Respiratory Syncytial Virus-Induced Oxidative Stress in Lung Pathogenesis

2019 ◽  
pp. 297-330 ◽  
Author(s):  
Yashoda Madaiah Hosakote ◽  
Kempaiah Rayavara
Keyword(s):  
Oxidative Stress ◽  
Respiratory Syncytial Virus ◽  
Lung Pathogenesis ◽  
Syncytial Virus

scholarly journals Analysis of lung transcriptome in calves infected with Bovine Respiratory Syncytial Virus and treated with antiviral and/or cyclooxygenase inhibitor

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246695
Author(s):  
Maxim Lebedev ◽  
Heather A. McEligot ◽  
Victoria N. Mutua ◽  
Paul Walsh ◽  
Francisco R. Carvallo Chaigneau ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Respiratory Syncytial Virus ◽  
Differential Gene Expression ◽  
Lung Tissue ◽  
Bovine Respiratory Syncytial Virus ◽  
Pathway Enrichment Analysis ◽  
Adaptive Immune ◽  
Differential Gene ◽  
Syncytial Virus

Bovine Respiratory Syncytial virus (BRSV) is one of the major infectious agents in the etiology of the bovine respiratory disease complex. BRSV causes a respiratory syndrome in calves, which is associated with severe bronchiolitis. In this study we describe the effect of treatment with antiviral fusion protein inhibitor (FPI) and ibuprofen, on gene expression in lung tissue of calves infected with BRSV. Calves infected with BRSV are an excellent model of human RSV in infants: we hypothesized that FPI in combination with ibuprofen would provide the best therapeutic intervention for both species. The following experimental treatment groups of BRSV infected calves were used: 1) ibuprofen day 3–10, 2) ibuprofen day 5–10, 3) placebo, 4) FPI day 5–10, 5) FPI and ibuprofen day 5–10, 6) FPI and ibuprofen day 3–10. All calves were infected with BRSV on day 0. Daily clinical evaluation with monitoring of virus shedding by qRT-PCR was conducted. On day10 lung tissue with lesions (LL) and non-lesional (LN) was collected at necropsy, total RNA extracted, and RNA sequencing performed. Differential gene expression analysis was conducted with Gene ontology (GO) and KEGG pathway enrichment analysis. The most significant differential gene expression in BRSV infected lung tissues was observed in the comparison of LL with LN; oxidative stress and cell damage was especially noticeable. Innate and adaptive immune functions were reduced in LL. As expected, combined treatment with FPI and Ibuprofen, when started early, made the most difference in gene expression patterns in comparison with placebo, especially in pathways related to the innate and adaptive immune response in both LL and LN. Ibuprofen, when used alone, negatively affected the antiviral response and caused higher virus loads as shown by increased viral shedding. In contrast, when used with FPI Ibuprofen enhanced the specific antiviral effect of FPI, due to its ability to reduce the damaging effect of prostanoids and oxidative stress.

Respiratory syncytial virus infection induces the release of transglutaminase 2 from human airway epithelial cells

2021 ◽  
Author(s):  
Kempaiah Rayavara ◽  
Alexander Kurosky ◽  
Yashoda Madaiah Hosakote
Keyword(s):  
Oxidative Stress ◽  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Stress Responses ◽  
Transglutaminase 2 ◽  
Lung Epithelial Cells ◽  
Cross Linking ◽  
Lung Epithelial ◽  
Syncytial Virus ◽  
Tract Infections

Respiratory syncytial virus (RSV) is an important human pathogen that causes severe lower respiratory tract infections in young children, the elderly, and the immunocompromised, yet no effective treatments or vaccines are available. The precise mechanism underlying RSV-induced acute airway disease and associated sequelae are not fully understood; however, early lung inflammatory and immune events are thought to play a major role in the outcome of the disease. Moreover, oxidative stress responses in the airways plays a key role in the pathogenesis of RSV. Oxidative stress has been shown to elevate cytosolic calcium (Ca2+) levels, which in turn activate Ca2+-dependent enzymes, including transglutaminase 2 (TG2). Transglutaminase 2 is a multifunctional cross-linking enzyme implicated in various physiological and pathological conditions; however, its involvement in respiratory virus-induced airway inflammation is largely unknown. In this study, we demonstrated that RSV-induced oxidative stress promotes enhanced activation and release of TG2 from human lung epithelial cells as a result of its translocation from the cytoplasm and subsequent release into the extracellular space, which was mediated by Toll-like receptor (TLR)-4 and NF-κB pathways. Antioxidant treatment significantly inhibited RSV-induced TG2 extracellular release and activation via blocking viral replication. Also, treatment of RSV-infected lung epithelial cells with TG2 inhibitor significantly reduced RSV-induced matrix metalloprotease activities. These results suggested that RSV-induced oxidative stress activates innate immune receptors in the airways, such as TLRs, that can activate TG2 via the NF-κB pathway to promote cross-linking of extracellular matrix proteins, resulting in enhanced inflammation.

scholarly journals p38 and OGT Sequestration into Viral Inclusion Bodies in Cells Infected with Human Respiratory Syncytial Virus Suppresses MK2 Activities and Stress Granule Assembly

