Interferon α/β receptor knockout mice as a model to study bluetongue virus infection

doi:10.1016/j.virusres.2013.09.038

Virus Research

Volume 182, 28 March 2014, Pages 35-42

https://doi.org/10.1016/j.virusres.2013.09.038 Get rights and content

Highlights

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Adult mice with gene knockouts of the interferon α/β receptor (IFNAR(−/−)) are susceptible to the infection of BTV and the related orbivirus AHSV and EHDV.
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BTV induces interferon α/β and proinflammatory immune responses in IFNAR(−/−) mice.
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IFNAR(−/−) mice facilitates the studies of protection and immune response conferred by recombinant marker vaccines against BTV.

Abstract

Bluetongue is an arthropod-borne disease caused by a virus of the genus Orbivirus, the bluetongue virus (BTV), which affects ruminant livestock such as cattle, sheep, and goats and wild ruminants such as deer, and camelids. Recently, adult mice with gene knockouts of the interferon α/β receptor (IFNAR−/−) have been described as a model of lethal BTV infection. IFNAR(−/−) mice are highly susceptible to BTV-1, BTV-4 and BTV-8 infection when the virus is administered intravenously or subcutaneosuly. Disease progression and pathogenesis closely mimics signs of bluetongue disease in ruminants. In the present paper we review the studies where IFNAR(−/−) mice have been used as an animal model to study BTV transmission, pathogenesis, virulence, and protective efficacy of inactivated and new recombinant marker BTV vaccines. Furthermore, we report new data on protective efficacy of different strategies of BTV vaccination and also on induction of interferon α/β and proinflammatory immune responses in IFNAR(−/−) mice infected with BTV.

Section snippets

IFNAR(−/−) mice as a model to study viral infections

Blocking IFN-α/β activity in mice leads to a dramatically increased sensitivity to many viruses. Mice lacking the type I interferon (IFN) receptor (IFNAR (−/−)) were generated to elucidate the physiological role of the type I IFN system by Müller and colleagues (Muller et al., 1994). These mice were unresponsive to the antiviral action of natural murine type I IFN, a mixture of IFN-α and IFN-β. Comparative cytofluorometry revealed no abnormalities in the major lymphocyte subsets in terms of

Bluetongue and type I interferon

The innate immune response is the first line of defense against viruses resulting in the production of IFNα/β and other proinflammatory cytokines that control de infection (Randall and Goodbourn, 2008). BTV infection induces type I IFN in cells in culture and ruminants (Foster et al., 1991, Fulton and Pearson, 1982, Huismans, 1969, Jameson and Grossberg, 1978, Jameson and Grossberg, 1981, MacLachlan and Thompson, 1985). Although the induction of type I IFN after BTV infection was described more

IFNAR (−/−) mice as a model to study BTV virulence

Bluetongue (BT) is an arthropod-borne disease caused by a virus of the genus Orbivirus, the BTV, which affects ruminant livestock such as cattle, sheep, and goats and wild ruminants such as deer, and camelids. For years, different groups have tried to establish a laboratory animal model to facilitate the studies of pathogenesis, immune response and vaccination against BTV. Natural hosts are expensive and require specialized animal facilities with biosafety level 3 for these studies. It is known

IFNAR(−/−) mice as a model to study BTV transmission

BTV is transmitted among ruminants predominantly through feeding of biting midges that are members of the genus Culicoides (Verwoerd, 2004). Besides ruminants, natural BTV infection among African carnivores as a result of oral infection (Alexander et al., 1994), as well as the deaths of two Eurasian lynx caused by BTV-8 after feeding ruminant fetuses (Jauniaux et al., 2008) have been reported. These data suggested the possibility of oral transmission of BTV. IFNAR(−/−) mice were used to confirm

IFNAR(−/−) mice as a model to study BTV pathogenesis

IFNAR(−/−) mice can be also useful for investigating various facets of BTV-host interaction, including virus pathogenesis. The innate immune response elicited by dsRNA viruses, including the production of type I IFN (alpha/beta) and other inflammatory cytokines are likely to be key factors in the expression of their variable pathogenicity levels (Johansson et al., 2007). Experimental studies have been conducted to examine the expression of pro-inflammatory cytokines (IL-1, IL-6, IL-12, IFN-γ

IFNAR(−/−) mice as a model of infection for BTV related orbivirus

After the characterization of BTV infection in IFNAR(−/−) mice, these animals have also been used as a model of infection for African horse sickness virus (AHSV) and epizootic hemorrhagic disease virus (EHDV), two BTV related orbivirus. AHSV-4 infects IFNAR(−/−) mice and the pathology, with the exception of the central nervous system lesions, resemble those found in AHSV infected horses. Hemorrhages and inflammatory changes in the lung, splenomegalia and congestion of other internal organs such

