Review Article

PPRV-Induced Immunosuppression at the Interface of Virus-Host Interaction

José M. Rojas, Noemí Sevilla and Verónica Martín*

Centro de Investigación en Sanidad Animal (CISA). Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA). 28130-Valdeolmos (Madrid) Spain.

Abstract | Peste des petits ruminants virus (PPRV) is the causal agent of a highly contagious disease that affects domestic and wild small ruminants, Peste des petits ruminants (PPR). Due to the important economical losses caused by this virus in Africa and Asia, the development of more effective, targeted and successful treatments for the disease are necessary. Like other Morbilliviruses, PPRV induces a suppression of the immune system during the acute disease, which favours the establishment and exacerbates the progression of secondary infections. This review gives an overview of the known immunosuppressive strategies of PPRV, among the Paramyxoviruses, as well as the strategies developed by this virus to evade the immune system, focusing on the newly identified factors involved. In the last years substantial progress has been reported in the identification of viral factors involved in the host immunosuppression, although future studies employing in vivo infection models are needed to clearly understand the mechanisms developed by these viruses, in particular PPRV, to interact with the host immune system. A better comprehension of this behaviour could lead the global strategy for the control and eradicaton of PPR, initiated by Food and Agriculture Organization of the United Nations (FAO) and World Organisation for Animal Health (OIE) on 2015.

Editor | Muhammad Munir, The Pirbright Institute, UK.

Received | October 02, 2016; Accepted | October 15, 2016; Published | October 20, 2016

*Correspondence | Verónica Martín, Centro de Investigación en Sanidad Animal (CISA). Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA). 28130-Valdeolmos (Madrid) Spain; Email: veronica.martin@inia.es

DOI | http://dx.doi.org/10.17582/journal.bjv/2016.3.5.140.160

Citation | Rojas, J.M., N. Sevilla and V. Martín. 2017. PPRV-induced immunosupression at the interface of virus-host interaction. British Journal of Virology, 3(5): 140-160.

Keywords: PPRV, immunosuppression, host-virus interaction, Paramyxovirus, Morbillivirus, type I IFN.

Viruses use different strategies to avoid immunosurveillance that include the induction of immunosuppression. While immunosuppression provides the infecting pathogen with the opportunity to maximize their chances of survival, replication and transmission, the clinical consequences on the host may be severe. Thus, the generalized immunosuppression induced by viral infections is often associated with secondary infections with related or unrelated viral or bacterial infections, being a serious clinical problem. Understanding the different mechanisms involved in the induction in immunosuppression is crucial for controlling important human and animal pathogens.

Peste des petits ruminants (PPR) is an acute and highly contagious disease that affects domestic and wild small ruminants, sheep and goats (Abraham et al., 2005; Ozkul et al., 2002). Infections in goats are typically more severe than in sheep, although some sheep populations can be highly susceptible (Shaila et al., 1989; Yesilbağ et al., 2005). In cattle, the disease is asymptomatic and not transmitted to other animals. Seroprevalence in camels and water buffalos has also been reported (Govindarajan et al., 1997; Saeed et al., 2010). Because of the high mortality and severe morbidity rates it causes and its prevalence in developing countries, PPR is an economical relevant disease for livestock and represents one of the main constraints in improving small ruminant productivity. Clinically, PPR infections vary from acute with severe clinical disease and death, to mild with little or no visible clinical signs. Acute infection can produce severe pyrexia with affected animals often becoming restless, having a dull coat, dry muzzle, mucopurulent nasal and ocular discharges, coughing, diarrhoea, enteritis, pneumonia and loss of appetite (Gargadenned and Lalanne, 1942; Lefèvre and Diallo, 1990).

PPR is caused by a Morbillivirus (Gibbs et al., 1979), peste des petits ruminants virus (PPRV) (Lefèvre and Diallo, 1990), that belongs to the Paramixoviridae family, order Meganoviridae. This large family of negative single-strand, enveloped RNA viruses, causes a number of relevant human and animal diseases. It currently includes seven known members: measles virus (MeV), Rinderpest Virus (RPV), PPRV, canine distemper virus (CDV), phocine distemper virus (PDV), cetacean Morbillivirus (CeMV) and feline Morbillivirus (FMV) (Woo et al., 2012). The structural and genetic elements are common in all these viruses. The Morbillivirus genome is a single-strand RNA molecule that encodes six structural proteins: two transmembrane glycoproteins sited in the viral envelop, the fusion (F) and the hemagglutinin (H), an helical nucleocapsid with the nucleoprotein (N) enveloping the RNA in combination with the phosphoprotein (P) and the viral polymerase (L) that form the ribonucleoprotein complex (RNP); and on the inner surface of the envelope, the matrix protein (M) that bridges the cytosolic tails of the F and H to the RNP. The viral RNA also encodes for two non-structural proteins C and V, and a putative protein W. Morbillivirus have been shown to be polyploid (Rager et al., 2002).

As other Morbillivirus, PPRV induces a suppression of immune functions during the acute disease (Rojas et al., 2014), which favours the establishment of and aggravates the course of secondary infections. Concomitant with this immunosuppression, a virus-specific immune response is generated which essentially clears the virus and allows the development of a long-lasting immune response. In this review, we will give an overview of the known immunosuppressive strategies of PPRV. We will discuss the cellular mechanisms of PPRV infection leading to immunosuppression, comparing them to other Morbillivirus. Moreover, the molecular mechanisms that PPRV uses to block immune related signalling are considered and contrasted with better-studied viruses (e.g. MeV) to provide a broader view of possible immunosuppressive strategies used by the virus.

Viral Infection, Dissemination and Cellular Immunosuppression

PPRV Experimental Infections

Typically, PPRV infections occur through the respiratory tract. In susceptible animals it leads to lesions in the respiratory tract, the gastrointestinal tract and in lymphoid organs (Kumar et al., 2004; Pope et al., 2013; Truong et al., 2014). Natural PPRV infections resemble those of other Morbillivirus and result in acute pneumonia and severe gastroenteritis (Chowdhury et al., 2014; Kul et al., 2007), producing an immunosuppression accompanied with leucopenia (Jagtap et al., 2012; Pope et al., 2013; Rojas et al., 2014). Over the years, experimental infections have been carried out in laboratory to better analyze early infection events (Baron et al., 2014; Couacy-Hymann et al., 2007, 2009; Hammouchi et al., 2012; Harrak et al., 2012; Kumar et al., 2004; Pope et al., 2013; Rajak et al., 2005; Truong et al., 2014; Wernike et al., 2014). Early studies often used subcutaneous inoculation, which recapitulated natural clinical signs quite accurately (Couacy-Hymann et al., 2007; Kumar et al., 2004). A comparative study of experimental administration routes indicated that clinical sign apparition was similar when inoculations were intranasal, intravenous or subcutaneous (Harrak et al., 2012). The clinical grade of the infections however differed, with subcutaneous inoculations often resulting in milder signs than intranasal or intravenous administration, accompanied with a slight delay in signs (Harrak et al., 2012). The similarities in the signs induced by different inoculation routes suggest that, as for other Morbillivirus, PPRV dissemination is probably systemic. Typically in experimental infections, clinical signs start to appear by day 4-5, peak by day 7-8, and eventually subside by day 10-11 when the infected animals start mounting an effective immune response. The kinetic of infection is probably slower in natural infections as the initial viral dose is low.

In most studies, experimental infections result in milder clinical signs than those observed naturally (Pope et al., 2013; Truong et al., 2014), although some studies have reported mortality rates up to 100% in subcutaneously infected goats (Couacy-Hymann et al., 2007; Kumar et al., 2004). Discrepancies in clinical signs between experimental studies are likely due to differences in virulence of the used PPRV strains, in host animals selected (goats are more susceptible than sheep), as well as in the health status of the animal at the start of the experiments. Concurrent parasitic or bacterial infections are likely to worsen clinical signs due to PPRV immunosuppressive effects (Emikpe et al., 2010; Malik et al., 2011). A major consideration for data interpretation in experimental infections should thus be that although other routes produce at least similar clinical signs, intranasal inoculation is likely to better recapitulate the natural pattern of infection.

PPRV Dissemination

Histological analysis of intranasal experimental infections with virulent PPRV strains have shown an initial site for virus replication in the tonsilar tissue and lymph nodes draining the inoculation site (Pope et al., 2013). Virus is then detected in distant lymphoid organs (Peyer’s patch, distant lymph nodes, spleen) pointing at a systemic dissemination (Truong et al., 2014). Finally viral antigens, N and H are detected by

immunohistochemical staining in most lymphoid organs, facial epithelia and gastrointestinal tract (Kumar et al., 2004; Parida et al., 2015; Pope et al., 2013; Truong et al., 2014) (Figure 1). This course of infection is very similar to aerosol MeV-infected macaques where early replication occurs in lung, where MeV infects antigen presenting cells (DC/macrophages/monocytes), which then migrate to draining lymphatic organs where further infection occur and systemic dissemination takes places (de Vries et al., 2010a; Ferreira et al., 2010; Lemon et al., 2011). There is histological evidence showing the existence of CD68+ (a monocyte/macrophage marker) syncitia in PPRV-infected lungs (Truong et al., 2014), which suggests that PPRV is likely to also target antigen presenting cells. Histological analysis at day 2 and 5 of goats inoculated intranasally with virulent PPRV showed no evidence of viral antigens in oral epithelia, confirming that epithelial infection occurs at a later stage, probably after systemic dissemination. Infection of the gastrointestinal tract also appears to take place after systemic dissemination in these experiments. The systemic route of dissemination is also confirmed by the observation that day 5 peripheral blood leucocytes tested positive for PPRV by RT-qPCR (Pope et al., 2013). It should be nonetheless noted that although epithelial PPRV infection occurs at a late stage, PPRV shedding could still take place before clinical signs fully appear, as exemplified by the detection of viral RNA in ocular and nasal swabs in day 3 samples (Couacy-Hymann et al., 2009; Hammouchi et al., 2012; Pope et al., 2013).

Evidence is mounting that PPRV uses cells of the immune system in the respiratory tract to initiate its replication and subsequently further infects immune cells in the draining lymphatic organs to facilitate its systemic dissemination in the host (Figure 1). Eventually, the virus reached the oral and intestinal epithelium where the more severe and observable signs are detected.

PPRV and Leucopenia

As a member of the Morbillivirus genus, PPRV bases its successful infection on targeting leucocytes. This lymphotropism causes severe leucopenia and lymphopenia during the acute phase of the disease in goats and sheep (Rajak et al., 2005; Rojas et al., 2014). Total white blood cell counts usually decrease by more than 25% during the acute phase of infection (Baron et al., 2014; Herbert et al., 2014; Pope et al., 2013; Rajak et al., 2005; Rojas et al., 2014). PPRV induces apoptosis in peripheral blood mononuclear cells in vitro (Mondal et al., 2001), and extensive necrotic lesions can be detected in spleen, lymph nodes, thymus and Peyer’s patches (Kul et al., 2007; Kumar et al., 2004; Pope et al., 2013). PPRV cytopathogenic effects could thus account for the leucocyte depletion.

