABSTRACT A BALB/c mouse model of enhanced pulmonary pathology following vaccination with formalin-inactivated alum-adsorbed respiratory syncytial virus (FI-RSV) and live RSV challenge was used to determine the type and kinetics of histopathologic lesions induced and chemokine gene expression profiles in lung tissues. These data were compared and contrasted with data generated following primary and/or secondary RSV infection or RSV challenge following vaccination with a promising subunit vaccine, BBG2Na. Severe peribronchiolitis and perivascularitis coupled with alveolitis and interstitial inflammation were the hallmarks of lesions in the lungs of FI-RSV-primed mice, with peak histopathology evident on days 5 and 9. In contrast, primary RSV infection resulted in no discernible lesions, while challenge of RSV-primed mice resulted in rare but mild peribronchiolitis and perivascularitis, with no evidence of alveolitis or interstitial inflammation. Importantly, mice vaccinated with a broad dose range (20 to 0.02 μg) of a clinical formulation of BBG2Na in aluminium phosphate demonstrated histopathology similar to that observed in secondary RSV infection. At the molecular level, FI-RSV priming was characterized by a rapid and strong up-regulation of eotaxin and monocyte chemotactic protein 3 (MCP-3) relative gene expression (potent lymphocyte and eosinophil chemoattractants) that was sustained through late time points, early but intermittent up-regulation of GRO/melanoma growth stimulatory activity gene and inducible protein 10 gene expression, while macrophage inflammatory protein 2 (MIP-2) and especially MCP-1 were up-regulated only at late time points. By comparison, primary RSV infection or BBG2Na priming resulted in considerably lower eotaxin and MCP-3 gene expression increases postchallenge, while expression of lymphocyte or monocyte chemoattractant chemokine genes (MIP-1β, MCP-1, and MIP-2) were of higher magnitude and kinetics at early, but not late, time points. Our combined histopathologic and chemokine gene expression data provide a basis for differentiating between aberrant FI-RSV-induced immune responses and normal responses associated with RSV infection in the mouse model. Consequently, our data suggest that BBG2Na may constitute a safe RSV subunit vaccine for use in seronegative infants.

scholarly journals Nasopharyngeal gene expression, a novel approach to study the course of respiratory syncytial virus infection

2014 ◽  
Vol 45 (3) ◽  
pp. 718-725 ◽  
Author(s):  
Corné H. van den Kieboom ◽  
Inge M.L. Ahout ◽  
Aldert Zomer ◽  
Kim H. Brand ◽  
Ronald de Groot ◽  
...  
Keyword(s):  
Gene Expression ◽  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Pathogen Detection ◽  
Severe Disease ◽  
Host Gene ◽  
Host Gene Expression ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections

Respiratory syncytial virus (RSV) causes mild infections in the vast majority of children. However, in some cases, it causes severe disease, such as bronchiolitis and pneumonia. Development of severe RSV infection is determined by the host response. Therefore, the main aim of this study was to identify biomarkers associated with severe RSV infection.To identify biomarkers, nasopharyngeal gene expression was profiled by microarray studies, resulting in the selection of five genes: ubiquitin D, tetraspanin 8, mucin 13, β-microseminoprotein and chemokine ligand 7.These genes were validated by real-time quantitative PCR in an independent validation cohort, which confirmed significant differences in gene expression between mildly and severely infected and between recovery and acute patients.Nasopharyngeal aspirate samples are regularly taken when a viral respiratory tract infection is suspected. In this article, we describe a method to discriminate between mild and severe RSV infection based on differential host gene expression. The combination of pathogen detection and host gene expression analysis in nasopharyngeal aspirates will significantly improve the diagnosis and prognosis of respiratory tract infections.

scholarly journals Respiratory Syncytial Virus (RSV) Infection in Elderly Mice Results in Altered Antiviral Gene Expression and Enhanced Pathology

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e88764 ◽  
Author(s):  
Terianne M. Wong ◽  
Sandhya Boyapalle ◽  
Viviana Sampayo ◽  
Huy D. Nguyen ◽  
Raminder Bedi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Respiratory Syncytial Virus ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Antiviral Gene

scholarly journals Identification of NF-κB-Dependent Gene Networks in Respiratory Syncytial Virus-Infected Cells

