Regulation of influenza virus replication by Wnt/β-catenin signaling

More, Sunil S.; Yang, Xiaoyun; Zhu, Zhengyu; Bamunuarachchi, Gayan; Guo, Yujie; Huang, Chaoqun; Bailey, Keith; Metcalf, Jordan P.; Liu, Lin

doi:10.1371/journal.pone.0191010

Cited by 46 publications

(46 citation statements)

References 46 publications

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“…However, this virus also produces markedly less severe symptoms in paediatric than adult COVID-19 patients Su et al, 2020). Upregulated type I and II interferon-associated gene expression in children ( Figure 2B) might be indicative of more effective anti-viral immunity whereas higher Wnt pathway-associated gene expression in adults ( Figure 2B) might be relevant since Wnt activation has been shown to increase rates of influenza replication (More et al, 2018). To further assess epithelial-intrinsic factors that might explain the disparity in symptom severity, we compared the expression of a manually curated list of 99 genes associated with viral infection in epithelial cells (Table S2) in our laser-capture microdissected whole tracheobronchial epithelium dataset ( Figure 6A).…”

Section: Cultured Basal Cells Demonstrate Greater Age-related Transcrmentioning

confidence: 99%

Cell-intrinsic differences between human airway epithelial cells from children and adults

Nigro

Pennycuick

Gowers

et al. 2020

Preprint

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The airway epithelium is a key protective barrier whose integrity is preserved by the selfrenewal and differentiation of basal progenitor cells. Epithelial cells are central to the pathogenesis of multiple lung diseases. In chronic diseases, increasing age is a principle risk factor. In acute diseases, such as COVID-19, children suffer less severe symptoms than adults and have a lower rate of mortality. Few studies have explored differences between airway epithelial cells in children and adults to explain this age dependent variation in diseases. Here, we perform bulk RNA sequencing studies in laser-capture microdissected whole epithelium, FACS-sorted basal cells and cultured basal cells, as well as in vitro cell proliferation experiments, to address the intrinsic molecular differences between paediatric and adult airway basal cells. We find that, while the cellular composition of the paediatric and adult tracheobronchial epithelium is broadly similar, in cell culture, paediatric airway epithelial cells displayed higher colony forming ability, better in vitro growth and outcompeted adult cells in competitive proliferation assays. In RNA sequencing experiments, we observed potentially important differences in airway epithelial gene expression between samples from children and adults. However, genes known to be associated with SARS-CoV-2 infection were not differentially expressed between children and adults. Our results chart cell-intrinsic differences in transcriptional profile and regenerative capacity between proximal airway epithelial cells of children and adults.

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Section: Cultured Basal Cells Demonstrate Greater Age-related Transcrmentioning

confidence: 99%

Cell-intrinsic differences between human airway epithelial cells from children and adults

Nigro

Pennycuick

Gowers

et al. 2020

Preprint

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“…As influenza pathogenesis is determined in part by the host response, understanding the key host modulators of viral infection and virus-induced disease is a promising approach to host-oriented drug development for preventing the disease. The Wnt/β-catenin signalling pathway has been shown to play an important role in virus replication (More et al, 2018;Shapira et al, 2009) and virus-induced immune responses (Hillesheim, Nordhoff, Boergeling, Ludwig, & Wixler, 2014). Identification of miRNAs that interfere with IAV replication by modulating Wnt/β-catenin will provide new insights into the miRNA-Wnt/β-catenin signalling-IAV interaction network.…”

Section: Discussionmentioning

confidence: 99%

“…We then assessed whether the effects of miR-193b on IAV infection were dependent on the viral strain using an IAV luciferase reporter assay (More et al, 2018). The IAV luciferase reporter vector contains a firefly luciferase under control of NP 5′ and 3′ UTRs of influenza A/WSN/33, so it is able to respond to IAV.…”

Section: Further Characterisation Of the Anti-iav Activities Of Mirmentioning

confidence: 99%

“…We have recently demonstrated a beneficial role of Wnt/βcatenin signalling in IAV infection. The activation of Wnt/β-catenin with Wnt3a enhances influenza virus replication, whereas the inhibition of the pathway with iCRT14 decreases influenza infection (More et al, 2018). In the present study, we sought to identify miRNAs that regulate IAV replication by modulating the Wnt/β-catenin pathway.…”

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confidence: 99%

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miR‐193b represses influenza A virus infection by inhibiting Wnt/β‐catenin signalling