2012 ◽  
Vol 87 (3) ◽  
pp. 1333-1347 ◽  
Author(s):  
Jens Fricke ◽  
Lily Y. Koo ◽  
Charles R. Brown ◽  
Peter L. Collins
Keyword(s):  
Oxidative Stress ◽  
Respiratory Syncytial Virus ◽  
Protein Kinase ◽  
Stress Responses ◽  
Inclusion Bodies ◽  
Cellular Response ◽  
Substantial Reduction ◽  
Cytoplasmic Inclusion ◽  
Stress Granule ◽  
Syncytial Virus

ABSTRACTRespiratory syncytial virus (RSV) forms cytoplasmic inclusion bodies (IBs) that are thought to be sites of nucleocapsid accumulation and viral RNA synthesis. The present study found that IBs also were the sites of major sequestration of two proteins involved in cellular signaling pathways. These are phosphorylated p38 mitogen-activated protein kinase (MAPK) (p38-P), a key regulator of cellular inflammatory and stress responses, and O-linkedN-acetylglucosamine (OGN) transferase (OGT), an enzyme that catalyzes the posttranslational addition of OGN to protein targets to regulate cellular processes, including signal transduction, transcription, translation, and the stress response. The virus-induced sequestration of p38-P in IBs resulted in a substantial reduction in the accumulation of a downstream signaling substrate, MAPK-activated protein kinase 2 (MK2). Sequestration of OGT in IBs was associated with suppression of stress granule (SG) formation. Thus, while the RSV IBs are thought to play an essential role in viral replication, the present results show that they also play a role in suppressing the cellular response to viral infection. The sequestration of p38-P and OGT in IBs appeared to be reversible: oxidative stress resulting from arsenite treatment transformed large IBs into a scattering of smaller bodies, suggestive of partial disassembly, and this was associated with MK2 phosphorylation and OGN addition. Unexpectedly, the RSV M2-1 protein was found to localize in SGs that formed during oxidative stress. This protein was previously shown to be a viral transcription elongation factor, and the present findings provide the first evidence of possible involvement in SG activities during RSV infection.

scholarly journals Respiratory Syncytial Virus Induces Oxidative Stress by Modulating Antioxidant Enzymes

2009 ◽  
Vol 41 (3) ◽  
pp. 348-357 ◽  
Author(s):  
Yashoda M. Hosakote ◽  
Tianshuang Liu ◽  
Shawn M. Castro ◽  
Roberto P. Garofalo ◽  
Antonella Casola
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Respiratory Syncytial Virus ◽  
Syncytial Virus

scholarly journals Respiratory Syncytial Virus-Induced Oxidative Stress Leads to an Increase in Labile Zinc Pools in Lung Epithelial Cells

mSphere ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Naseem Ahmed Khan ◽  
Mohit Singla ◽  
Sweety Samal ◽  
Rakesh Lodha ◽  
Guruprasad R. Medigeshi
Keyword(s):  
Oxidative Stress ◽  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Zinc Supplementation ◽  
Lung Epithelial Cells ◽  
Zinc Homeostasis ◽  
Lung Epithelial ◽  
Rsv Infection ◽  
Infected Cells ◽  
Syncytial Virus

ABSTRACT Zinc supplementation in cell culture has been shown to inhibit various viruses, like herpes simplex virus, rotavirus, severe acute respiratory syndrome (SARS) coronavirus, rhinovirus, and respiratory syncytial virus (RSV). However, whether zinc plays a direct antiviral role in viral infections and whether viruses have adopted strategies to modulate zinc homeostasis have not been investigated. Results from clinical trials of zinc supplementation in infections indicate that zinc supplementation may be beneficial in a pathogen- or disease-specific manner, further underscoring the importance of understanding the interaction between zinc homeostasis and virus infections at the molecular level. We investigated the effect of RSV infection on zinc homeostasis and show that RSV infection in lung epithelial cells leads to modulation of zinc homeostasis. The intracellular labile zinc pool increases upon RSV infection in a multiplicity of infection (MOI)-dependent fashion. Small interfering RNA (siRNA)-mediated knockdown of the ubiquitous zinc uptake transporter ZIP1 suggests that labile zinc levels are increased due to the increased uptake by RSV-infected cells as an antiviral response. Adding zinc to culture medium after RSV infection led to significant inhibition of RSV titers, whereas depletion of zinc by a zinc chelator, N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) led to an increase in RSV titers. The inhibitory effect of zinc was specific, as other divalent cations had no effect on RSV titers. Both RSV infection and zinc chelation by TPEN led to reactive oxygen species (ROS) induction, whereas addition of zinc blocked ROS induction. These results suggest a molecular link between RSV infection, zinc homeostasis, and oxidative-stress pathways and provide new insights for developing strategies to counter RSV infection. IMPORTANCE Zinc deficiency rates in developing countries range from 20 to 30%, and zinc supplementation trials have been shown to correct clinical manifestations attributed to zinc deficiency, but the outcomes in the case of respiratory infections have been inconsistent. We aimed at understanding the role of zinc homeostasis in respiratory syncytial virus (RSV) infection. Infection of lung epithelial cell lines or primary small-airway epithelial cells led to an increase in labile zinc pools, which was due to increased uptake of zinc. Zinc supplementation inhibited RSV replication, whereas zinc chelation had an opposing effect, leading to increases in RSV titers. Increases in labile zinc in RSV-infected cells coincided with induction of reactive oxygen species (ROS). Both zinc depletion and addition of exogenous ROS led to enhanced RSV infection, whereas addition of the antioxidant inhibited RSV, suggesting that zinc is part of an interplay between RSV-induced oxidative stress and the host response to maintain redox balance.

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