A significant decline in both CD4+ and CD8+ T-cells was observed by day 3 after challenge with a virulent PPRV strain (Rojas et al., 2014). Moreover, T-cell responsiveness to mitogen stimulation was significantly reduced by PPRV in sheep and goats (Heaney et al., 2002; Liu et al., 2008; Rojas et al., 2014). These studies indicate that PPRV infection not only depletes T cells, it also impairs T cell activation. It is noteworthy that leucopenia and partial immunosuppression is observed in animals vaccinated with an attenuated live PPRV vaccine while this is not detected in vector based vaccine immunized animals (Herbert et al., 2014; Rajak et al., 2005; Rojas et al., 2014). Concomitantly with infection, a significant increase in B cells was observed, suggesting a T-cell-independent B-cell activation response (Herbert et al., 2014; Rojas et al., 2014). Seven days post-challenge, Herbert et al. (2014) detect a slight increase in the percentage of CD8+ T-cells in both unvaccinated and vaccinated goats, and Rojas et al. (2014) detect an increase in CD4+ T-cells in unvaccinated sheep, suggesting induction of T cell responses by PPRV infection at this stage.

Because of the lymphotropism and immunosuppressive effects induced by PPRV (Herbert et al., 2014; Rajak et al., 2005; Rojas et al., 2014), T cell responses are likely to be delayed, providing the virus with a window of opportunity where it can replicate and spread. T cell responses are eventually mounted in unvaccinated animals after challenge as indicated by the increased production of PPRV specific IgG (Rojas et al., 2014), which requires T-cell help for class switching (Fazilleau et al., 2009).

Other mechanisms of cellular inhibition may also come into play. For instance, in the Morbillivirus prototype MeV, the N protein can suppress T cell proliferation when released by epithelial cells (Laine et al., 2003). MeV-N protein can also block antibody production (Ravanel et al., 1997) and thus further contribute to lymphocyte immunosuppression. Whether PPRV uses similar approaches as MeV will require further work. These studies highlight the profound immunosuppressive effects that PPRV has on lymphocytes during the acute phase of infection. This can lead in some cases to the host death probably due to secondary infections that take advantage of the suppressed immune system.

Cytokine Expression Profile during Infection

PPRV infection produces an increase in the expression of a classical pro-inflammatory cytokines IL-1β, IL-6, IL-8, IL-12, IFNβ and IFNγ, (Atmaca and Kul, 2012; Baron et al., 2014; Patel et al., 2012; Truong et al., 2014). RNA levels of IFN-β and IFN-γ appears rapidly after infection, however their levels decrease by day 6 (Baron et al., 2014). The RNA levels of other pro-inflammatory cytokines (IL-1β, IL-6, IL-8) do not appear to be altered at later stages of infections. Eventually, IFN-β production recovers probably coinciding with the generation of the adaptive immune response (Patel et al., 2012; Truong et al., 2014). It could be speculated that early IFNs production is probably necessary to trigger the activation and migration of infected antigen-presenting cells from the lung to the draining lymphatic tissue. Once the virus arrives in the lymphoid tissue, it can rapidly replicate and induce an adequate IFN blockade resulting in the decreased IFN levels detected in blood by Baron et al (Baron et al., 2014).

The expression of pro-inflammatory cytokines is also accompanied by an early induction of T helper 2 cytokine IL-4, which is likely to promote anti-PPRV B cell responses (Baron et al., 2014; Patel et al., 2012). IL-4 expression is nonetheless transient in blood and decreases by day 6 (Baron et al., 2014). Whether this is due to PPRV immunosuppressive effects remain to be determined. Baron et al have also described an early induction of the immunomodulatory cytokine IL-10 following PPRV infection. IL-10 induction correlated with a decrease in IL-12A transcripts, which encode for the subunit specific for the inflammatory cytokine IL-12 (Baron et al., 2014). IL-10 is a key regulator of inflammatory and T helper 2 responses, whose role is essential for infection resolution (Couper et al., 2008; Filippi and Herrath, 2008). Early expression of IL-10 in PPRV-infected animals could thus play a role in PPRV pathogenesis and inhibit early inflammatory responses in order to delay adaptive immunity. IL-10 detection nonetheless occurs in infected goats independently of the strain virulence, and could thus also be part of a normal anti-PPRV immune response. Indeed, IL-10 is induced in goat PBMC along with classical pro-inflammatory cytokines (Dhanasekaran et al., 2014). Further work on cytokine profiling during infection is therefore necessary to shed more light on the contribution of these factors to immunosuppression.

PPRV Interaction with the Immune System

Innate immune response: PPRV has two natural host receptors: the signalling lymphocyte activation molecule (SLAM) protein, exclusively expressed in immune cells and Nectin-4 present in epithelium (Birch et al., 2013). PPRV infect the host through the respiratory tract, where its interaction with SLAM makes possible the infection of mucosal lymphocytes, macrophages and dendritic cells (Pawar et al., 2008; Pope et al., 2013), leading to its transport to the lymph nodes for multiplication and spread. The Morbillivirus H protein interacts with the cell receptor(s) that allow viral attachment to cells, thus representing the first contact point between virus and host cell. H protein properties vary between viruses, e.g. H from PPRV or MeV agglutinate red blood cells, whereas H from RPV does not (Langedijk et al., 1997; Lecouturier et al., 1996; Scheid and Choppin, 1974a, b; Seth and Shaila, 2001). The H protein from MeV interacts with TLR2 and induces SLAM expression in monocytes (Bieback et al., 2002). This increased expression of SLAM could in turn favour further infection leading to increased viral replication and spreading.

The interaction of PPRV H protein with host cells could thus be part of the different pathogen associated molecular patterns (PAMPs) such as dsRNA, CpG DNA and uncapped ssRNA with 5’ triphosphate that are generated by RNA viruses (Akira et al., 2006; Medzhitov, 2007) and can be recognized by pattern recognition receptors (PRRs). Viral components are mainly detected by three types of PRRs (Kawai and Akira, 2010; Takeuchi and Akira, 2009): Toll-like receptors (TLRs), 3/7/8 (Finberg and Kurt-Jones, 2004; Finberg et al., 2007), melanoma differentiation associated factor 5 (MDA-5) and retinoic acid-inducible gene-I (RIG-I) like receptors (RLRs) (Kato et al., 2006), and nucleotide oligomerisation domain-like receptors (NLRs) (Ichinohe et al., 2009). The innate immune system acts first through these mechanisms to establish an antiviral state in the host (Platanias, 2005; Randall and Goodbourn, 2008).

Studies addressing the immunological correlation between PPRV and TLRs start to appear and to become relevant in the landscape of PPRV immunosuppression. TLRs play a key role in innate immunity initiating a complex signalling cascade that activates different inflammatory cytokines and transcription factors (Takeda and Akira, 2003). TLRs engagement also lead the activation of apoptosis, phagocytosis, complement and pro-inflammatory mediators, essential for the initiation of T-cell mediated immunity (Janeway et al., 1997; Janeway and Medzhitov, 2002; Pasare and Medzhitov, 2004; West et al., 2006). In 2006, the bovine and ovine tissue pattern expression of TLRs 1-10 were elucidated (Menzies and Ingham, 2006), followed by the caprine profile in 2010 (Raja et al., 2011). These patterns are useful tools to correlate TLR expression in different cells and tissues with virulence or susceptibility to a pathogen. Dhanasekaran et al. (2014) describe that high levels of TLR3 and TLR7 and their signal transducers correlates with increased inflammatory cytokine expression and reduced immunomodulatory cytokines favouring the antiviral host state during PPRV infection in four Indian goat breeds and in water buffaloes. TLR3 is expressed in the jejunum or ovine gut epithelium (Menzies and Ingham, 2006) and detects the dsRNA present at some stage in almost all viral infections, whereas immune cells like plasmacytoid dendritic cells express TLR7, a receptor involved in type I IFNs production in response to viral ssRNA. Although, there was no TLR7 nucleotide differences between breeds to which PPRV susceptibility could be attributed, the TLR3 and 7 still appear to play a critical role in PPRV recognition during infection. These differences in viral susceptibility could also be due to polymorphisms in leucine rich repeats domains in the toll-interleukin 1 receptor domain from TLRs (Chang et al., 2009; Raja et al., 2011).

Protective immune response: Different researchers have demonstrated that PPRV infection induces strong virus-specific humoral and cellular immune responses resulting in lifelong immunity (Cosby et al. 2006). Humoral and cellular responses against the virus are mainly directed against the two PPRV glycoproteins (F and H) and the N protein (Sinnathamby et al., 2001). Immunisation with F and/or H induces protective humoral immunity probably through the production of neutralizing antibodies, whilst the antibodies generated with the N protein immunisation are not neutralizing (Diallo et al., 2007; Rojas et al., 2014). However, a strong cellular immune response was developed to N, which is thought to correlate with protection (Sinnathamby et al., 2001). Strategies allowing the expression of PPRV F and/or H proteins using different vectors, including recombinant poxviral (Berhe et al., 2003; Chen et al., 2010), adenoviral (Herbert et al., 2014; Liu et al., 2008; Qin et al., 2012; Rojas et al., 2014) or chimeric RPV vectors (Das et al., 2000; Taylor, 1979) can induce long lasting neutralizing antibody responses against PPRV in goats or sheep as well as partial or total protection against the disease.

As in MeV infection, virus neutralizing antibodies are an important correlate of protection against PPRV infection. Although, a study on RPV did not correlate neutralizing antibodies with protection (Bassiri et al., 1993), suggesting that protection was not solely due to the antibody responses. Indeed, the resolution of Morbillivirus prototype MeV infection correlates with lymphoproliferation (Griffin et al., 1989; Mongkolsapaya et al., 1999) and lymph nodes enlargement (de Vries et al., 2012). Cytotoxic T-lymphocytes are also crucial for clearance of MeV-infected cells (de Vries et al., 2010b; van Binnendijk et al., 1990). Ultimately, MeV replication is efficiently restricted, infected cells cleared by the immune system, and lymphocyte numbers restored to normality.

However, viral RNA persists long after infectious virus is not longer detected (Riddell et al., 2007). The slow clearance of MeV RNA after apparent recovery has been related with the switch of T cell responses from type 1 to type 2 with production of IL-10 and IL-4 cytokines (Yu et al., 2008), similar to results obtained in PPRV infections. The prolonged presence of viral RNA might be relevant to the development of persistent infections, described for MeV, and could explain the immunological abnormalities that often persists for weeks after viral clearance (Auwaerter et al., 1999). Although long-term PPRV immunosuppression has not been studied in animals surviving the infection, it could be inferred from MeV data that after the burst of anti-PPRV adaptive immunity, a second wave of immune response could occur to resolve RNA persistent infection. Studies designed to further dissect the multiple immune mechanisms that PPRV employs will therefore be beneficial for the design of more effective PPR therapy.

Suppression of the interferon response by PPRV: Interferons (IFNs) are the main group of cytokines secreted by host cells in response to PAMP recognition by PRRs. The antiviral state established by IFNs is one of the most important cellular defence mechanisms against viral infections. Type I IFN (α/β) (IFN-I) bind their universally expressed receptor (IFNARI and IFNARII) and regulate the expression of a large set of genes known as interferon stimulated genes (ISGs) (Sen, 2001), such as 2’, 5’- oligoadenylate synthetase (2-5OAS), ds RNA-activated protein kinase (PKR), ISG15 or MxA protein (Fujii, 1994; Honda et al., 2006; Samuel, 1991; Sen and Ransohoff, 1993). The intracellular IFN signal transduction pathway signals through Janus protein kinase (JAK)

family members that subsequently phosphorylate signal transducer and activator of transcription (STAT) family proteins (Stark et al., 1998). The IFNARI transduces the signal through Jak1 and Tyk2 that in turn phosphorylate STAT1 and 2 triggering their heterodimerization via SH2-phosphotyrosine interactions. The phosphorylated STAT1/STAT2 dimer then associates with interferon regulatory factor 9 (IRF9) to form the transcriptional factor complex ISGF3 that binds IFN-responsive promoter elements (ISRE) into the nucleus and directs ISG expression. The IFN-γ receptor (IFNARII) signals through Jak1 and Jak2 leading to STAT1 phosphorylation and its homodimerization. This homodimer, also called GAF, binds to the IFN-γ-responsive element, called the γ activation sequence (GAS) and drives ISG expression (Goodbourn et al., 2000; Levy et al., 1989; Sen and Ransohoff, 1993) (Figure 2).