Yang

Zhao

Bamunuarachchi

et al. 2019

Cellular Microbiology

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Due to an increasing emergence of new and drug-resistant strains of the influenza A virus (IAV), developing novel measures to combat influenza is necessary. We have previously shown that inhibiting Wnt/β-catenin pathway reduces IAV infection. In this study, we aimed to identify antiviral human microRNAs (miRNAs) that target the Wnt/β-catenin signalling pathway. Using a miRNA expression library, we identified 85 miRNAs that up-regulated and 20 miRNAs that down-regulated the Wnt/β-catenin signalling pathway. Fifteen miRNAs were validated to up-regulate and five miRNAs to down-regulate the pathway. Overexpression of four selected miRNAs (miR-193b, miR-548f-1, miR-1-1, and miR-509-1) that down-regulated the Wnt/βcatenin signalling pathway reduced viral mRNA, protein levels in A/PR/8/34-infected HEK293 cells, and progeny virus production. Overexpression of miR-193b in lung epithelial A549 cells also resulted in decreases of A/PR/8/34 infection. Furthermore, miR-193b inhibited the replication of various strains, including H1N1 (A/PR/8/34, A/WSN/ 33, A/Oklahoma/3052/09) and H3N2 (A/Oklahoma/309/2006), as determined by a viral reporter luciferase assay. Further studies revealed that β-catenin was a target of miR-193b, and β-catenin rescued miR-193b-mediated suppression of IAV infection. miR-193b induced G0/G1 cell cycle arrest and delayed vRNP nuclear import. Finally, adenovirus-mediated gene transfer of miR-193b to the lung reduced viral load in mice challenged by a sublethal dose of A/PR/8/34. Collectively, our findings suggest that miR-193b represses IAV infection by inhibiting Wnt/β-catenin signalling. KEYWORDS cell cycle arrest, influenza A virus, microRNA, miR-193b, vRNP nuclear import, Wnt/β-catenin signaling

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“…TGFβ signaling pathway was demonstrated to being a doubtful advantage in normal and pathogenic development, especially in organ fibrosis, vascular disorders, and carcinoma. Previous studies reported the dysregulation of the Wnt signaling pathway during pseudorabies virus (PRV) infection [24] and the enhanced influenza virus mRNA and virus production by triggering Wnt pathway [32]. The reaction to EBOV infection was regulated by TGFβ signaling pathway [33], and the improved secretion of TGF-β1 and vascular endothelial growth factor (VEGF) in EBOV-infected cells were improved by temporally upregulating TGF-β-modulated signaling responses.…”

Section: Discussionmentioning

confidence: 99%

iTRAQ-based high-throughput proteomics analysis reveals alterations of plasma proteins in patients infected with human bocavirus

et al. 2019

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Human bocavirus (HBoV) is a member of the genus Bocavirus, family Parvoviridae, and subfamily Parvovirus and was first identified in nasopharyngeal aspirates of Swedish children with acute respiratory tract infection (ARTI) in 2005. It is the causative agent of nasopharyngeal aspirate disease and death in children. The HboV genomic structure is a linear single-stranded DNA (ssDNA). Its clinical pathogenic characteristics have been extensively studied, however, at present the molecular mechanism underlying the pathogenesis of HBoV infection is not completely clear. In this study, a total of 293 differentially expressed proteins (DEPs) between ARTI cases and healthy plasma samples were characterized using isobaric tags for relative and absolute quantitation (iTRAQ)-coupled bioinformatics analysis, among which 148 were up-regulated and 135 were down-regulated. Gene Ontology (GO) and Cluster of Orthologous Groups of proteins (COG) annotated an enrichment of DEPs in complement activation and biological processes like immunity, inflammation, signal transduction, substance synthesis, and metabolism. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis enriched DEPs mainly in the Wnt signaling pathway (ko04310), PPAR signaling pathway (ko03320), intestinal immune network for IgA production (ko04672), complement and coagulation cascades (ko04610), Toll-like receptor signaling pathway (ko04620) and B cell receptor signaling pathway (ko04662). Further, expression levels of three candidate proteins (upregulated PPP2R1A and CUL1, and downregulated CETP) were validated using western blotting. Our investigation is the first analysis of the proteomic profile of HBoV-infected ARTI cases using the iTRAQ approach, providing a foundation for a better molecular understanding of the pathogenesis of ARTI in children.

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Regulation of influenza virus replication by Wnt/β-catenin signaling

Cited by 46 publications

References 46 publications

Cell-intrinsic differences between human airway epithelial cells from children and adults

Cell-intrinsic differences between human airway epithelial cells from children and adults

miR‐193b represses influenza A virus infection by inhibiting Wnt/β‐catenin signalling

iTRAQ-based high-throughput proteomics analysis reveals alterations of plasma proteins in patients infected with human bocavirus

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