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The double-stranded RNA bluetongue virus induces type I interferon in plasmacytoid dendritic cells via a MYD88-dependent TLR7/8-independent signaling pathway.

ABSTRACT: Dendritic cells (DCs), especially plasmacytoid DCs (pDCs), produce large amounts of alpha/beta interferon (IFN-?/?) upon infection with DNA or RNA viruses, which has impacts on the physiopathology of the viral infections and on the quality of the adaptive immunity. However, little is known about the IFN-?/? production by DCs during infections by double-stranded RNA (dsRNA) viruses. We present here novel information about the production of IFN-?/? induced by bluetongue virus (BTV), a vector-borne dsRNA Orbivirus of ruminants, in sheep primary DCs. We found that BTV induced IFN-?/? in skin lymph and in blood in vivo. Although BTV replicated in a substantial fraction of the conventional DCs (cDCs) and pDCs in vitro, only pDCs responded to BTV by producing a significant amount of IFN-?/?. BTV replication in pDCs was not mandatory for IFN-?/? production since it was still induced by UV-inactivated BTV (UV-BTV). Other inflammatory cytokines, including tumor necrosis factor alpha (TNF-?), interleukin-6 (IL-6), and IL-12p40, were also induced by UV-BTV in primary pDCs. The induction of IFN-?/? required endo-/lysosomal acidification and maturation. However, despite being an RNA virus, UV-BTV did not signal through Toll-like receptor 7 (TLR7) for IFN-?/? induction. In contrast, pathways involving the MyD88 adaptor and kinases dsRNA-activated protein kinase (PKR) and stress-activated protein kinase (SAPK)/Jun N-terminal protein kinase (JNK) were implicated. This work highlights the importance of pDCs for the production of innate immunity cytokines induced by a dsRNA virus, and it shows that a dsRNA virus can induce IFN-?/? in pDCs via a novel TLR-independent and Myd88-dependent pathway. These findings have implications for the design of efficient vaccines against dsRNA viruses.

SUBMITTER: Ruscanu S

PROVIDER: S-EPMC3347300 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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The double-stranded RNA bluetongue virus induces type I interferon in plasmacytoid dendritic cells via a MYD88-dependent TLR7/8-independent signaling pathway.

Ruscanu Suzana S Pascale Florentina F Bourge Mickael M Hemati Behzad B Elhmouzi-Younes Jamila J Urien Céline C Bonneau Michel M Takamatsu Haru H Hope Jayne J Mertens Peter P Meyer Gilles G Stewart Meredith M Roy Polly P Meurs Eliane F EF Dabo Stéphanie S Zientara Stéphan S Breard Emmanuel E Sailleau Corinne C Chauveau Emilie E Vitour Damien D Charley Bernard B Schwartz-Cornil Isabelle I

Journal of virology 20120321 10

Dendritic cells (DCs), especially plasmacytoid DCs (pDCs), produce large amounts of alpha/beta interferon (IFN-α/β) upon infection with DNA or RNA viruses, which has impacts on the physiopathology of the viral infections and on the quality of the adaptive immunity. However, little is known about the IFN-α/β production by DCs during infections by double-stranded RNA (dsRNA) viruses. We present here novel information about the production of IFN-α/β induced by bluetongue virus (BTV), a vector-borne ...[more]

PMID: 22438548

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Project description:Ross River virus (RRV) is a mosquito-borne alphavirus that causes epidemics of debilitating musculoskeletal disease. To define the innate immune mechanisms that mediate control of RRV infection, we studied a RRV strain encoding 6 nonsynonymous mutations in nsP1 (RRV-T48-nsP16M) that is attenuated in wild-type (WT) mice and Rag1-/- mice, which are unable to mount adaptive immune responses, but not in mice that lack the capacity to respond to type I interferon (IFN) (Ifnar1-/- mice). Utilizing this attenuated strain, our prior studies revealed that mitochondrial antiviral signaling (MAVS)-dependent production of type I IFN by Ly6Chi monocytes is critical for control of acute RRV infection. Here, we infected Mavs-/- mice with either WT RRV or RRV-T48-nsP16M to elucidate MAVS-independent protective mechanisms. Mavs-/- mice infected with WT RRV developed severe disease and succumbed to infection, whereas those infected with RRV-T48-nsP16M exhibited minimal disease signs. Mavs-/- mice infected with RRV-T48-nsP16M had higher levels of systemic type I IFN than Mavs-/- mice infected with WT virus, and treatment of Mavs-/- mice infected with the attenuated nsP1 mutant virus with an IFNAR1-blocking antibody resulted in a lethal infection. In vitro, type I IFN expression was induced in plasmacytoid dendritic cells (pDCs) cocultured with RRV-infected cells in a MAVS-independent manner, and depletion of pDCs in Mavs-/- mice resulted in increased viral burdens in joint and muscle tissues, suggesting that pDCs are a source of the protective IFN in Mavs-/- mice. These data suggest that pDC production of type I IFN through a MAVS-independent pathway contributes to control of RRV infection.IMPORTANCE Arthritogenic alphaviruses, including Ross River virus (RRV), are human pathogens that cause debilitating acute and chronic musculoskeletal disease and are a significant public health burden. Using an attenuated RRV with enhanced susceptibility to host innate immune responses has revealed key cellular and molecular mechanisms that can mediate control of attenuated RRV infection and that are evaded by more virulent RRV strains. In this study, we found that pDCs contribute to the protective type I interferon response during RRV infection through a mechanism that is independent of the mitochondrial antiviral signaling (MAVS) adaptor protein. These findings highlight a key innate immune mechanism that contributes to control of alphavirus infections.

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The double-stranded RNA bluetongue virus induces type I interferon in plasmacytoid dendritic cells via a MYD88-dependent TLR7/8-independent signaling pathway.

Publications

The double-stranded RNA bluetongue virus induces type I interferon in plasmacytoid dendritic cells via a MYD88-dependent TLR7/8-independent signaling pathway.

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