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-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 dsRNA Orbivirus of ruminants, in sheep primary DCs. We found that BTV induced IFN-α/β 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-α/β. BTV replication in pDCs was not mandatory for IFN-α/β production since it was still induced by UV-inactivated BTV (UV-BTV). Other inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-12p40, were also induced by UV-BTV in primary pDCs. The induction of IFN-α/β 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-α/β 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-α/β in pDCs via a novel TLR-independent and Myd88-dependent pathway. These findings have implications for the design of efficient vaccines against dsRNA viruses.

Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

“…A report suggesting that the IFN-␣ response to rotavirus in pDCs requires an endosomal receptor such as TLR7 or TLR9 is in accordance with this finding (7). In a recent study, Ruscanu et al have found that BTV infects both sheep pDCs and cDCs but only induces IFN-␣/␤ in pDCs via a mechanism that requires the maturation of endosomal vesicles but not viral replication (50). They also showed that BTV activates the IFN-␣/␤ signaling pathway in pDCs via the MyD88 adaptor, as well as by the PKR and JNK kinases.…”

“…Thus, induction of IFN-␤ required viral replication, as described recently for rotavirus in murine embryonic fibroblasts (57). This observation, however, is in disagreement with previous reports suggesting that replication of rotavirus and BTV in human or ovine pDCs, respectively, is dispensable for IFN-␣/␤ induction (7,50). This discrepancy can be explained by the existence of different cellular responses between immune and nonimmune cells.…”

Dual Modulation of Type I Interferon Response by Bluetongue Virus

“…Recently, our group has shown that the RLR pathway controls both the sensing and the antiviral response to BTV in nonhematopoietic target cells (36). In contrast, it has been shown that BTV activates the IFN-I signaling pathway in plasmacytoid dendritic cells (pDCs) via the MyD88 adaptor, independently of TLR7 and TLR8 (TLR7/8), and via a mechanism implicating the dsRNA-activated protein kinase (PKR) and Jun N-terminal protein kinase (JNK) (37). BTV is then able to induce the production of IFN-I through different pathways, depending on the type of cells involved.…”

Type I Interferon Limits the Capacity of Bluetongue Virus To Infect Hematopoietic Precursors and Dendritic Cells In Vitro and In Vivo

“…Immune cells play a key role in the production of type I IFN in vivo during the infection by other members of the Reoviridae family such as reovirus (20). Similarly, BTV induces IFN-I production in plasmacytoid DCs (pDCs) through signaling of the MyD88 adaptor (21). Thus, hematopoietic cells might play a relevant role in response to BTV infection and IFN-I.…”