Viral manipulation of STAT3: Evade, exploit, and injure

Suarez, Armando Andres Roca; Renne, Nicolaas Van; Baumert, Thomas F.; Lupberger, Joachim

doi:10.1371/journal.ppat.1006839

Cited by 88 publications

(77 citation statements)

References 133 publications

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“…When observing a fierce induction of gene expression downstream the IL6-JAK-STAT3 signaling cascade in PCV2 patients (Fig S2A), STAT3 emerges as a druggable candidate host factor. Interestingly, STAT3 is a key regulator of inflammation often exploited by viruses with pathogenic consequences [28]. In a drug assay, treatment with selective STAT3 inhibitor Cpd188 exhibits a dose-dependent effect on PCV2 infection in PPLs at 72 hpi (Fig 6A).…”

Section: Resultsmentioning

confidence: 99%

PorSignDB: a database of in vivo perturbation signatures for dissecting clinical outcome of PCV2 infection

Wei

Pochet

et al. 2018

Preprint

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23Porcine Circovirus Type 2 (PCV2) is a pathogen that has the ability to cause often devastating 24 disease manifestations in pig populations with major economic implications. How PCV2 25 establishes subclinical persistence and why certain individuals progress to lethal lymphoid 26 depletion remain to be elucidated. Here we present PorSignDB, a gene signature database 27 describing in vivo porcine tissue physiology that we generated from a large compendium of in 28 vivo transcriptional profiles and that we subsequently leveraged for deciphering the distinct 29 physiological states underlying PCV2-affected lymph nodes. This systems biology approach 30 indicated that subclinical PCV2 infections shut down the immune system. A robust signature 31 of PCV2 disease emphasized that immune activation is dysfunctional in subclinical infections, 32 however, in contrast it is promoted in PCV2 patients with clinical manifestations. Functional 33 genomics further uncovered IL-2 as a driver of PCV2-mediated disease and we identified 34 STAT3 as a druggable PCV2 host factor candidate. Our systematic dissection of the 35 mechanistic basis of PCV2 reveals that subclinical and clinical PCV2 display two diametrically 36 opposed immunotranscriptomic recalibrations that represent distinct physiological states in 37 vivo, which suggests a paradigm shift in this field. Finally, our PorSignDB signature database 38 is publicly available as a community resource

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Section: Resultsmentioning

confidence: 99%

PorSignDB: a database of in vivo perturbation signatures for dissecting clinical outcome of PCV2 infection

Wei

Pochet

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…Further, the suppression of SOCS7 has been reported to activate STAT3 protein which promotes inflammation . The STAT3 has been reported to either activate the immune responses through IL‐6 or suppress the inflammatory responses by activating the antiinflammatory cytokine IL‐10 signaling . The modulation of STAT3 has been reported among various viruses which promote viral replication and persistence .…”

Section: Discussionmentioning

confidence: 99%

“…44 The STAT3 has been reported to either activate the immune responses through IL-6 or suppress the inflammatory responses by activating the antiinflammatory cytokine IL-10 signaling. 45 The modulation of STAT3 has been reported among various viruses which promote viral replication and persistence. 46,47 There are reports on CHIKV-induced inflammation and prolonged virus persistence, therefore, the suppression of SOCS7 by hsa-miR-4299 and activation of STAT3 may have a role in CHIKV persistence.…”

Section: Discussionmentioning

confidence: 99%

Chikungunya virus modulates the miRNA expression patterns in human synovial fibroblasts

Agrawal

Pandey

Rastogi

et al. 2019

Journal of Medical Virology

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Chikungunya virus (CHIKV) is an alphavirus transmitted by mosquitoes. CHIKV infection leads to polyarthritis and polyarthralgia among patients. The synovial fibroblasts are the primary target for CHIKV. The microRNAs (miRNAs) are the small endogenous noncoding RNAs which posttranscriptionally regulate the expression of genes by binding to their target messenger RNAs (mRNAs) through their 3′‐untranslated regions. The miRNAs are the key regulators for various pathological processes including viral infection, cancer, cardiovascular disease, and neurodegeneration. This study was designed to dissect out the roles of miRNAs during CHIKV (Ross Strain E1: A226V) infection in primary human synovial fibroblasts. The miRNA microarray profiling was performed on the primary human synovial fibroblasts infected by CHIKV. The gene target prediction analysis, enrichment, and network analysis were performed by various bioinformatics analyses. The subset of 26 differentially expressed microRNAs (DEMs) were identified through microarray profiling and were further screened for gene predictions, Gene Ontology, pathway enrichment, and miRNA‐mRNA network using various bioinformatics tools. The bioinformatics analysis indicates the role of DEMs by suppressing the immune response which may contribute to CHIKV persistence in human primary synovial fibroblasts. Our study provides the plausible roles of DEMs, miRNAs, and mRNA interactions and pathways involved in the molecular pathogenesis of CHIKV.

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“…Several oncogenic viruses activate STAT3 to drive cellular proliferation, viral replication and tumourigenesis [18]. Using a primary cell culture model, we have previously shown that E6 activates the STAT3 signalling pathway in primary keratinocytes during the HPV lifecycle [19].…”

Section: Discussionmentioning

confidence: 99%

Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Akt - NF?B - IL-6 signalling axis

Morgan

Macdonald

2018

Preprint

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Persistent human papillomavirus (HPV) infection is the leading cause of cervical cancer. Although the fundamental link between HPV infection and oncogenesis is established, the specific mechanisms of virus-mediated transformation remain poorly understood. We previously demonstrated that the HPV encoded E6 protein increases the activity of the proto-oncogenic transcription factor STAT3 in primary human keratinocytes; however, the molecular basis for STAT3 activation in cervical cancer remains unclear. Here, we show that STAT3 phosphorylation in HPV positive cervical cancer cells is mediated primarily via autocrine activation by the pro-inflammatory cytokine Interleukin 6 (IL-6). Antibody-mediated blockade of IL-6 signalling in HPV positive cells inhibits STAT3 phosphorylation, whereas both recombinant IL-6 and conditioned media from HPV positive cells leads to increased STAT3 phosphorylation within HPV negative cervical cancer cells. Interestingly, we demonstrate that non-conventional activation of the transcription factor NF?B, involving the protein kinase Akt, is required for IL-6 production and subsequent STAT3 activation. Our data provides new insights into the molecular re-wiring of cancer cells by HPV E6. We reveal that activation of an IL-6 signalling axis drives the autocrine and paracrine phosphorylation of STAT3 within HPV positive cervical cancers cells. Greater understanding of this pathway provides a potential opportunity for the use of existing clinically approved drugs for the treatment of HPV-mediated cervical cancer.

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Viral manipulation of STAT3: Evade, exploit, and injure

Cited by 88 publications

References 133 publications

PorSignDB: a database of in vivo perturbation signatures for dissecting clinical outcome of PCV2 infection

PorSignDB: a database of in vivo perturbation signatures for dissecting clinical outcome of PCV2 infection

Chikungunya virus modulates the miRNA expression patterns in human synovial fibroblasts

Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Akt - NF?B - IL-6 signalling axis

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