Viruses have evolved molecular mechanisms to suppress this antiviral host state to establish infections (Fujii, 1994; García-Sastre, 2001; Goodbourn et al., 2000) by interfering with the IFN induction pathway activated by PAMPs-PRRs and/or with the IFN transducer signal route. Viruses belonging to the Paramyxoviridae family harnessed several strategies to block at different levels the IFN-I signal transduction pathways, such as: (i) suppression of the IFN induction by inhibiting STAT and JAK phosphorylation, used by Sendai virus or human parainfluenza virus type 3 belonging to the Respirovirus genus (Gao et al., 2001; Garcin et al., 1999; Huang et al., 2014; Ikegame et al., 2010; Kato et al., 2001; Komatsu et al., 2004, 2000; Ning et al., 2014), (ii) inactivation of IFN-induced antiviral proteins employed by viruses from the Henipavirus genus (Metz et al., 2012; Zhao et al., 2013), and (iii) interference with IFN signal transduction by modification of the constitutive or basal levels of molecules involved in the JAK/STAT pathway that members of the Rubulavirus genus, like Simian virus 5, mumps virus or human parainfluenza virus type 2, utilize (Chinnakannan et al., 2013; Devaux et al., 2007; Didcock et al., 1999; Fujii et al., 1999; Kubota et al., 2001; Nakatsu et al., 2008; Ramachandran et al., 2008; Sun et al., 2004; Yokosawa et al., 1998).

Next, the role of different PPRV proteins involved in some of these immune system evasion mechanisms are detailed, schematized and summarized in Figure 2.

P Protein

The P gene of Paramyxovirus can encode for up to 6 genes, which can be accessed by a variety of mechanisms (Audsley and Moseley, 2013). The products of these genes are often involved in the suppression of IFN signalling and production. In Morbillivirus, the P gene can potentially encode for 4 proteins: P, V, W and C. The P protein is essential for viral RNA synthesis and acts as a polymerase cofactor. In MeV, it can also impair STAT1 phosphorylation and block its translocation to the nucleus (Devaux et al., 2007), thereby limiting IFN-I and II signalling. Similarly, RPV-P protein can block STAT1 phosphorylation and impair IFN signalling (Nanda and Baron, 2006). In PPRV, the P protein also reduces the ISRE and GAS promoter activity, but little to no inhibition of the IFN-β promoter activity was observed (Ma et al., 2015). It should be noted nonetheless that the P protein contribution to IFN signalling and production blockade is probably less critical than that of V (Nanda and Baron, 2006), another product of the P cistron.

V Protein

The different strategies for IFN signalling evasion are orchestrated in the Paramyxovirus mainly by the virus-encoded V protein, present in the Respirovirus, Henipavirus, Rubulavirus and Morbillivirus genera. This viral protein with a molecular weight ranging from 28-32 KDa, is phosphorylated and binds N and L proteins (Sweetman et al., 2001). The V protein, and the W protein only described for some of these genera, are produced by an unusual editing strategy consisting in a frame shift in the open reading frame for the P cistron, due to the insertion of 1 (G) or two (GG) guanine/s at the conserved RNA editing site 5’-TTAAAAGGGCACAG-3’, leading to the production of V or W protein respectively; with no insertion at the site resulting in P protein synthesis (Mahapatra et al., 2003). The PPRV-V protein presents an amino-terminal domain, common to the viral P, V and W proteins but not highly conserved among Paramyxovirus, and a carboxy-terminal domain containing a zinc finger structure consisting in a histidine and a cysteine-rich V-specific domain, which is conserved among all them (Liston and Briedis, 1994; Paterson et al., 1995).

Recent studies have demonstrated that the Morbillivirus V proteins interfere with different steps in the IFN-I transduction pathway, blocking the IFN signalling and contributing to the inhibition of the cellular antiviral state. There is a notable diversity in the mechanisms used by Paramyxovirus genera that even vary between members of the same genus.

wild strains of the Morbillivirus genus prototype, MeV, display nearly complete suppression of IFN-α induced antiviral state, but not IFN-γ induced state. The MeV-V protein interacts via its amino-terminal domain with Jak1 and inhibits STAT-1 and STAT-2 phosphorylation, thereby preventing their dimerization and nuclear import, and thus impairing signal transduction (Caignard et al., 2009, 2007; Chinnakannan et al., 2013; Fujii et al., 1990, 1988; Ramachandran et al., 2008; Yokota et al., 2003). Similar interactions between the V proteins from other Morbillivirus (CDV, RPV) and STAT1 are also described (Nanda and Baron, 2006; Rodriguez et al., 2004). Moreover, a zinc finger domain and specific residues in the carboxy-terminal domain of the MeV-V protein are involved in the association with STAT2 (Ramachandran et al., 2008).

PPRV shares some of the immune system evasion mechanisms with other members of the same genus, like MeV or RPV. In the closely related-RPV, the amino-terminal domain in the V protein binds STAT1, whereas the carboxy-terminal domain interacts with the IFN receptor-associated kinases Jak1 and Tyk2. Like for the Morbillivirus prototype MeV, both RPV amino- and carboxy- V domains were necessary to block the IFN-induced antiviral state (Chinnakannan et al., 2014). Likewise, the PPRV-V protein contributes to innate immune evasion by blocking IFN-I signalling pathway through its interaction with STAT1 and STAT2. As for MeV, the amino-terminal and carboxy-terminal V domains, bind STAT1 and STAT2, respectively, disturbing their distribution and nuclear translocation but not inducing their degradation. PPRV-V protein produces stronger inhibition of the ISRE and GAS promoter expression than N and P proteins (Ma et al., 2015). The mutation of the Tyr-110 residue to Ala in the PPRV-V amino-terminal domain impaired its ability to inhibit IFN signalling, supporting this domain role in antagonising the IFN transduction pathways (Ma et al., 2015). The conserved Cys cluster and the Trp motif in the zinc finger structure in the carboxy-terminal domain of PPRV-V protein are implicated in the STAT2 interaction, with two amino acids (275 and 277) critical for this route blockade (Ma et al., 2015). PPRV-V thus allows the virus to suppress both IFN signalling pathways.

The virulence factor V from Morbillivirus not only acts on STAT1 and STAT2, it can also interfere upstream of these factors and inhibits the phosphorylation of Jak family members. The V protein from MeV, CDV, RPV and PPRV can inhibit Tyk2 phosphorylation, whereas only the V protein from a virulent RPV strain could impair Jak1 phosphorylation (Chinnakannan et al, 2013). In these experiments, all V proteins co-immunoprecipitated both Jak1 and Tyk2 independently of their effect on phosphorylation. This indicates that the V protein probably binds the Jak1/Tyk2 complex at the IFNAR receptor, which in turn could impair signal transduction. This complementary IFN-I signalling inhibitory mechanism illustrates the diverse routes that Morbillivirus can employ to block IFN-I and –II signalling, and highlights the importance of this pathway in the pathogenicity of this genus.

Fewer studies have looked at PPRV-V inhibition (or closely-related RPV) of the IFN production route or its interaction with RIG-I-like receptors (RLR). The V proteins tested in at least 13 Paramyxovirus bind to MDA5 inhibiting IFN induction (Childs et al., 2007; Parisien et al., 2009; Ramachandran and Horvath, 2010). The carboxy-terminal domain from the MeV-V protein has been implicated in MDA-5 binding. This domain from MeV-V can also interact with the laboratory of genetics and physiology 2 protein (LGP2), instead of directly with RIG-I to inhibit its signal transduction (Childs et al., 2012; Parisien et al., 2009). MeV-V can also interfere with signalling pathways induced by other PRRs. MeV-V can inhibit IFN production induced by TLR7/9 in plasmacytoid DC (Pfaller and Conzelmann, 2008; Schlender et al., 2005). MeV-V protein interacts with IKKα preventing IRF7 activation and thus IFN-β production. MeV-V (and to a lesser extent the P protein) can also suppress NF-κB activity (Schuhmann et al., 2011). Although, the interaction of RPV- or PPRV- V proteins with RLR or TLR transduction pathway members have not been explored, it appears that RPV inhibits MDA-5 signalling through the C protein rather than with the V protein (Boxer et al., 2009). PPRV-V can nonetheless inhibit the IFN-β promoter activity (Ma et al., 2015), which indicates that RPV-V and PPRV-V function do not fully overlap. Whether PPRV-V uses similar targets as MeV-V to block PRR transduction signals remains to be determined. Similarly to other V proteins in Morbillivirus, the PPRV-V protein plays an essential role in inhibiting the antiviral cellular response by impairing IFN-I and –II signalling and but also by blocking IFN production.

Although, STAT1 and STAT2 inhibition by Morbillivirus V proteins have been extensively studied, the Morbillivirus V could also target other antiviral signalling routes. MeV-V can also interact with STAT3 and target it for proteasomal degradation (Palosaari et al., 2003). Interference with STAT3 is also described in mumps virus, another Paramyxovirus (Ulane et al., 2003). The role of STAT3 is complex since it can be activated by multiple cytokines and regulates genes with opposite effects (Kuchipudi, 2015). Since Paramyxovirus target STAT3 for degradation, it appears that this virus family benefit from STAT3 inhibition. STAT3 activity is important in adaptive immunity, particularly in T cell survival and proliferation (Durant et al., 2010; Oh et al., 2011; Takeda et al., 1998; Yu et al., 2013). STAT3 is also the main transducer of IL-6 signalling, which is a key component of the transition from innate to adaptive immunity (Jones, 2005). It could thus be speculated that inhibition of T cell responses via STAT3 degradation by V proteins could extend the window for virus replication before an adequate adaptive immune response is mounted. Moreover, activated STAT3 can bind GAS to promote IFN-II-regulated gene expression (Darnell et al., 1994; Timofeeva et al., 2012). Whether V proteins target this route to complement GAS inhibition or to favour other pathogenic effects remains to be determined. Although viral inhibition of this route has not been widely studied, in part probably due to its complexity, the observation that MeV targets this pathway is likely to contribute to immunosuppression. Given that most Morbillivirus V proteins have similar signalling targets, it would be relevant to determine whether PPRV-V also uses STAT3 degradation to evade immunity.

