The anti-inflammatory master regulator IL-10 is critical to protect the host from tissue damage during acute phases of immune responses. This regulatory mechanism, central to T cell homeostasis, can be hijacked by viruses to evade immunity. IL-10 can be produced by virtually all immune cells, and it can also modulate the function of these cells. Understanding the effects of this multifunctional cytokine is therefore a complex task. In the present review we discuss the factors driving IL-10 production and the cellular sources of the cytokine during antiviral immune responses. We particularly focus on the IL-10 regulatory mechanisms that impact antiviral immune responses and how viruses can use this central regulatory pathway to evade immunity and establish chronic/latent infections.

The mammalian interferon (IFN) signaling pathway is a primary component of the innate antiviral response, and viral pathogens have evolved multiple mechanisms to antagonize this pathway and to facilitate infection. Bluetongue virus (BTV), an orbivirus of the Reoviridae family, is transmitted by midges to ruminants and causes a disease that produces important economic losses and restriction to animal trade and is of compulsory notification to the World Organization for Animal Health (OIE). Here, we show that BTV interferes with IFN-I and IFN-II responses in two ways, by blocking STAT1 phosphorylation and by degrading STAT2. BTV-NS3 protein, which is involved in virion egress, interacts with STAT2, and induces its degradation by an autophagy-dependent mechanism. This STAT2 degradative process requires the recruitment of an E3-Ub-ligase to NS3 as well as NS3 K63 polyubiquitination. Taken together, our study identifies a new mechanism by which a virus degrades STAT2 for IFN signaling blockade, highlighting the diversity of mechanisms employed by viruses to subvert the IFN response.

Bluetongue virus (BTV) is an economically important Orbivirus of the Reoviridae family that causes a hemorrhagic disease in ruminants. Its control has been achieved by inactivated-vaccines that have proven to protect against homologous BTV challenge although unable to induce long-term immunity. Therefore, a more efficient control strategy needs to be developed. Recombinant adenovirus vectors are lead vaccine candidates for protection of several diseases, mainly because of their potency to induce potent T cell immunity. Here we report the induction of humoral and T-cell mediated responses able to protect animals against BTV challenge by recombinant replication-defective human adenovirus serotype 5 (Ad5) expressing either VP7, VP2 or NS3 BTV proteins. First we used the IFNAR(-/-) mouse model system to establish a proof of principle, and afterwards we assayed the protective efficacy in sheep, the natural host of BTV. Mice were completely protected against BTV challenge, developing humoral and BTV-specific CD8+- and CD4+-T cell responses by vaccination with the different rAd5. Sheep vaccinated with Ad5-BTV-VP2 and Ad5-BTV-VP7 or only with Ad5-BTV-VP7 and challenged with BTV showed mild disease symptoms and reduced viremia. This partial protection was achieved in the absence of neutralizing antibodies but strong BTV-specific CD8+ T cell responses in those sheep vaccinated with Ad5-BTV-VP7. These data indicate that rAd5 is a suitable vaccine vector to induce T cell immunity during BTV vaccination and provide new data regarding the relevance of T cell responses in protection during BTV infection.

Peste des petits ruminants virus (PPRV) causes an economically important disease that limits productivity in small domestic ruminants and often affects the livestock of the poorest populations in developing countries. Animals that survive PPRV develop strong cellular and humoral responses, which are probably necessary for protection. Vaccination should thus aim at mimicking these natural responses. Immunization strategies against this morbillivirus using recombinant adenoviruses expressing PPRV-F or -H proteins can protect PPRV-challenged animals and permit differentiation of infected from vaccinated animals. Little is known of the T cell repertoire these recombinant vaccines induce. In the present work, we identified several CD4+ and CD8+ T cell epitopes in sheep infected with PPRV. We also show that recombinant adenovirus vaccination induced T cell responses to the same epitopes, and led to memory T cell differentiation. T cells primed by these recombinant adenovirus vaccines expanded after PPRV challenge and probably contributed to protection. These data validate the use of recombinant adenovirus expressing PPRV genes as DIVA strategies to control this highly contagious disease.Electronic supplementary materialThe online version of this article (10.1186/s13567-017-0482-x) contains supplementary material, which is available to authorized users.

Viral infections have long provided a platform to understand the workings of immunity. For instance, great strides towards defining basic immunology concepts, such as MHC restriction of antigen presentation or T-cell memory development and maintenance, have been achieved thanks to the study of lymphocytic choriomeningitis virus (LCMV) infections. These studies have also shaped our understanding of antiviral immunity, and in particular T-cell responses. In the present review, we discuss how bluetongue virus (BTV), an economically important arbovirus from the Reoviridae family that affects ruminants, affects adaptive immunity in the natural hosts. During the initial stages of infection, BTV triggers leucopenia in the hosts. The host then mounts an adaptive immune response that controls the disease. In this work, we discuss how BTV triggers CD8+ T-cell expansion and neutralizing antibody responses, yet in some individuals viremia remains detectable after these adaptive immune mechanisms are active. We present some unpublished data showing that BTV infection also affects other T cell populations such as CD4+ T-cells or γδ T-cells, as well as B-cell numbers in the periphery. This review also discusses how BTV evades these adaptive immune mechanisms so that it can be transmitted back to the arthropod host. Understanding the interaction of BTV with immunity could ultimately define the correlates of protection with immune mechanisms that would improve our knowledge of ruminant immunology.