2002 ◽  
Vol 76 (13) ◽  
pp. 6800-6814 ◽  
Author(s):  
Bing Tian ◽  
Yuhong Zhang ◽  
Bruce A. Luxon ◽  
Roberto P. Garofalo ◽  
Antonella Casola ◽  
...  
Keyword(s):  
Gene Expression ◽  
Respiratory Syncytial Virus ◽  
Gene Networks ◽  
Nuclear Translocation ◽  
Constitutive Expression ◽  
Dominant Negative ◽  
Expression Levels ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections

ABSTRACT Respiratory syncytial virus (RSV) is a mucosa-restricted virus that is a leading cause of epidemic respiratory tract infections in children. In epithelial cells, RSV replication activates nuclear translocation of the inducible transcription factor nuclear factor κB (NF-κB) through proteolysis of its cytoplasmic inhibitor, IκB. In spite of a putative role in mediating virus-inducible gene expression, the spectrum of NF-κB-dependent genes induced by RSV infection has not yet been determined. To address this, we developed a tightly regulated cell system expressing a nondegradable, epitope-tagged IκBα isoform (Flag-IκBα Mut) whose expression could be controlled by exogenous addition of nontoxic concentrations of doxycycline. Flag-IκBα Mut expression potently inhibited IκBα proteolysis, NF-κB binding, and NF-κB-dependent gene transcription in cells stimulated with the prototypical NF-κB-activating cytokine tumor necrosis factor alpha (TNF-α) and in response to RSV infection. High-density oligonucleotide microarrays were then used to profile constitutive and RSV-induced gene expression in the absence or presence of Flag-IκBα Mut. Comparison of these profiles revealed 380 genes whose expression was significantly changed by the dominant-negative NF-κB. Of these, 236 genes were constitutive (not RSV regulated), and surprisingly, only 144 genes were RSV regulated, representing numerically ∼10% of the total population of RSV-inducible genes at this time point. Hierarchical clustering of the 144 RSV- and Flag-IκBα Mut-regulated genes identified two discrete gene clusters. The first group had high constitutive expression, and its expression levels fell in response to RSV infection. In this group, constitutive mRNA expression was increased by Flag-IκBα Mut expression, and the RSV-induced decrease in expression was partly inhibited. In the second group, constitutive expression was very low (or undetectable) and, after RSV infection, expression levels strongly increased. In this group, NF-κB was required for RSV-inducible expression because Flag-IκBα Mut expression blocked their induction by RSV. This latter cluster includes chemokines, transcriptional regulators, intracellular proteins regulating translation and proteolysis, and secreted proteins (complement components and growth factor regulators). These data suggest that NF-κB action induces global cellular responses after viral infection.

scholarly journals Respiratory Syncytial Virus Infects and Abortively Replicates in the Lungs in Spite of Preexisting Immunity

2007 ◽  
Vol 81 (17) ◽  
pp. 9443-9450 ◽  
Author(s):  
Marina S. Boukhvalova ◽  
Gregory A. Prince ◽  
Jorge C. G. Blanco
Keyword(s):  
Gene Expression ◽  
Respiratory Syncytial Virus ◽  
Viral Gene Expression ◽  
The Elderly ◽  
Productive Infection ◽  
Viral Gene ◽  
Rna Transcripts ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and viral pneumonia in young children and a serious health risk in immunocompromised individuals and the elderly. Immunity to RSV is not completely understood. In this work, we established a method for monitoring RSV infection by real-time PCR and applied this method for analysis of RSV replication in vivo in the cotton rat model in naïve animals and in animals rendered immune to RSV by prior RSV infection. We found that even though no virus could be isolated from the lungs of RSV-challenged immune animals, RSV infection in fact took place and an accumulation of viral RNA transcripts was observed. This type of replication, therefore, can be termed “abortive,” as RSV is capable of entering the cells in the lungs of immune animals, yet the production of progeny viruses is impaired. Similar patterns of RSV gene expression gradient were observed between naïve and reinfected animals, indicating that the skewing of mRNA gradient of viral gene expression, a mechanism documented during latent infection by other viruses, is not likely to be responsible for abortive replication of RSV during reinfection. We found that passive administration of antibodies to RSV prevents productive infection normally accompanied by viral release in the lung, but it does not prevent abortive replication of the virus. To the best of our knowledge, this is the first evidence of abortive replication of RSV in vivo.

