Dendritic Cell Subtypes from Lymph Nodes and Blood Show Contrasted Gene Expression Programs upon Bluetongue Virus Infection

Ruscanu, Suzana; Jouneau, Luc; Urien, Céline; Bourge, Mickaël; Lecardonnel, Jérôme; Moroldo, Marco; Loup, Benoît; Dalod, Marc; Elhmouzi-Younes, Jamila; Bevilacqua, Claudia; Hope, Jayne; Vitour, Damien; Zientara, Stéphan; Meyer, Gilles; Schwartz-Cornil, Isabelle

doi:10.1128/jvi.00631-13

Cited by 12 publications

(9 citation statements)

References 57 publications

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“…BTV infection in sheep showed enrichment of pro-inflammatory pathways in pDCs of blood and anti-inflammatory pathways in pDCs of regional lymph nodes [27]. Our analysis revealed that BTV infection in PBMCs showed enrichment of RNA sensing RIG and other multiple host immune signaling pathways viz.…”

Section: Discussionmentioning

confidence: 73%

Transcriptome analysis reveals common differential and global gene expression profiles in bluetongue virus serotype 16 (BTV-16) infected peripheral blood mononuclear cells (PBMCs) in sheep and goats

et al. 2017

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Bluetongue is an economically important infectious, arthropod borne viral disease of domestic and wild ruminants, caused by Bluetongue virus (BTV). Sheep are considered the most susceptible hosts, while cattle, buffalo and goats serve as reservoirs. The viral pathogenesis of BTV resulting in presence or absence of clinical disease among different hosts is not clearly understood. In the present study, transcriptome of sheep and goats peripheral blood mononuclear cells infected with BTV-16 was explored. The differentially expressed genes (DEGs) identified were found to be significantly enriched for immune system processes - NFκB signaling, MAPK signaling, Ras signaling, NOD signaling, RIG signaling, TNF signaling, TLR signaling, JAK-STAT signaling and VEGF signaling pathways. Greater numbers of DEGs were found to be involved in immune system processes in goats than in sheep. Interestingly, the DEHC (differentially expressed highly connected) gene network was found to be dense in goats than in sheep. Majority of the DEHC genes in the network were upregulated in goats but down-regulated in sheep. The network of differentially expressed immune genes with the other genes further confirmed these findings. Interferon stimulated genes - IFIT1 (ISG56), IFIT2 (ISG54) and IFIT3 (ISG60) responsible for antiviral state in the host were found to be upregulated in both the species. STAT2 was the TF commonly identified to co-regulate the DEGs, with its network showing genes that are downregulated in sheep but upregulated in goats. The genes dysregulated and the networks perturbed in the present study indicate host variability with a positive shift in immune response to BTV in goats than in sheep.

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Section: Discussionmentioning

confidence: 73%

Transcriptome analysis reveals common differential and global gene expression profiles in bluetongue virus serotype 16 (BTV-16) infected peripheral blood mononuclear cells (PBMCs) in sheep and goats

et al. 2017

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“…Ruscanu et al (2012) have found that BTV can induce the expression of multiple cytokine genes like TNF-␣, IL-6 and IL-12, as well as surface CD80/86, in purified primary sheep blood pDCs in vitro. Furthermore, upon in vivo infection, sheep blood pDCs displayed a strong inflammatory gene expression profile, with up-regulation of CCL2, CCL4, IL-8, IFN-␥ and TNF transcripts (Ruscanu et al, 2013).…”

Section: Btv Induces Type I Ifn Production Both In Vitro and In Vivomentioning

confidence: 99%

Induction and control of the type I interferon pathway by Bluetongue virus

et al. 2014

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The innate immune response is the first line of defence against viruses, involving the production of type I IFN (IFN-α/β) and other pro-inflammatory cytokines that control the infection. It also shapes the adaptive immune response generated by both T and B cells. Production of type I IFN occurs both in vivo and in vitro in response to Bluetongue virus (BTV), an arthropod-borne virus. However, the mechanisms responsible for the production of IFN-β in response to BTV remained unknown until recently and are still not completely understood. In this review, we describe the recent advances in the identification of cellular sensors and signalling pathways involved in this process. The RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) were shown to be involved in the expression of IFN-β as well as in the control of BTV infection in non-haematopoietic cells. In contrast, induction of IFN-α/β synthesis in sheep primary plasmacytoid dendritic cells (pDCs) required the MyD88 adaptor independently of the Toll-like receptor 7 (TLR7), as well as the kinases dsRNA-activated protein kinase (PKR) and stress-activated protein kinase (SAPK)/Jun N-terminal protein kinase (JNK). As type I IFN is essential for the establishment of an antiviral cellular response, most of viruses have elaborated counteracting mechanisms to hinder its action. This review also addresses the ability of BTV to interfere with IFN-β synthesis and the recent findings describing the non-structural viral protein NS3 as a powerful antagonist of the host cellular response.