The adaptive immune system utilizes multiple effector mechanisms to clear viral infections. Among those antibody-dependent cell-mediated cytotoxicity (ADCC) can help recognize and clear virus-infected cells. In the present work we evaluated ADCC contribution to immunity in two economically important viral diseases that affect ruminants: bluetongue and peste des petits ruminants. Immune sera obtained from sheep experimentally infected with bluetongue virus (BTV) serotype 8 or peste des petits ruminant virus (PPRV) IC'89 were used for this study. PPRV immune sera could bind to the surface of PPRV-infected ovine B cells while BTV immune sera was unable to bind to the surface of BTV-infected sheep cells but could recognize intracellular BTV antigens. BTV and PPRV immune serum ADCC potency was established using an ovine autologous cytotoxicity assay that employed an NK cell-enriched fraction as effector cells and a virus-infected B cell-enriched fraction as target cells. In this system, immune sera triggered ADCC against PPRV-infected cells, but not against BTV-infected cells. PPRV immune sera could recognize PPRV fusion and hemagglutinin proteins on the surface of transfected cells, and enhanced lysis of these cells in ADCC assays. This indicated that these viral antigens are natural ADCC targets during PPRV infection. The present work describes a novel effector immune mechanism against PPRV in the natural host that could contribute to virus clearance highlighting the importance of studying protective immune mechanisms to improve current vaccines by invoking all effector arms of immunity.

bOvine interferon tau (IFN-) is a unique type I interferon with low toxicity and a broad host range in vivo. We report the generation of a nonreplicative recombinant adenovirus expressing biologically active IFN-. Using the B6.A2G-Mx1 mouse model, we showed that single-dose intranasal administration of recombinant Ad5-IFN-can effectively prevent lethality and disease induced by highly virulent hv-PR8 influenza virus by activating the interferon response and preventing viral replication.T ype I interferons (IFN) are crucial inducers of the antiviral response that act by binding to their universally expressed receptor (IFNAR) and regulating the expression of a large set of genes known as interferon-stimulated genes (ISGs) (1). Collectively, these ISGs mediate the establishment of an antiviral state directly precluding or diminishing viral replication within the cell (1, 2). Additionally, IFN modulates the deployment of a correct adaptive antiviral immune response by acting on cells of the immune system. For these reasons, IFN has long been thought of as an important antiviral treatment option (3, 4). However, its use in clinical settings as a broad-spectrum antiviral agent has been delayed due to its short half-life and the toxicity associated with its systemic or sustained delivery (5-8).Therefore, vectors for a localized delivery and tailoring of the signaling properties of IFN are important goals. Recently, adenoviral vectors expressing type I IFN have been generated and shown to be efficient in the prevention of a number of viral diseases in vertebrate hosts, including SARS coronavirus infections in ferrets and Ebola virus infection in macaques (9-12). IFN-is a type I interferon expressed in ruminants only which is known to induce low toxicity while maintaining its antiviral capacities (6,(13)(14)(15)(16)(17)(18). In contrast to other type I IFNs, IFN-can act on receptors from a broad range of species (17,19), and it has shown efficacy in reducing replication of different viruses, including human and feline immunodeficiency viruses (HIV and FIV), human papillomavirus (HPV) (7,20,21), and bovine leukemia virus (BKV) (8).Thus, we generated a recombinant nonreplicative second-generation human adenovirus (method previously described [22]), termed Ad5-IFN-, as a vector for the local delivery of IFN-in vivo (23). We first tested the ability of Ad5-IFN-to drive the expression and secretion of active IFN-. To do so, we assayed increasing amounts of medium from Vero cells, which lack endogenous type I IFN genes, infected with Ad5-IFN-or the parental control Ad5-DsRed virus and harvested at 48 h postinfection (hpi) in an antiviral activity assay. Vero cells were protected in a dose-dependent manner from vesicular stomatitis virus (VSV) infection when incubated with different amounts of the conditioned medium from Ad5-IFN--infected cells (Fig. 1A), indicating the presence of a secreted antiviral activity most likely corresponding to IFN-. As expected, control medium did not prevent VSV infection and showed no toxicity to...

Bluetongue virus (BTV) is the prototypical orbivirus that belongs to the Reoviridae family. BTV infection produces a disease in ruminants, particularly in sheep, that results in economic losses through reduced productivity. BTV is transmitted by the bite of Culicoides spp. midges and is nowadays distributed globally throughout subtropical and even temperate regions. As most viruses, BTV is susceptible to the IFN response, the first line of defense employed by the immune system to combat viral infections. In turn, BTV has evolved strategies to counter the IFN response and promote its replication. The present review we will revise the works describing how BTV interferes with the IFN response.