W Protein

Little is known about the role of Morbillivirus W protein in immunosuppression. In MeV, W transcripts account for only 5% of total transcripts from the P cistron, but no evidence of W protein expression in this virus was obtained (Bankamp et al., 2008). Sequence analysis in PPRV reveals that PPRV-W has a longer C-terminal tail (11 amino-acids) than MeV (5-10 amino-acids) or RPV (3 amino-acids), which could give these proteins properties other than those of a “truncated” P or V protein (unpublished data from our laboratory). In RPV, W binds STAT1 (Nanda and Baron, 2006) and inhibits both ISRE and GAS promoter activity in reporter assays (Chinnakannan et al., 2014). The presence in W and P proteins of an amino-terminal domain similar to V indicates that these proteins share the ability to bind STAT1, probably through the conserved domain proximal to Tyr110 (Chinnakannan et al., 2014; Devaux et al., 2007). RPV-W can also inhibit Tyk2 phosphorylation (Chinnakannan et al., 2014, 2013), but unlike RPV-V does not bind STAT2, indicating that W and V only share some IFN-signalling inhibitory features. Further work needs to be done to thoroughly assess Morbillivirus W protein expression, and to determine the relevance of PPRV-W in inhibiting the antiviral cellular state.

C Protein

PPRV genome, as all the Paramyxovirus, encodes for the C protein, another non-structural virulence factor expressed from an alternate open reading frame, from a second ATG codon embedded in the first half of the P cistron (Bellini et al., 1985; Cattaneo et al., 1989; Devaux et al., 2007; Yamaguchi et al., 2014). This protein has a predicted molecular weight of 20 KDa, is not phosphorylated, binds to the L protein and, is localized in the nucleus and cytoplasm (Bellini et al., 1985; Sweetman et al., 2001). The C protein has different roles in immune evasion and pathogenicity (Gotoh et al., 2001; Horvath, 2004; Patterson et al., 2000). In Morbillivirus, C is usually associated with the inhibition of IFN production through two main mechanisms: firstly, C protein reduces viral replication, thereby decreasing the amount of motifs that PRRs can recognize and consequently limiting IFN production (Bankamp et al., 2005; Nakatsu et al., 2008, 2006); and secondly, C proteins directly interfere with the PRRs signalling that leads to IFN transcription (Boxer et al., 2009; Schuhmann et al., 2011; Sparrer et al., 2012).

MeV-C and RPV-C targets in PRRs signalling have been identified, but, to the best of our knowledge, PPRV-C has not been studied. MeV-C and RPV-C target IRF3 in the nucleus and block the induction of IFN-I, although the exact mechanism of action is unknown (Boxer et al., 2009; Sparrer et al., 2012). The C protein interferes with IRF3-dependent transcription without affecting IRF3 phosphorylation, dimerization or nuclear accumulation (Sparrer et al., 2012), and thus its mechanism of action could rely on a steric hindrance of IRF3 dimers with the IFN-β promoter. MeV-C can also block NF-kB signalling, though to a lesser extent than V, suggesting that Morbillivirus C proteins may still use other mechanisms to suppress host immune responses (Schuhmann et al., 2011). MeV-C is also reported to block IFN-I signalling (Shaffer et al., 2003), although the V protein is probably the main IFN signalling antagonist during infection (Nakatsu et al., 2008). Overall, the Morbillivirus C protein suppresses the IFN induction pathways, an essential component in the initiation of the innate immune response. To further our understanding of PPRV immunosuppressive mechanisms, it will thus be of great significance to assess if, as predicted, PPRV-C behaves like its MeV and RPV counterparts and/or if it affects other members of the PRRs pathways.

Non-Coding RNA, Pathogenicity and Immune Evasion

Non-coding RNA segments are involved in immune modulation in some viruses (Kincaid and Sullivan, 2012). Morbillivirus have long untranslated regions (UTR) that regulate M and F gene expression. In MeV, the long M 3’ UTR promotes M protein production and virus replication, whereas the long F 5’ UTR reduces F protein production and thus cytopathogenicity. It could be speculated that reduced cytopathogenicity would reduce virus exposure to the immune system and thus favour immune evasion (Wohlsein and Saliki, 2006). Indeed, cell-cell fusion induced by MeV can increase IFN-I response and thus antiviral immunity (Herschke et al., 2007). In CDV, a similar control of F and M expression is described (Anderson and Messling, 2008). Short M 3’ UTR in CDV has also been linked to attenuation of experimental infection and a reduction in immunosuppression (Anderson et al., 2012; Rudd et al., 2006). The immunosuppressive effects of these UTR could be due to a combination of several processes e.g. reduced recognition of these long UTRs by PRRs, presence of small RNA species in these regions capable of interfering with the pathogen recognition processes, and/or indirect effects derived from reduced pathogen exposure to the immune system. Overall, these regions appear to be important for Morbillivirus virulence. PPRV also possesses these long M 3’ UTR and F 5’ UTR that can potentially contribute to immunosuppression (Haffar et al., 1999; Meyer and Diallo, 1995); although further work will be necessary to assess the role of these non-translated regions in PPRV immune evasion and suppression.

Conclusions

The multitude of mechanisms that the Morbillivirus genus employs to impair immune response turns out to be the seal of the diseases they cause. These mechanisms lead to the hallmark immunosuppression generated in hosts, increasing the susceptibility to opportunistic infections that often are the agents causing mortality (Wohlsein and Saliki, 2006).

The immunosuppression features triggered by Morbillivirus, and PPRV among them, are closely related to the damage in lymphoid organs detected. The leucopenia detected in PPRV infections could be attributed to extensive necrosis in spleen, thymus, pulmonary lymph nodes and Peyer’s patches (Kul et al., 2007; Kumar et al., 2004; Pope et al., 2013) and to PBMCs apoptosis as showed in vitro (Mondal et al., 2001). Aside from this direct infection and consequent destruction of lymphoid cells, it is clear that the IFN route is affected and modulated through different mechanisms by PPRV. Different viral proteins are implicated in this process, from viral attachment glycoproteins, such as H, that interact with cell receptors and could promote infection, to non-structural proteins like C or V that interact directly or indirectly with different members of the IFN transduction and production pathways. PPRV, like most of the Paramyxovirus has multiple strategies to overcome the host interferon-mediated innate immune response through the activity of his principal IFN antagonist protein, V. Although there is a remarkable IFN inhibition mechanism diversity between different genera of this viral family, such as inhibition of phosphorylation, proteasome degradation and subcellular miss-localization, the common targets of the IFN system, are the following molecules: MDA-5, RIG-I, STAT1, STAT2 and IRF3. At present, the inhibition of IFN signalling by PPRV is documented by its interaction and subsequent miss-localization of STAT1 and 2. TLR3 and 7 have been proposed as possible PPRV targets due to the interrelationship between TLR3/TLR7 amounts and PPRV susceptibility.

The immunosuppression provoked by PPRV is an intricate and multifactorial process. A deeper and more accurate understanding of the mechanisms by which PPRV immunosuppresses its hosts is needed and will allow the development of more effective, targeted and successful treatment of the disease. Opportunistic infections could progress during the delay in the immune response observed after PPRV infection but also after vaccination with attenuated live vaccines. This drawback produced by current live attenuated vaccines could be overcome with vaccines based on recombinant vectors or protein expression.

In the last years substantial progress has been made in the identification of viral factors involved in the host immunosuppression, although future studies using in vivo infection models are needed to clearly understand the mechanisms employed by these viruses, in particular PPRV, to interact with the host immune system.

Acknowledgments

Work was funded by grants number RyC2010-06516 and AGL2011-25025 and AGL2012-33289 from Ministerio de Ciencia e Innovación (http://www.mineco.gob.es/portal/site/mineco/idi), BIO2015-68990-REDT and S2013/ABI-2906-PLATESA from Comunidad de Madrid.