scholarly journals Respiratory Syncytial Virus Regulates Human MicroRNAs by Using Mechanisms Involving Beta Interferon and NF-κB

mBio ◽  
2012 ◽  
Vol 3 (6) ◽  
Author(s):  
Natalie J. Thornburg ◽  
Sarah L. Hayward ◽  
James E. Crowe
Keyword(s):  
Gene Expression ◽  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Host Cell ◽  
Innate Immune ◽  
Cell Type ◽  
Rsv Infection ◽  
Respiratory Tract Illness ◽  
Syncytial Virus ◽  
Antigen Presenting

ABSTRACTRespiratory syncytial virus (RSV) is the most common viral cause of severe lower respiratory tract illness in infants and children. The virus replicates in polarized epithelial cells in the airway and, to a lesser extent, infects airway antigen-presenting cells, such as dendritic cells (DCs). RSV possesses a number of expressed genes that antagonize the effect of type I interferons and other related host factor pathways that inhibit replication efficiency. Virus infection alters host gene transcription and the translation of host transcripts through specific antagonism of the function of host proteins, through induction of RNA stress granules, and through induction of altered patterns of host gene expression. In healthy cells, microRNAs (miRNAs) regulate gene expression by targeting the noncoding region of mRNA molecules to cause silencing or degradation of transcripts. It is not known whether or not RSV infection alters the level of microRNAs in cells. We profiled the pattern of expression of host cell microRNAs in RSV-infected epithelial cells or DCs and found that RSV did alter microRNA expression but in a cell-type-specific manner. The studies showed that let-7b was upregulated in DCs, while let-7i and miR-30b were upregulated in epithelial cells in a process that required viral replication. Interestingly, we found that the RSV nonstructural genes NS1 and NS2 antagonized the upregulation of let-7i and miR-30b. RSV appears to manipulate host cell gene expression through regulation of expression of miRNAs related to the interferon response. The data suggest a new mechanism of virus-host cell interactions for paramyxoviruses.IMPORTANCERespiratory syncytial virus (RSV) is the most common cause of serious lower respiratory tract illness in infants and children. The human innate immune response inhibits RSV replication early after inoculation, principally through the effect of substances called interferons. The virus, however, has developed several mechanisms for counteracting the host innate immune response. It is not known whether or not RSV infection alters the expression of host microRNAs, which are short RNA sequences that are posttranscriptional regulators. This paper shows that RSV does induce unique patterns of microRNA expression related to the NF-κB pathway or interferon pathways. The microRNA profiles differed depending on the cell type that was infected, airway cell or antigen-presenting cell. Interestingly, the virus appears to counteract the microRNA response by expressing nonstructural viral genes in the cell that reduce microRNA induction. The data suggest a new way in which paramyxoviruses regulate the host cell response to infection.

scholarly journals Statin-mediated disruption of Rho GTPase prenylation and activity inhibits respiratory syncytial virus infection

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Manpreet Malhi ◽  
Michael J. Norris ◽  
Wenming Duan ◽  
Theo J. Moraes ◽  
Jason T. Maynes
Keyword(s):  
Respiratory Syncytial Virus ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Surface Expression ◽  
Functional Enrichment ◽  
Host Protein ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections

AbstractRespiratory syncytial virus (RSV) is a leading cause of severe respiratory tract infections in children. To uncover new antiviral therapies, we developed a live cell-based high content screening approach for rapid identification of RSV inhibitors and characterized five drug classes which inhibit the virus. Among the molecular targets for each hit, there was a strong functional enrichment in lipid metabolic pathways. Modulation of lipid metabolites by statins, a key hit from our screen, decreases the production of infectious virus through a combination of cholesterol and isoprenoid-mediated effects. Notably, RSV infection globally upregulates host protein prenylation, including the prenylation of Rho GTPases. Treatment by statins or perillyl alcohol, a geranylgeranyltransferase inhibitor, reduces infection in vitro. Of the Rho GTPases assayed in our study, a loss in Rac1 activity strongly inhibits the virus through a decrease in F protein surface expression. Our findings provide new insight into the importance of host lipid metabolism to RSV infection and highlight geranylgeranyltransferases as an antiviral target for therapeutic development.

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