IFNAR(−/−) mice as a model to study vaccine efficacy

The cost of testing new vaccines in target species is a major obstacle for laboratories and industries. For this reason, the intracerebral inoculation of newborn mice with BTV vaccines has been used as an animal model to evaluate the level of attenuation of live attenuated BTV vaccines (Franchi et al., 2008). Several studies have shown that adult IFNAR(−/−) mice serve as a good animal model to test BTV vaccines. Even though the lack of type I interferon signals may have an effect in the

Conclusions

IFNAR(−/−) mice are susceptible to the infection of BTV and the related orbivirus AHSV and EHDV. After infection, BTV infected mice show clinical signs characterized by ocular discharges, apathy and the disease progression led to animal death and infectious virus is recovered from the spleen, lung, thymus, lymph nodes and blood. Disease progression and pathogenesis closely mimics hallmarks of bluetongue disease in ruminants, and this mouse model of BTV infection is being used to study BTV

Acknowledgment

This work was supported by grants from the Comisión Interministerial de Ciencia y Tecnología (CICYT) (AGL2011-23506).

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Citation Excerpt :
Previous studies characterizing this antibody have reported that the half-life of 2.5 mg is 5.2 days and of 0.25 mg is 1.5 days [14,16,17]. The clinical manifestations were similar to those reported in earlier studies in IFNAR(−/−) mice [4–6,10,32,33]. In the present study, a lower rate of mortality was noticed at prolonged intervals than the early mortality and abnormally severe clinical disease in IFNAR(−/−) mice infected with BTV-1, -4, and -8, which is undesirable to study the efficacy of vaccines and immune responses against BTV [5,6,32,33].
Wild-type adult mice with intact interferon (IFN) system were neither susceptible to bluetongue virus (BTV) infection nor showed signs of morbidity/mortality. Establishment of immunologically competent wild-type adult mouse model with type I IFNs blockade is necessary to assess the pathogenesis, immune responses and testing of BTV vaccines.
Present study aimed to establish and characterize BTV serotype 1 infection in immunocompetent adult mice with type I IFNs blockade at the time of infection by studying immune responses and sequential pathology.
Adult mice were administered with anti-mouse IFN-α/β receptor subunit-1 (IFNAR1) blocking antibody (Clone: MAR1-5A3) 24 h before and after BTV serotype 1 infection, and sacrificed at various time points. Sequential pathology, BTV localization by immunohistochemistry and quantification by qRT-PCR, immune cell kinetics and apoptosis by flow cytometry, and cytokines estimation by c-ELISA and qRT-PCR were studied.
IFNAR blocked-infected mice developed clinical signs and typical lesions of BT; whereas, isotype-infected control mice did not develop any disease. The IFNAR blocked-infected mice showed enlarged, edematous, and congested lymph nodes (LNs) and spleen, and vascular (congestion and hemorrhage) and pneumonic lesions in lungs. Histopathologically, marked lymphoid depletion with “starry-sky pattern” due to lymphocytes apoptosis was noticed in the LNs and spleen. BTV antigen was detected and quantified in lymphoid organs, lungs, and other organs at various time points. Initial leukopenia (increased CD4⁺/CD8⁺ T cells ratio) followed by leukocytosis (decreased CD4⁺/CD8⁺ T cells ratio) and significantly increased biochemical values were noticed in IFNAR blocked-infected mice. Increased apoptotic cells in PBMCs and tissues coincided with viral load and levels of different cytokines in blood, spleen and draining LNs and notably varied between time points in IFNAR blocked-infected mice.
Present study is first to characterize BTV serotype 1 infection in immunocompetent adult mouse with type I IFNs blockade. The findings will be useful for studying pathogenesis and testing the efficacy of BTV vaccines.
Recombinant bluetongue virus with hemagglutinin epitopes in VP2 has potential as a labeled vaccine
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An animal model of BTV infection had been established in IFNAR(−/−) mice previously. This model can replicate BTV infection in ruminants, and has been widely used in the evaluation of various types of BTV vaccines (Calvo-Pinilla et al., 2009; Ortego et al., 2014). In our experiments, infecting IFNAR(−/−) mice with a 1 × 107 TCID50/mouse dose of BTV-16 did not lead to mortality, indicating that the virulence of the BTV-16 stock was attenuated.
Bluetongue (BT) is an arbovirus-borne disease of ruminants caused by bluetongue virus (BTV) that has the potential to have a serious economic impact. Currently available commercial vaccines include attenuated vaccines and inactivated vaccines, both of which have achieved great success in the prevention and control of BTV. However, these vaccines cannot distinguish between infected animals and immunized animals. To control outbreaks of BTV, the development of labeled vaccines is urgently needed. In this study, we used the plasmid-based reverse genetics system (RGS) of BTV to rescue four recombinant viruses in which HA (influenza hemagglutinin) tags were inserted at different sites of VP2. In vitro, the recombinant tagged viruses exhibited morphologies, plaque, and growth kinetics similar to the parental BTV-16, and expressed both VP2 and HA tag. Subsequently, the selected recombinant tagged viruses were prepared as inactivated vaccines to immunize IFNAR(−/−) mice and sheep, and serological detection results of anti-HA antibody provided discriminative detection. In summary, we used plasmid-based RGS to rescue BTV recombinant viruses with HA tags inserted into VP2, and detected several sites on VP2 that can accommodate HA tags. Some of the recombinant tagged viruses have potential to be developed into distinctive inactivated vaccines.
Rh-IFN-α attenuates neuroinflammation and improves neurological function by inhibiting NF-κB through JAK1-STAT1/TRAF3 pathway in an experimental GMH rat model
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Neuroinflammation occurs after germinal matrix hemorrhage (GMH) and induces secondary brain injury. Interferon-α (IFN-α) has been shown to exert anti-inflammatory effects in infectious diseases via activating IFNAR and its downstream signaling. We aimed to investigate the anti-inflammatory effects of Recombinant human IFN-α (rh-IFN-α) and the underlying mechanisms in a rat GMH model. Two hundred and eighteen P7 rat pups of both sexes were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Rh-IFN-α was administered intraperitoneally. Small interfering RNA (siRNA) of IFNAR, and siRNA of tumor necrosis factor receptor associated factor 3 (TRAF3) were administered through intracerebroventricular (i.c.v.) injections. JAK1 inhibitor ruxolitinib was given by oral lavage. Post-GMH evaluation included neurobehavioral function, Nissl staining, Western blot analysis, and immunofluorescence. Our results showed that endogenous IFN-α and phosphorylated IFNAR levels were increased after GMH. Administration of rh-IFN-α improved neurological functions, attenuated neuroinflammation, inhibited microglial activation, and ameliorated post-hemorrhagic hydrocephalus after GMH. These observations were concomitant with IFNAR activation, increased expression of phosphorylated JAK1, phosphorylated STAT1 and TRAF3, and decreased levels of phosphorylated NF-κB, IL-6 and TNF-α. Specifically, knockdown of IFNAR, JAK1 and TRAF3 abolished the protective effects of rh-IFN-α. In conclusion, our findings demonstrated that rh-IFN-α treatment attenuated neuroinflammation, neurological deficits and hydrocephalus formation through inhibiting microglial activation after GMH, which might be mediated by IFNAR/JAK1-STAT1/TRAF3/NF-κB signaling pathway. Rh-IFN-α may be a promising therapeutic agent to attenuate brain injury via its anti-inflammatory effect.
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Interferon α/β receptor knockout mice as a model to study bluetongue virus infection