References

- • Abraham, G., Sintayehu, A., Libeau, G., Albina, E., Roger, F., Laekemariam, Y., Abayneh, D., Awoke, K.M. Antibody seroprevalences against peste des petits ruminants (PPR) virus in camels, cattle, goats and sheep in Ethiopia. Preventive Veterinary Medicine, 2005; 70, 51–57. https://doi.org/10.1016/j.prevetmed.2005.02.011
- • Akira, S., Uematsu, S., Takeuchi, O. Pathogen recognition and innate immunity. Cell, 2006; 124, 783–801. https://doi.org/10.1016/j.cell.2006.02.015
- • Anderson, D.E., Castan, A., Bisaillon, M., von Messling, V. Elements in the canine distemper virus M 3’ UTR contribute to control of replication efficiency and virulence. PLoS One, 2012; 7, e31561. https://doi.org/10.1371/journal.pone.0031561
- • Anderson, D.E., Messling, von, V. Region between the canine distemper virus M and F genes modulates virulence by controlling fusion protein expression. Journal of Virology, 2008; 82, 10510–10518. https://doi.org/10.1128/JVI.01419-08
- • Atmaca, H.T., Kul, O. Examination of epithelial tissue cytokine response to natural peste des petits ruminants virus (PPRV) infection in sheep and goats by immunohistochemistry. Histology Histopathology, 2012; 27, 69–78.
- • Audsley, M.D., Moseley, G.W. Paramyxovirus evasion of innate immunity: Diverse strategies for common targets. World Journal of Virology, 2013; 2, 57–70. https://doi.org/10.5501/wjv.v2.i2.57
- • Auwaerter, P.G., Rota, P.A., Elkins, W.R., Adams, R.J., DeLozier, T., Shi, Y., Bellini, W.J., Murphy, B.R., Griffin, D.E.. Measles virus infection in rhesus macaques: altered immune responses and comparison of the virulence of six different virus strains. The Journal of Infectious Diseases, 1999; 180, 950–958. https://doi.org/10.1086/314993
- • Bankamp, B., Lopareva, E.N., Kremer, J.R., Tian, Y., Clemens, M.S., Patel, R., Fowlkes, A.L., Kessler, J.R., Muller, C.P., Bellini, W.J., Rota, P.A.. Genetic variability and mRNA editing frequencies of the phosphoprotein genes of wild-type measles viruses. Virus Research, 2008; 135, 298–306. https://doi.org/10.1016/j.virusres.2008.04.008
- • Bankamp, B., Wilson, J., Bellini, W.J., Rota, P.A. Identification of naturally occurring amino acid variations that affect the ability of the measles virus C protein to regulate genome replication and transcription. Virology, 2005; 336, 120–129. https://doi.org/10.1016/j.virol.2005.03.009
- • Baron, J., Bin-Tarif, A., Herbert, R., Frost, L., Taylor, G., Baron, M.D. Early changes in cytokine expression in peste des petits ruminants disease. Veterinary Research, 2014; 45, 22. https://doi.org/10.1186/1297-9716-45-22
- • Bassiri, M., Ahmad, S., Giavedoni, L., Jones, L., Saliki, J.T., Mebus, C., Yilma, T. Immunological responses of mice and cattle to baculovirus-expressed F and H proteins of rinderpest virus: lack of protection in the presence of neutralizing antibody. Journal of Virology, 1993; 67, 1255–1261.
- • Bellini, W.J., Englund, G., Rozenblatt, S., Arnheiter, H., Richardson, C.D. Measles virus P gene codes for two proteins. Journal of Virology, 1985; 53, 908–919.
- • Berhe, G., Minet, C., Le Goff, C., Barrett, T., Ngangnou, A., Grillet, C., Libeau, G., Fleming, M., Black, D.N., Diallo, A. Development of a dual recombinant vaccine to protect small ruminants against peste-des-petits-ruminants virus and capripoxvirus infections. Journal of Virology, 2003; 77, 1571–1577. https://doi.org/10.1128/JVI.77.2.1571-1577.2003
- • Bieback, K., Lien, E., Klagge, I.M., Avota, E., Schneider-Schaulies, J., Duprex, W.P., Wagner, H., Kirschning, C.J., Meulen, Ter, V., Schneider-Schaulies, S. Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. Journal of Virology, 2002; 76, 8729–8736. https://doi.org/10.1128/JVI.76.17.8729-8736.2002
- • Birch, J., Juleff, N., Heaton, M.P., Kalbfleisch, T., Kijas, J., Bailey, D. Characterization of ovine Nectin-4, a novel peste des petits ruminants virus receptor. Journal of Virology, 2013; 87, 4756–4761. https://doi.org/10.1128/JVI.02792-12
- • Boxer, E.L., Nanda, S.K., Baron, M.D. The rinderpest virus non-structural C protein blocks the induction of type 1 interferon. Virology, 2009; 385, 134–142. https://doi.org/10.1016/j.virol.2008.11.022
- • Caignard, G., Bouraï, M., Jacob, Y., Infection-MAPping project I-MAP, Tangy, F., Vidalain, P.-O. Inhibition of IFN-alpha/beta signaling by two discrete peptides within measles virus V protein that specifically bind STAT1 and STAT2. Virology, 2009; 383, 112–120. https://doi.org/10.1016/j.virol.2008.10.014
- • Caignard, G., Guerbois, M., Labernardière, J.-L., Jacob, Y., Jones, L.M., Infectious Mapping Project I-MAP, Wild, F., Tangy, F., Vidalain, P.-O. Measles virus V protein blocks Jak1-mediated phosphorylation of STAT1 to escape IFN-alpha/beta signaling. Virology, 2007; 368, 351–362. https://doi.org/10.1016/j.virol.2007.06.037
- • Cattaneo, R., Kaelin, K., Baczko, K., Billeter, M.A. Measles virus editing provides an additional cysteine-rich protein. Cell, 1989; 56, 759–764. https://doi.org/10.1016/0092-8674(89)90679-X
- • Chang, J.-S., Russell, G.C., Jann, O., Glass, E.J., Werling, D., Haig, D.M. Molecular cloning and characterization of Toll-like receptors 1-10 in sheep. Veterinary Immunology Immunopathology, 2009; 127, 94–105. https://doi.org/10.1016/j.vetimm.2008.09.026
- • Chen, W., Hu, S., Qu, L., Hu, Q., Zhang, Q., Zhi, H., Huang, K., Bu, Z. A goat poxvirus-vectored peste-des-petits-ruminants vaccine induces long-lasting neutralization antibody to high levels in goats and sheep. Vaccine, 2010; 28, 4742–4750. https://doi.org/10.1016/j.vaccine.2010.04.102
- • Childs, K., Randall, R., Goodbourn, S. Paramyxovirus V proteins interact with the RNA Helicase LGP2 to inhibit RIG-I-dependent interferon induction. Journal of Virology, 2012; 86, 3411–3421. https://doi.org/10.1128/JVI.06405-11
- • Childs, K., Stock, N., Ross, C., Andrejeva, J., Hilton, L., Skinner, M., Randall, R., Goodbourn, S. mda-5, but not RIG-I, is a common target for paramyxovirus V proteins. Virology, 2007; 359, 190–200. https://doi.org/10.1016/j.virol.2006.09.023
- • Chinnakannan, S.K., Holzer, B., Bernardo, B.S., Nanda, S.K., Baron, M.D. Different functions of the common P/V/W and V-specific domains of rinderpest virus V protein in blocking IFN signalling. Journal of General Virology, 2014 95, 44–51. https://doi.org/10.1099/vir.0.056739-0
- • Chinnakannan, S.K., Nanda, S.K., Baron, M.D. Morbillivirus v proteins exhibit multiple mechanisms to block type 1 and type 2 interferon signalling pathways. PLoS ONE, 2013; 8, e57063. https://doi.org/10.1371/journal.pone.0057063
- • Chowdhury, E.H., Bhuiyan, A.R., Rahman, M.M., Siddique, M.S.A., Islam, M.R. Natural peste des petits ruminants virus infection in Black Bengal goats: virological, pathological and immunohistochemical investigation. BMC Veterinary Research, 2014; 10, 263. https://doi.org/10.1186/s12917-014-0263-y
- • Couacy-Hymann, E., Bodjo, C., Danho, T., Libeau, G., Diallo, A. Evaluation of the virulence of some strains of peste-des-petits-ruminants virus (PPRV) in experimentally infected West African dwarf goats. Veterinary Journal, 2007; 173, 178–183. https://doi.org/10.1016/j.tvjl.2005.08.020
- • Couacy-Hymann, E., Bodjo, S.C., Koffi, M.Y., Kouakou, C., Danho, T. The early detection of peste-des-petits-ruminants (PPR) virus antigens and nucleic acid from experimentally infected goats using RT-PCR and immunocapture ELISA techniques. Research in Veterinary Science, 2009; 87, 332–335. https://doi.org/10.1016/j.rvsc.2009.03.002
- • Couper, K.N., Blount, D.G., Riley, E.M. IL-10: the master regulator of immunity to infection. The Journal of Immunology, 2008; 180, 5771–5777. https://doi.org/10.4049/jimmunol.180.9.5771
- • Darnell, J.E., Kerr, I.M., Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994; 264, 1415–1421. https://doi.org/10.1126/science.8197455
- • Das, S.C., Baron, M.D., Barrett, T. Recovery and characterization of a chimeric rinderpest virus with the glycoproteins of peste-des-petits-ruminants virus: homologous F and H proteins are required for virus viability. Journal of Virology, 2000; 74, 9039–9047. https://doi.org/10.1128/JVI.74.19.9039-9047.2000
- • de Vries, R.D., Lemon, K., Ludlow, M., McQuaid, S., Yüksel, S., van Amerongen, G., Rennick, L.J., Rima, B.K., Osterhaus, A.D.M.E., de Swart, R.L., Duprex, W.P. In vivo tropism of attenuated and pathogenic measles virus expressing green fluorescent protein in macaques. Journal of Virology, 2010a; 84, 4714–4724. https://doi.org/10.1128/JVI.02633-09
- • de Vries, R.D., McQuaid, S., van Amerongen, G., Yüksel, S., Verburgh, R.J., Osterhaus, A.D.M.E., Duprex, W.P., de Swart, R.L. Measles immune suppression: lessons from the macaque model. PLoS Pathogens, 2012; 8, e1002885. https://doi.org/10.1371/journal.ppat.1002885
- • de Vries, R.D., Yüksel, S., Osterhaus, A.D.M.E., de Swart, R.L. Specific CD8(+) T-lymphocytes control dissemination of measles virus. European Journal of Immunology, 2010b; 40, 388–395. https://doi.org/10.1002/eji.200939949
- • Devaux, P., Messling, von, V., Songsungthong, W., Springfeld, C., Cattaneo, R. Tyrosine 110 in the measles virus phosphoprotein is required to block STAT1 phosphorylation. Virology, 2007; 360, 72–83. https://doi.org/10.1016/j.virol.2006.09.049
- • Dhanasekaran, S., Biswas, M., Vignesh, A.R., Ramya, R., Raj, G.D., Tirumurugaan, K.G., Raja, A., Kataria, R.S., Parida, S., Subbiah, E. Toll-like receptor responses to Peste des petits ruminants virus in goats and water buffalo. PLoS One, 2014; 9, e111609. https://doi.org/10.1371/journal.pone.0111609
- • Diallo, A., Minet, C., Le Goff, C., Berhe, G., Albina, E., Libeau, G., Barrett, T. The threat of peste des petits ruminants: progress in vaccine development for disease control. Vaccine, 2007; 25, 5591–5597. https://doi.org/10.1016/j.vaccine.2007.02.013
- • Didcock, L., Young, D.F., Goodbourn, S., Randall, R.E. The V protein of simian virus 5 inhibits interferon signalling by targeting STAT1 for proteasome-mediated degradation. Journal of Virology, 1999; 73, 9928–9933.
- • Durant, L., Watford, W.T., Ramos, H.L., Laurence, A., Vahedi, G., Wei, L., Takahashi, H., Sun, H.-W., Kanno, Y., Powrie, F., O’Shea, J.J. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity, 2010; 32, 605–615. https://doi.org/10.1016/j.immuni.2010.05.003
- • Emikpe, B.O., Sabri, M.Y., Akpavie, S.O., Zamri-Saad, M. Experimental infection of Peste des Petit Ruminant virus and Mannheimia haemolytica A2 in goats: immunolocalisation of Mannheimia haemolytica antigens. Veterinary Research Communication, 2010; 34, 569–578. https://doi.org/10.1007/s11259-010-9425-y