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“…Although the expression of cytokines and chemokines is critical for developing an efficient antiviral response, their excessive production could also lead to deleterious inflammation by causing tissue damage and therefore contribute to disease pathogenesis. Indeed, both in vivo and in vitro studies have shown that BTV-infected cells secrete numerous proinflammatory cytokines, including IL-6 and IL-8 (51)(52)(53)(54)(55)(56)(57). A consequence of such production could be an aggravation of the endothelial injury associated with an increased vascular permeability, as already observed in severe cases of BT disease (10,58).…”

Section: Btv-ns3 Inhibits the Induction Of Ifn-␣/␤ Independently Of Mmentioning

confidence: 93%

Novel Function of Bluetongue Virus NS3 Protein in Regulation of the MAPK/ERK Signaling Pathway

Kundlacz

Pourcelot

Fablet

et al. 2019

J Virol

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Bluetongue virus (BTV) is an arbovirus transmitted by blood-feeding midges to a wide range of wild and domestic ruminants. In this report, we showed that BTV, through its nonstructural protein NS3 (BTV-NS3), is able to activate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, as assessed by phosphorylation levels of ERK1/2 and the translation initiation factor eukaryotic translation initiation factor 4E (eIF4E). By combining immunoprecipitation of BTV-NS3 and mass spectrometry analysis from both BTV-infected and NS3-transfected cells, we identified the serine/threonine-protein kinase B-Raf (BRAF), a crucial player in the MAPK/ERK pathway, as a new cellular interactor of BTV-NS3. BRAF silencing led to a significant decrease in the MAPK/ERK activation by BTV, supporting a model wherein BTV-NS3 interacts with BRAF to activate this signaling cascade. This positive regulation acts independently of the role of BTV-NS3 in counteracting the induction of the alpha/beta interferon response. Furthermore, the intrinsic ability of BTV-NS3 to bind BRAF and activate the MAPK/ERK pathway is conserved throughout multiple serotypes/strains but appears to be specific to BTV compared to other members of Orbivirus genus. Inhibition of MAPK/ERK pathway with U0126 reduced viral titers, suggesting that BTV manipulates this pathway for its own replication. Altogether, our data provide molecular mechanisms that unravel a new essential function of NS3 during BTV infection. IMPORTANCE Bluetongue virus (BTV) is responsible of the arthropod-borne disease bluetongue (BT) transmitted to ruminants by blood-feeding midges. In this report, we found that BTV, through its nonstructural protein NS3 (BTV-NS3), interacts with BRAF, a key component of the MAPK/ERK pathway. In response to growth factors, this pathway promotes cell survival and increases protein translation. We showed that BTV-NS3 enhances the MAPK/ERK pathway, and this activation is BRAF dependent. Treatment of MAPK/ERK pathway with the pharmacologic inhibitor U0126 impairs viral replication, suggesting that BTV manipulates this pathway for its own benefit. Our results illustrate, at the molecular level, how a single virulence factor has evolved to target a cellular function to increase its viral replication.

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Dendritic Cell Subtypes from Lymph Nodes and Blood Show Contrasted Gene Expression Programs upon Bluetongue Virus Infection

Cited by 12 publications

References 57 publications

Transcriptome analysis reveals common differential and global gene expression profiles in bluetongue virus serotype 16 (BTV-16) infected peripheral blood mononuclear cells (PBMCs) in sheep and goats

Transcriptome analysis reveals common differential and global gene expression profiles in bluetongue virus serotype 16 (BTV-16) infected peripheral blood mononuclear cells (PBMCs) in sheep and goats

Induction and control of the type I interferon pathway by Bluetongue virus

Novel Function of Bluetongue Virus NS3 Protein in Regulation of the MAPK/ERK Signaling Pathway

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