Highlights

Abstract

Section snippets

IFNAR(−/−) mice as a model to study viral infections

Bluetongue and type I interferon

IFNAR (−/−) mice as a model to study BTV virulence

IFNAR(−/−) mice as a model to study BTV transmission

IFNAR(−/−) mice as a model to study BTV pathogenesis

IFNAR(−/−) mice as a model of infection for BTV related orbivirus

IFNAR(−/−) mice as a model to study vaccine efficacy

Conclusions

Acknowledgment

Vet. Microbiol.

Vaccine

Vaccine

Vet. Immunol. Immunopathol.

Virology

Vet. Immunol. Immunopathol.

Vet. Microbiol.

Vaccine

J. Virol. Methods

Methods Enzymol.

Res. Vet. Sci.

Vaccine

J. Comp. Pathol.

J. Clin. Virol.

Vaccine

Vet. Microbiol.

Virology

Res. Vet. Sci.

Vaccine

Virology

Vaccine

Vet. Microbiol.

Evidence of natural bluetongue virus infection among African carnivores

Am. J. Trop. Med. Hyg.

Development of mouse hepatocyte lines permissive for hepatitis C virus (HCV)

PLoS ONE

Evaluation of the immunogenicity of an experimental subunit vaccine that allows differentiation between infected and vaccinated animals against bluetongue Virus serotype 8 in ca ttle

Clin. Vaccine Immunol.

Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice

J. Gen. Virol.

Genetic evidence for an interferon-antagonistic function of Rift valley fever virus nonstructural protein NSs

J. Virol.

Interaction of bluetongue virus with preimplantation embryos from mice and cattle

Am. J. Vet. Res.

Multiserotype protection elicited by a combinatorial prime-boost vaccination strategy against bluetongue virus

PLoS ONE

Experimental oral infection of bluetongue virus serotype 8 in type I interferon receptor-deficient mice

J. Gen. Virol.

Establishment of a bluetongue virus infection model in mice that are deficient in the alpha/beta interferon receptor

PLoS ONE

Determinants of bluetongue virus virulence in murine models of disease

J. Virol.

A modified vaccinia Ankara virus (MVA) vaccine expressing African horse sickness virus (AHSV) VP2 protects against AHSV challenge in an IFNAR −/− mouse model

PLoS ONE

Sensing and control of bluetongue virus infection in epithelial cells via RIG-I and MDA5 helicases

J. Virol.

Establishment and application of hepatitis B virus persistent replication model in IFNAR(−/−) mouse

J. Huazhong Univ. Sci. Technol. Med. Sci.

Ns1 is a key protein in the vaccine composition to protect ifnar(−/−) mice against infection with multiple serotypes of African horse sickness virus

PLoS ONE