- • Fazilleau, N., Mark, L., McHeyzer-Williams, L.J., McHeyzer-Williams, M.G. Follicular helper T cells: lineage and location. Immunity, 2009; 30, 324–335. https://doi.org/10.1016/j.immuni.2009.03.003
- • Ferreira, C.S.A., Frenzke, M., Leonard, V.H.J., Welstead, G.G., Richardson, C.D., Cattaneo, R. Measles virus infection of alveolar macrophages and dendritic cells precedes spread to lymphatic organs in transgenic mice expressing human signaling lymphocytic activation molecule (SLAM, CD150). Journal of Virology, 2010; 84, 3033–3042. https://doi.org/10.1128/JVI.01559-09
- • Filippi, C.M., Herrath, von, M.G., 2008. IL-10 and the resolution of infections. The Journal of Pathology, 2008; 214, 224–230. https://doi.org/10.1002/path.2272
- • Finberg, R.W., Kurt-Jones, E.A. Viruses and Toll-like receptors. Microbes and Infection, 2004; 6, 1356–1360. https://doi.org/10.1016/j.micinf.2004.08.013
- • Finberg, R.W., Wang, J.P., Kurt-Jones, E.A., 2007. Toll like receptors and viruses. Reviews in Medical Virology, 2007; 17, 35–43. https://doi.org/10.1002/rmv.525
- • Fujii, N. 2-5A and virus infection. Progress in Molecular and Subcellular Biology, 1994; 14, 150–175. https://doi.org/10.1007/978-3-642-78549-8_9
- • Fujii, N., Kimura, K., Murakami, T., Indoh, T., Ishida, S., Fujinaga, K., Oguma, K. Suppression of interferon-induced oligo-2“,5-”adenylate synthetase induction in persistent infection. Journal of General Virology, 1990; 71 (Pt 12), 3071–3074. https://doi.org/10.1099/0022-1317-71-12-3071
- • Fujii, N., Oguma, K., Kimura, K., Yamashita, T., Ishida, S., Fujinaga, K., Yashiki, T. Oligo-2“,5-”adenylate synthetase activity in K562 cell lines persistently infected with measles or mumps virus. Journal of General Virology, 1988; 69 (Pt 8), 2085–2091. https://doi.org/10.1099/0022-1317-69-8-2085
- • Fujii, N., Yokosawa, N., Shirakawa, S. Suppression of interferon response gene expression in cells persistently infected with mumps virus, and restoration from its suppression by treatment with ribavirin. Virus Research, 1999; 65, 175–185. https://doi.org/10.1016/S0168-1702(99)00114-8
- • Gao, J., De, B.P., Han, Y., Choudhary, S., Ransohoff, R., Banerjee, A.K. Human parainfluenza virus type 3 inhibits gamma interferon-induced major histocompatibility complex class II expression directly and by inducing alpha/beta interferon. Journal of Virology, 2001; 75, 1124–1131. https://doi.org/10.1128/JVI.75.3.1124-1131.2001
- • Garcin, D., Latorre, P., Kolakofsky, D. Sendai virus C proteins counteract the interferon-mediated induction of an antiviral state. Journal of Virology, 1999; 73, 6559–6565.
- • García-Sastre, A. Inhibition of interferon-mediated antiviral responses by influenza A viruses and other negative-strand RNA viruses. Virology, 2001; 279, 375–384. https://doi.org/10.1006/viro.2000.0756
- • Gargadenned, L., Lalanne, A. La peste des petits ruminants (in French). Bull. Serv. Zoot. Epiz. Afr. Occ. Fr., 1942; 5, 16–21.
- • Gibbs, E.P., Lawman, M.J., Bryant, J. Classification of peste des petits ruminants virus as the fourth member of the genus Morbillivirus. Intervirology, 1979; 11, 268–274. https://doi.org/10.1159/000149044
- • Goodbourn, S., Didcock, L., Randall, R.E. Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. Journal of General Virology, 2000; 81, 2341–2364. https://doi.org/10.1099/0022-1317-81-10-2341
- • Gotoh, B., Komatsu, T., Takeuchi, K., Yokoo, J. Paramyxovirus accessory proteins as interferon antagonists. Microbiology and Immunology, 2001; 45, 787–800. https://doi.org/10.1111/j.1348-0421.2001.tb01315.x
- • Govindarajan, R., Koteeswaran, A., Venugopalan, A.T., Shyam, G., Shaouna, S., Shaila, M.S., Ramachandran, S. Isolation of pestes des petits ruminants virus from an outbreak in Indian buffalo (Bubalus bubalis). Veterinary Record, 1997; 141, 573–574. https://doi.org/10.1136/vr.141.22.573
- • Griffin, D.E., Ward, B.J., Jauregui, E., Johnson, R.T., Vaisberg, A. Immune activation in measles. New England Journal of Medicine, 1989; 320, 1667–1672. https://doi.org/10.1056/NEJM198906223202506
- • Haffar, A., Libeau, G., Moussa, A., Cécile, M., Diallo, A. The matrix protein gene sequence analysis reveals close relationship between peste des petits ruminants virus (PPRV) and dolphin morbillivirus. Virus Research, 1999; 64, 69–75. https://doi.org/10.1016/S0168-1702(99)00080-5
- • Hammouchi, M., Loutfi, C., Sebbar, G., Touil, N., Chaffai, N., Batten, C., Harif, B., Oura, C., Harrak, El, M. Experimental infection of alpine goats with a Moroccan strain of peste des petits ruminants virus (PPRV). Veterinary Microbiology, 2012; 160, 240–244. https://doi.org/10.1016/j.vetmic.2012.04.043
- • Harrak, El, M., Touil, N., Loutfi, C., Hammouchi, M., Parida, S., Sebbar, G., Chaffai, N., Harif, B., Messoudi, N., Batten, C., Oura, C.A.L. A reliable and reproducible experimental challenge model for peste des petits ruminants virus. Journal of Clinical Microbiology, 2012; 50, 3738–3740.
- • Heaney, J., Barrett, T., Cosby, S.L. Inhibition of in vitro leukocyte proliferation by morbilliviruses. Journal of Virology, 2002; 76, 3579–3584. https://doi.org/10.1128/JVI.76.7.3579-3584.2002
- • Herbert, R., Baron, J., Batten, C., Baron, M., Taylor, G. Recombinant adenovirus expressing the haemagglutinin of Peste des petits ruminants virus (PPRV) protects goats against challenge with pathogenic virus; a DIVA vaccine for PPR. Veterinary Research, 2014; 45, 24. https://doi.org/10.1186/1297-9716-45-24
- • Herschke, F., Plumet, S., Duhen, T., Azocar, O., Druelle, J., Laine, D., Wild, T.F., Rabourdin-Combe, C., Gerlier, D., Valentin, H. Cell-cell fusion induced by measles virus amplifies the type I interferon response. Journal of Virology, 2007; 81, 12859–12871. https://doi.org/10.1128/JVI.00078-07
- • Honda, K., Takaoka, A., Taniguchi, T. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity, 2006; 25, 349–360. https://doi.org/10.1016/j.immuni.2006.08.009
- • Horvath, C.M. Silencing STATs: lessons from paramyxovirus interferon evasion. Cytokine Growth Factor Reviews, 2004; 15, 117–127. https://doi.org/10.1016/j.cytogfr.2004.08.001
- • Huang, C., Zhang, Q., Guo, X.-K., Yu, Z.-B., Xu, A.-T., Tang, J., Feng, W.-H. Porcine reproductive and respiratory syndrome virus nonstructural protein 4 antagonizes beta interferon expression by targeting the NF-κB essential modulator. Journal of Virology, 2014; 88, 10934–10945. https://doi.org/10.1128/JVI.01396-14
- • Ichinohe, T., Lee, H.K., Ogura, Y., Flavell, R., Iwasaki, A., 2009. Inflammasome recognition of influenza virus is essential for adaptive immune responses. Journal of Experimental Medicine, 2009; 206, 79–87. https://doi.org/10.1084/jem.20081667
- • Ikegame, S., Takeda, M., Ohno, S., Nakatsu, Y., Nakanishi, Y., Yanagi, Y. Both RIG-I and MDA5 RNA helicases contribute to the induction of alpha/beta interferon in measles virus-infected human cells. Journal of Virology, 2010; 84, 372–379. https://doi.org/10.1128/JVI.01690-09
- • Jagtap, S.P., Rajak, K.K., Garg, U.K., Sen, A., Bhanuprakash, V., Sudhakar, S.B., Balamurugan, V., Patel, A., Ahuja, A., Singh, R.K., Vanamayya, P.R. Effect of immunosuppression on pathogenesis of peste des petits ruminants (PPR) virus infection in goats. Microbial Pathogenesis, 2012; 52, 217–226. https://doi.org/10.1016/j.micpath.2012.01.003
- • Janeway, C.A., Chervonsky, A.V., Sant’Angelo, D. T-cell receptors: is the repertoire inherently MHC-specific? Current Biology, 1997; 7, R299–300. https://doi.org/10.1016/S0960-9822(06)00142-4
- • Janeway, C.A., Medzhitov, R. Innate immune recognition. Annual Review Immunology, 2002; 20, 197–216. https://doi.org/10.1146/annurev.immunol.20.083001.084359
- • Jones, S.A. Directing transition from innate to acquired immunity: defining a role for IL-6. The Journal of Immunology, 2005; 175, 3463–3468. https://doi.org/10.4049/jimmunol.175.6.3463
- • Kato, A., Ohnishi, Y., Kohase, M., Saito, S., Tashiro, M., Nagai, Y. Y2, the smallest of the Sendai virus C proteins, is fully capable of both counteracting the antiviral action of interferons and inhibiting viral RNA synthesis. Journal of Virology, 2001; 75, 3802–3810. https://doi.org/10.1128/JVI.75.8.3802-3810.2001
- • Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K.J., Yamaguchi, O., Otsu, K., Tsujimura, T., Koh, C.-S., Reis e Sousa, C., Matsuura, Y., Fujita, T., Akira, S. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature, 2006; 441, 101–105. https://doi.org/10.1038/nature04734
- • Kawai, T., Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunology, 2010; 11, 373–384. https://doi.org/10.1038/ni.1863
- • Kincaid, R.P., Sullivan, C.S. Virus-encoded microRNAs: an overview and a look to the future. PLoS Pathogens, 2012; 8, e1003018. https://doi.org/10.1371/journal.ppat.1003018
- • Komatsu, T., Takeuchi, K., Yokoo, J., Gotoh, B. C and V proteins of Sendai virus target signaling pathways leading to IRF-3 activation for the negative regulation of interferon-beta production. Virology, 2004; 325, 137–148. https://doi.org/10.1016/j.virol.2004.04.025
- • Komatsu, T., Takeuchi, K., Yokoo, J., Tanaka, Y., Gotoh, B. Sendai virus blocks alpha interferon signaling to signal transducers and activators of transcription. Journal of Virology, 2000; 74, 2477–2480. https://doi.org/10.1128/JVI.74.5.2477-2480.2000
- • Kubota, T., Yokosawa, N., Yokota, S., Fujii, N., 2001. C terminal CYS-RICH region of mumps virus structural V protein correlates with block of interferon alpha and gamma signal transduction pathway through decrease of STAT 1-alpha. Biochemical and Biophysical Research Communication, 2001; 283, 255–259. https://doi.org/10.1006/bbrc.2001.4764
- • Kuchipudi, S.V. The Complex Role of STAT3 in Viral Infections. Journal of Immunology Research, 2015; 2015, 272359–9.
- • Kul, O., Kabakci, N., Atmaca, H.T., Ozkul, A. Natural peste des petits ruminants virus infection: novel pathologic findings resembling other morbillivirus infections. Veterinary Pathology, 2007; 44, 479–486. https://doi.org/10.1354/vp.44-4-479
- • Kumar, P., Tripathi, B.N., Sharma, A.K., Kumar, R., Sreenivasa, B.P., Singh, R.P., Dhar, P., Bandyopadhyay, S.K. Pathological and immunohistochemical study of experimental peste des petits ruminants virus infection in goats. Journal of Veterinary Medicine. B Infectious Diseases and Veterinary Public Health, 2004; 51, 153–159. https://doi.org/10.1111/j.1439-0450.2004.00747.x
- • Laine, D., Trescol-Biémont, M.-C., Longhi, S., Libeau, G., Marie, J.C., Vidalain, P.-O., Azocar, O., Diallo, A., Canard, B., Rabourdin-Combe, C., Valentin, H. Measles virus (MV) nucleoprotein binds to a novel cell surface receptor distinct from FcgammaRII via its C-terminal domain: role in MV-induced immunosuppression. Journal of Virology, 2003; 77, 11332–11346. https://doi.org/10.1128/JVI.77.21.11332-11346.2003
- • Langedijk, J.P., Daus, F.J., van Oirschot, J.T. Sequence and structure alignment of Paramyxoviridae attachment proteins and discovery of enzymatic activity for a morbillivirus hemagglutinin. Journal of Virology, 1997; 71, 6155–6167.
- • Lecouturier, V., Fayolle, J., Caballero, M., Carabaña, J., Celma, M.L., Fernandez-Muñoz, R., Wild, T.F., Buckland, R. Identification of two amino acids in the hemagglutinin glycoprotein of measles virus (MV) that govern hemadsorption, HeLa cell fusion, and CD46 downregulation: phenotypic markers that differentiate vaccine and wild-type MV strains. Journal of Virology, 1996; 70, 4200–4204.
- • Lefèvre, P.C., Diallo, A. Peste des petits ruminants. Revue- International Office of Epizootic, 1990; 9, 935–981.
- • Lemon, K., de Vries, R.D., Mesman, A.W., McQuaid, S., van Amerongen, G., Yüksel, S., Ludlow, M., Rennick, L.J., Kuiken, T., Rima, B.K., Geijtenbeek, T.B.H., Osterhaus, A.D.M.E., Duprex, W.P., de Swart, R.L. Early target cells of measles virus after aerosol infection of non-human primates. PLoS Pathogens, 2011; 7, e1001263. https://doi.org/10.1371/journal.ppat.1001263
- • Levy, D.E., Kessler, D.S., Pine, R., Darnell, J.E. Cytoplasmic activation of ISGF3, the positive regulator of interferon-alpha-stimulated transcription, reconstituted in vitro. Genes Development, 1989; 3, 1362–1371. https://doi.org/10.1101/gad.3.9.1362
- • Liston, P., Briedis, D.J. Measles virus V protein binds zinc. Virology, 1994; 198, 399–404. https://doi.org/10.1006/viro.1994.1050
- • Liu, Y., Zhang, S., Ma, G., Zhang, F., Hu, R. Efficacy and safety of a live canine adenovirus-vectored rabies virus vaccine in swine. Vaccine, 2008; 26, 5368–5372. https://doi.org/10.1016/j.vaccine.2008.08.001
- • Ma, X., Yang, X., Nian, X., Zhang, Z., Dou, Y., Zhang, X., Luo, X., Su, J., Zhu, Q., Cai, X. Identification of amino-acid residues in the V protein of peste des petits ruminants essential for interference and suppression of STAT-mediated interferon signaling. Virology, 2015; 483, 54–63. https://doi.org/10.1016/j.virol.2015.03.039
- • Mahapatra, M., Parida, S., Egziabher, B.G., Diallo, A., Barrett, T. Sequence analysis of the phosphoprotein gene of peste des petits ruminants (PPR) virus: editing of the gene transcript. Virus Research, 2003; 96, 85–98. https://doi.org/10.1016/S0168-1702(03)00176-X
- • Malik, Y.S., Singh, D., Chandrashekar, K.M., Shukla, S., Sharma, K., Vaid, N., Chakravarti, S. Occurrence of dual infection of peste-des-petits-ruminants and goatpox in indigenous goats of central India. Transbound Emerging Diseases, 2011; 58, 268–273. https://doi.org/10.1111/j.1865-1682.2011.01201.x
- • Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature, 2007; 449, 819–826. https://doi.org/10.1038/nature06246
- • Menzies, M., Ingham, A. Identification and expression of Toll-like receptors 1-10 in selected bovine and ovine tissues. Veterinary Immunology and Immunopathoogy, 2006; 109, 23–30. https://doi.org/10.1016/j.vetimm.2005.06.014
- • Metz, P., Dazert, E., Ruggieri, A., Mazur, J., Kaderali, L., Kaul, A., Zeuge, U., Windisch, M.P., Trippler, M., Lohmann, V., Binder, M., Frese, M., Bartenschlager, R. Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication. Hepatology, 2012; 56, 2082–2093. https://doi.org/10.1002/hep.25908
- • Meyer, G., Diallo, A. The nucleotide sequence of the fusion protein gene of the peste des petits ruminants virus: the long untranslated region in the 5’-end of the F-protein gene of morbilliviruses seems to be specific to each virus. Virus Research, 1995; 37, 23–35. https://doi.org/10.1016/0168-1702(95)00013-G
- • Mondal, B., Sreenivasa, B.P., Dhar, P., Singh, R.P., Bandyopadhyay, S.K. Apoptosis induced by peste des petits ruminants virus in goat peripheral blood mononuclear cells. Virus Research, 2001; 73, 113–119. https://doi.org/10.1016/S0168-1702(00)00214-8
- • Mongkolsapaya, J., Jaye, A., Callan, M.F., Magnusen, A.F., McMichael, A.J., Whittle, H.C. Antigen-specific expansion of cytotoxic T lymphocytes in acute measles virus infection. Journal of Virology, 1999; 73, 67–71.
- • Nakatsu, Y., Takeda, M., Ohno, S., Koga, R., Yanagi, Y. Translational inhibition and increased interferon induction in cells infected with C protein-deficient measles virus. Journal of Virology, 2006; 80, 11861–11867. https://doi.org/10.1128/JVI.00751-06
- • Nakatsu, Y., Takeda, M., Ohno, S., Shirogane, Y., Iwasaki, M., Yanagi, Y. Measles virus circumvents the host interferon response by different actions of the C and V proteins. Journal of Virology, 2008; 82, 8296–8306. https://doi.org/10.1128/JVI.00108-08
- • Nanda, S.K., Baron, M.D. Rinderpest virus blocks type I and type II interferon action: role of structural and nonstructural proteins. Journal of Virology, 2006; 80, 7555–7568. https://doi.org/10.1128/JVI.02720-05
- • Ning, Y.-J., Wang, M., Deng, M., Shen, S., Liu, W., Cao, W.-C., Deng, F., Wang, Y.-Y., Hu, Z., Wang, H. Viral suppression of innate immunity via spatial isolation of TBK1/IKKε from mitochondrial antiviral platform. Journal of Molecular Cell Biology, 2014; 6, 324–337. https://doi.org/10.1093/jmcb/mju015
- • Oh, H.-M., Yu, C.-R., Golestaneh, N., Amadi-Obi, A., Lee, Y.S., Eseonu, A., Mahdi, R.M., Egwuagu, C.E. STAT3 protein promotes T-cell survival and inhibits interleukin-2 production through up-regulation of Class O Forkhead transcription factors. The Journal of Biological Chemistry, 2011; 286, 30888–30897. https://doi.org/10.1074/jbc.M111.253500
- • Ozkul, A., Akca, Y., Alkan, F., Karaoglu, T., Dagalp, S.B., Anderson, J., Yesilbag, K., Cokcaliskan, C., Gencay, A., Burgu, I. Prevalence, distribution, and host range of Peste des petits ruminants virus, Turkey. Emerging Infectious Disease, 2002; 8, 708–712. https://doi.org/10.3201/eid0807.010471
- • Palosaari, H., Parisien, J.-P., Rodriguez, J.J., Ulane, C.M., Horvath, C.M. STAT protein interference and suppression of cytokine signal transduction by measles virus V protein. Journal of Virology, 2003; 77, 7635–7644. https://doi.org/10.1128/JVI.77.13.7635-7644.2003
- • Parida, S., Muniraju, M., Mahapatra, M., Muthuchelvan, D., Buczkowski, H., Banyard, A.C. Peste des petits ruminants. Veterinary Microbiology, 2015; 181, 90–106. https://doi.org/10.1016/j.vetmic.2015.08.009
- • Parisien, J.-P., Bamming, D., Komuro, A., Ramachandran, A., Rodriguez, J.J., Barber, G., Wojahn, R.D., Horvath, C.M. A shared interface mediates paramyxovirus interference with antiviral RNA helicases MDA5 and LGP2. Journal of Virology, 2009; 83, 7252–7260. https://doi.org/10.1128/JVI.00153-09
- • Pasare, C., Medzhitov, R. Toll-dependent control mechanisms of CD4 T cell activation. Immunity, 2004; 21, 733–741. https://doi.org/10.1016/j.immuni.2004.10.006
- • Patel, A., Rajak, K.K., Balamurugan, V., Sen, A., Sudhakar, S.B., Bhanuprakash, V., Singh, R.K., Pandey, A.B. Cytokines expression profile and kinetics of Peste des petits ruminants virus antigen and antibody in infected and vaccinated goats. Virologica Sinica, 2012; 27, 265–271. https://doi.org/10.1007/s12250-012-3240-2
- • Paterson, R.G., Leser, G.P., Shaughnessy, M.A., Lamb, R.A. The paramyxovirus SV5 V protein binds two atoms of zinc and is a structural component of virions. Virology, 1995; 208, 121–131. https://doi.org/10.1006/viro.1995.1135
- • Patterson, J.B., Thomas, D., Lewicki, H., Billeter, M.A., Oldstone, M.B. V and C proteins of measles virus function as virulence factors in vivo. Virology, 2000; 267, 80–89. https://doi.org/10.1006/viro.1999.0118
- • Pawar, R.M., Dhinakar Raj, G., Balachandran, C. Relationship between the level of signaling lymphocyte activation molecule mRNA and replication of Peste-des-petits-ruminants virus in peripheral blood mononuclear cells of host animals. Acta Virologica, 2008; 52, 231–236.
- • Pfaller, C.K., Conzelmann, K.-K. Measles virus V protein is a decoy substrate for IkappaB kinase alpha and prevents Toll-like receptor 7/9-mediated interferon induction. Journal of Virology, 2008; 82, 12365–12373. https://doi.org/10.1128/JVI.01321-08
- • Platanias, L.C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature Review of Immunology, 2005; 5, 375–386. https://doi.org/10.1038/nri1604
- • Pope, R.A., Parida, S., Bailey, D., Brownlie, J., Banyard, A.C. Early events following experimental infection with Peste-Des-Petits ruminants virus suggest immune cell targeting. PLoS One, 2013; 8, e55830. https://doi.org/10.1371/journal.pone.0055830
- • Protection of goats against peste-des-petits-ruminants with attenuated rinderpest virus. Protection of goats against peste-des-petits-ruminants with attenuated rinderpest virus. Research in Veterinary Science, 1979; 27, 321–324.
- • Qin, J., Huang, H., Ruan, Y., Hou, X., Yang, S., Wang, C., Huang, G., Wang, T., Feng, N., Gao, Y., Xia, X. A novel recombinant Peste des petits ruminants-canine adenovirus vaccine elicits long-lasting neutralizing antibody response against PPR in goats. PLoS One, 2012; 7, e37170. https://doi.org/10.1371/journal.pone.0037170
- • Rager, M., Vongpunsawad, S., Duprex, W.P., Cattaneo, R. Polyploid measles virus with hexameric genome length. EMBO Journal, 2002; 21, 2364–2372. https://doi.org/10.1093/emboj/21.10.2364
- • Raja, A., Vignesh, A.R., Mary, B.A., Tirumurugaan, K.G., Raj, G.D., Kataria, R., Mishra, B.P., Kumanan, K. Sequence analysis of Toll-like receptor genes 1-10 of goat (Capra hircus). Veterinary Immunology Immunopathology, 2011; 140, 252–258. https://doi.org/10.1016/j.vetimm.2011.01.007
- • Rajak, K.K., Sreenivasa, B.P., Hosamani, M., Singh, R.P., Singh, S.K., Singh, R.K., Bandyopadhyay, S.K. Experimental studies on immunosuppressive effects of peste des petits ruminants (PPR) virus in goats. Comparative Immunology, Microbiology and Infectious Disease, 2005; 28, 287–296. https://doi.org/10.1016/j.cimid.2005.08.002
- • Ramachandran, A., Horvath, C.M. Dissociation of paramyxovirus interferon evasion activities: universal and virus-specific requirements for conserved V protein amino acids in MDA5 interference. Journal of Virology, 2010; 84, 11152–11163. https://doi.org/10.1128/JVI.01375-10
- • Ramachandran, A., Parisien, J.-P., Horvath, C.M. STAT2 is a primary target for measles virus V protein-mediated alpha/beta interferon signaling inhibition. Journal of Virology, 2008; 82, 8330–8338. https://doi.org/10.1128/JVI.00831-08
- • Randall, R.E., Goodbourn, S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. Journal of General Virology, 2008; 89, 1–47. https://doi.org/10.1099/vir.0.83391-0
- • Ravanel, K., Castelle, C., Defrance, T., Wild, T.F., Charron, D., Lotteau, V., Rabourdin-Combe, C. Measles virus nucleocapsid protein binds to FcgammaRII and inhibits human B cell antibody production. Journal of Experimental Medicine, 1997; 186, 269–278. https://doi.org/10.1084/jem.186.2.269
- • Riddell, M.A., Moss, W.J., Hauer, D., Monze, M., Griffin, D.E. Slow clearance of measles virus RNA after acute infection. Journal of Clinical Virology, 2007; 39, 312–317. https://doi.org/10.1016/j.jcv.2007.05.006
- • Rodriguez, J.J., Cruz, C.D., Horvath, C.M. Identification of the nuclear export signal and STAT-binding domains of the Nipah virus V protein reveals mechanisms underlying interferon evasion. Journal of Virology, 2004; 78, 5358–5367. https://doi.org/10.1128/JVI.78.10.5358-5367.2004
- • Rojas, J.M., Moreno, H., Valcárcel, F., Peña, L., Sevilla, N., Martín, V. Vaccination with recombinant adenoviruses expressing the peste des petits ruminants virus F or H proteins overcomes viral immunosuppression and induces protective immunity against PPRV challenge in sheep. PLoS One, 2014; 9, e101226. https://doi.org/10.1371/journal.pone.0101226
- • Rudd, P.A., Cattaneo, R., Messling, von, V. Canine distemper virus uses both the anterograde and the hematogenous pathway for neuroinvasion. Journal of Virology, 2006; 80, 9361–9370. https://doi.org/10.1128/JVI.01034-06
- • Saeed, I.K., Ali, Y.H., Khalafalla, A.I., Rahman-Mahasin, E.A. Current situation of Peste des petits ruminants (PPR) in the Sudan. Tropical Animal Health Production, 2010; 42, 89–93. https://doi.org/10.1007/s11250-009-9389-5
- • Samuel, C.E. Antiviral actions of interferon. Interferon-regulated cellular proteins and their surprisingly selective antiviral activities. Virology, 1991; 183, 1–11. https://doi.org/10.1016/0042-6822(91)90112-O
- • Scheid, A., Choppin, P.W. Identification of biological activities of paramyxovirus glycoproteins. Activation of cell fusion, hemolysis, and infectivity of proteolytic cleavage of an inactive precursor protein of Sendai virus. Virology, 1974a; 57, 475–490. https://doi.org/10.1016/0042-6822(74)90187-1
- • Scheid, A., Choppin, P.W. The hemagglutinating and neuraminidase protein of a paramyxovirus: interaction with neuraminic acid in affinity chromatography. Virology, 1974b; 62, 125–133. https://doi.org/10.1016/0042-6822(74)90308-0
- • Schlender, J., Hornung, V., Finke, S., Günthner-Biller, M., Marozin, S., Brzózka, K., Moghim, S., Endres, S., Hartmann, G., Conzelmann, K.-K. Inhibition of toll-like receptor 7- and 9-mediated alpha/beta interferon production in human plasmacytoid dendritic cells by respiratory syncytial virus and measles virus. Journal of Virology, 2005; 79, 5507–5515. https://doi.org/10.1128/JVI.79.9.5507-5515.2005
- • Schuhmann, K.M., Pfaller, C.K., Conzelmann, K.-K. The measles virus V protein binds to p65 (RelA) to suppress NF-kappaB activity. Journal of Virology, 2011; 85, 3162–3171. https://doi.org/10.1128/JVI.02342-10
- • Sen, G.C. Viruses and interferons. Annual Review of Microbiology, 2001; 55, 255–281. https://doi.org/10.1146/annurev.micro.55.1.255
- • Sen, G.C., Ransohoff, R.M. Interferon-induced antiviral actions and their regulation. Advances in Virus Research, 1993; 42, 57–102. https://doi.org/10.1016/S0065-3527(08)60083-4
- • Seth, S., Shaila, M.S. The hemagglutinin-neuraminidase protein of peste des petits ruminants virus is biologically active when transiently expressed in mammalian cells. Virus Research, 2001; 75, 169–177. https://doi.org/10.1016/S0168-1702(01)00238-6
- • Shaffer, J.A., Bellini, W.J., Rota, P.A. The C protein of measles virus inhibits the type I interferon response. Virology, 2003; 315, 389–397. https://doi.org/10.1016/S0042-6822(03)00537-3
- • Shaila, M.S., Purushothaman, V., Bhavasar, D., Venugopal, K., Venkatesan, R.A. Peste des petits ruminants of sheep in India. Veterinary Records, 1989; 125, 602.
- • Sinnathamby, G., Renukaradhya, G.J., Rajasekhar, M., Nayak, R., Shaila, M.S. Immune responses in goats to recombinant hemagglutinin-neuraminidase glycoprotein of Peste des petits ruminants virus: identification of a T cell determinant. Vaccine, 2001; 19, 4816–4823. https://doi.org/10.1016/S0264-410X(01)00210-9
- • Sparrer, K.M.J., Pfaller, C.K., Conzelmann, K.-K. Measles virus C protein interferes with Beta interferon transcription in the nucleus. Journal of Virology, 2012; 86, 796–805. https://doi.org/10.1128/JVI.05899-11
- • Stark, G.R., Kerr, I.M., Williams, B.R., Silverman, R.H., Schreiber, R.D. How cells respond to interferons. Annual Review of Biochemistry, 1998; 67, 227–264. https://doi.org/10.1146/annurev.biochem.67.1.227
- • Sun, M., Rothermel, T.A., Shuman, L., Aligo, J.A., Xu, S., Lin, Y., Lamb, R.A., He, B. Conserved cysteine-rich domain of paramyxovirus simian virus 5 V protein plays an important role in blocking apoptosis. Journal of Virology, 2004; 78, 5068–5078. https://doi.org/10.1128/JVI.78.10.5068-5078.2004
- • Sweetman, D.A., Miskin, J., Baron, M.D. Rinderpest virus C and V proteins interact with the major (L) component of the viral polymerase. Virology, 2001; 281, 193–204. https://doi.org/10.1006/viro.2000.0805
- • Takeda, K., Kaisho, T., Yoshida, N., Takeda, J., Kishimoto, T., Akira, S. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. The Journal of Immunology, 1998; 161, 4652–4660.
- • Takeuchi, O., Akira, S. Innate immunity to virus infection. Immunological Reviews, 2009; 227, 75–86. https://doi.org/10.1111/j.1600-065X.2008.00737.x
- • Taylor, W. P. Protection of goats against peste-des-petits-ruminants with attenuated rinderpest virus. Res. Vet. Sci., 1979; 27, 321–324.
- • Timofeeva, O.A., Chasovskikh, S., Lonskaya, I., Tarasova, N.I., Khavrutskii, L., Tarasov, S.G., Zhang, X., Korostyshevskiy, V.R., Cheema, A., Zhang, L., Dakshanamurthy, S., Brown, M.L., Dritschilo, A. Mechanisms of unphosphorylated STAT3 transcription factor binding to DNA. The Journal of Biological Chemistry, 2012; 287, 14192–14200. https://doi.org/10.1074/jbc.M111.323899
- • Truong, T., Boshra, H., Embury-Hyatt, C., Nfon, C., Gerdts, V., Tikoo, S., Babiuk, L.A., Kara, P., Chetty, T., Mather, A., Wallace, D.B., Babiuk, S. Peste des petits ruminants virus tissue tropism and pathogenesis in sheep and goats following experimental infection. PLoS One, 2014; 9, e87145. https://doi.org/10.1371/journal.pone.0087145
- • Ulane, C.M., Rodriguez, J.J., Parisien, J.-P., Horvath, C.M. STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling. Journal of Virology, 2003; 77, 6385–6393. https://doi.org/10.1128/JVI.77.11.6385-6393.2003
- • van Binnendijk, R.S., Poelen, M.C., Kuijpers, K.C., Osterhaus, A.D., Uytdehaag, F.G. The predominance of CD8+ T cells after infection with measles virus suggests a role for CD8+ class I MHC-restricted cytotoxic T lymphocytes (CTL) in recovery from measles. Clonal analyses of human CD8+ class I MHC-restricted CTL. The Journal of Immunology, 1990; 144, 2394–2399.
- • Wernike, K., Eschbaumer, M., Breithaupt, A., Maltzan, J., Wiesner, H., Beer, M., Hoffmann, B. Experimental infection of sheep and goats with a recent isolate of peste des petits ruminants virus from Kurdistan. Veterinary Microbiology, 2014; 172, 140–145. https://doi.org/10.1016/j.vetmic.2014.05.010
- • West, N.P., Pyne, D.B., Renshaw, G., Cripps, A.W. Antimicrobial peptides and proteins, exercise and innate mucosal immunity. FEMS Immunological and Medical Microbiology, 2006; 48, 293–304. https://doi.org/10.1111/j.1574-695X.2006.00132.x
- • Wohlsein, P., Saliki, J. 2006. Rinderpest and Peste des petits ruminants virus: Plague of large and small ruminants. In: Biology of animal infections, London, UK, pp. 69–85.
- • Woo, P.C.Y., Lau, S.K.P., Wong, B.H.L., Fan, R.Y.Y., Wong, A.Y.P., Zhang, A.J.X., Wu, Y., Choi, G.K.Y., Li, K.S.M., Hui, J., Wang, M., Zheng, B.-J., Chan, K.H., Yuen, K.-Y. Feline morbillivirus, a previously undescribed paramyxovirus associated with tubulointerstitial nephritis in domestic cats. Proceedings of the National Academy of Sciences U.S.A., 2012; 109, 5435–5440. https://doi.org/10.1073/pnas.1119972109
- • Yamaguchi, M., Kitagawa, Y., Zhou, M., Itoh, M., Gotoh, B. An anti-interferon activity shared by paramyxovirus C proteins: inhibition of Toll-like receptor 7/9-dependent alpha interferon induction. FEBS Letters, 2014; 588, 28–34. https://doi.org/10.1016/j.febslet.2013.11.015
- • Yesilbağ, K., Yilmaz, Z., Gölcü, E., Ozkul, A. Peste des petits ruminants outbreak in western Turkey. Veterinary Record, 2005; 157, 260–261. https://doi.org/10.1136/vr.157.9.260
- • Yokosawa, N., Kubota, T., Fujii, N. Poor induction of interferon-induced 2“,5-”oligoadenylate synthetase (2-5 AS) in cells persistently infected with mumps virus is caused by decrease of STAT-1 alpha. Archives of Virology, 1998; 143, 1985–1992. https://doi.org/10.1007/s007050050434
- • Yokota, S.I., Saito, H., Kubota, T., Yokosawa, N., Amano, K.I., Fujii, N. Measles virus suppresses interferon-alpha signaling pathway: suppression of Jak1 phosphorylation and association of viral accessory proteins, C and V, with interferon-alpha receptor complex. Virology, 2003; 306, 135–146. https://doi.org/10.1016/S0042-6822(02)00026-0
- • Yu, C.-R., Dambuza, I.M., Lee, Y.-J., Frank, G.M., Egwuagu, C.E. STAT3 regulates proliferation and survival of CD8+ T cells: enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis. Mediators of Inflammation, 2013; 359674–10. https://doi.org/10.1155/2013/359674
- • Yu, X.L., Cheng, Y.M., Shi, B.S., Qian, F.X., Wang, F.B., Liu, X.N., Yang, H.Y., Xu, Q.N., Qi, T.K., Zha, L.J., Yuan, Z.H., Ghildyal, R. Measles virus infection in adults induces production of IL-10 and is associated with increased CD4+ CD25+ regulatory T cells. Journal of Immunology, 2008; 181, 7356–7366. https://doi.org/10.4049/jimmunol.181.10.7356
- • Zhao, C., Collins, M.N., Hsiang, T.-Y., Krug, R.M. Interferon-induced ISG15 pathway: an ongoing virus-host battle. Trends in Microbiology, 2013; 21, 181–186. https://doi.org/10.1016/j.tim.2013.01.005