A New Mouse Model Reveals a Critical Role for Host Innate Immunity in Resistance to Rift Valley Fever

Valle, Tânia Zaverucha do; Billecocq, Agnès; Guillemot, Laurent; Alberts, Rudi; Gommet, Céline; Geffers, Robert; Calabrese, Kátia da Silva; Schughart, Klaus; Bouloy, Michèle; Montagutelli, Xavier; Panthier, Jean‐Jacques

doi:10.4049/jimmunol.1000949

Cited by 60 publications

(72 citation statements)

References 43 publications

(32 reference statements)

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“…13,34,36 To analyze the impact of the different NSm-related proteins on viral virulence, we conducted an initial animal test in 8-week-old female C57BL/6 mice using mutant viruses in which single AUG codons were knocked out. Mice were injected intraperitoneally with 100 PFU of in vitro -reconstituted WT virus (ZH548) or the different mutant viruses, and the mice were monitored for 3 weeks (Figures 1C and 4A).…”

Section: Resultsmentioning

confidence: 99%

“…Groups of 8-week-old mice were inoculated intraperitoneally with 100 plaque-forming units (PFU) of RVFV and kept in biosafety level 3 isolators, as previously described. 34 The morbidity, mortality and clinical disease scores of the mice were monitored daily for 14 days following infection. Mice that showed signs of illness, i.e., ruffled fur and hunched posture, were euthanized.…”

Section: Methodsmentioning

confidence: 99%

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The Rift Valley fever accessory proteins NSm and P78/NSm-G _N are distinct determinants of virus propagation in vertebrate and invertebrate hosts

Kreher

Tamietti

Gommet

et al. 2014

Emerging Microbes & Infections

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Rift Valley fever virus (RVFV) is an enzootic virus circulating in Africa that is transmitted to its vertebrate host by a mosquito vector and causes severe clinical manifestations in humans and ruminants. RVFV has a tripartite genome of negative or ambisense polarity. The M segment contains five in-frame AUG codons that are alternatively used for the synthesis of two major structural glycoproteins, GN and GC, and at least two accessory proteins, NSm, a 14-kDa cytosolic protein, and P78/NSm-GN, a 78-kDa glycoprotein. To determine the relative contribution of P78 and NSm to RVFV infectivity, AUG codons were knocked out to generate mutant viruses expressing various sets of the M-encoded proteins. We found that, in the absence of the second AUG codon used to express NSm, a 13-kDa protein corresponding to an N-terminally truncated form of NSm, named NSm′, was synthesized from AUG 3. None of the individual accessory proteins had any significant impact on RVFV virulence in mice. However, a mutant virus lacking both NSm and NSm′ was strongly attenuated in mice and grew to reduced titers in murine macrophages, a major target cell type of RVFV. In contrast, P78 was not associated with reduced viral virulence in mice, yet it appeared as a major determinant of virus dissemination in mosquitoes. This study demonstrates how related accessory proteins differentially contribute to RVFV propagation in mammalian and arthropod hosts.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The Rift Valley fever accessory proteins NSm and P78/NSm-G _N are distinct determinants of virus propagation in vertebrate and invertebrate hosts

Kreher

Tamietti

Gommet

et al. 2014

Emerging Microbes & Infections

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“…The wild-type RVFV ZH548 strain (ZH) of the virus, whose genome codes for a nonstructural NSs protein, which suppresses IFN-␤ expression, and which is highly pathogenic, causes severe illness in humans and animals (53)(54)(55), whereas the RVFV ZH548 ⌬NSs strain (⌬NSs), from whose genome the region coding for the NSs protein is deleted, strongly activates IFN-␤ expression and is fully avirulent (56).…”

Section: Licl Treatment Enhances Constitutive Ifn-␤ Gene Expressionmentioning

confidence: 99%

β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites

Marcato

Luron

Laqueuvre

et al. 2016

Molecular and Cellular Biology

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. Rapid upregulation of IFN-␤ gene expression occurs after recognition of viral nucleic acids by pattern recognition receptors (PRRs) consisting of either cytosolic receptors, such as retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA-5), or membrane-associated Toll-like receptors, such as Toll-like receptor 3 (TLR3) (3). After sensing single-or doublestranded RNA of viral origin, these receptors activate signaling pathways, implicating the phosphorylation and nuclear translocation of several transcription factors, among which is interferon regulatory factor 3 (IRF3), rapidly leading downstream to a robust activation of expression of the IFN-␤ gene. After being secreted, the IFN-␤ protein binds to the type I interferon receptor and triggers the JAK-STAT1/2 signal transduction pathway. This pathway leads to the activation and inhibition of the expression of a large set of genes that constitute the type I IFN response mounted to antagonize viral infection at different levels (4).Mice lacking IFN-␤ (5) or the subunit of the type I interferon receptor (6, 7) are highly susceptible to viral infections. They succumb to sublethal doses of a variety of viruses, thus confirming the main role of IFN-␤ in the establishment of an innate antiviral response. However, beyond the antiviral response, IFN-␤ affects a wide range of other biological functions; for the most part, these are related to modulation of the immune (innate and adaptive) and inflammatory responses as well as to cell proliferation and differentiation. Even though IFN-␤ has been described to have an anti-inflammatory benefit, it has also been implicated in the development of several inflammatory and autoimmune diseases (8-10). Hence, the beneficial or detrimental outcome of IFN-␤ expression for the organism depends on the timing and kinetics of IFN-␤ synthesis and the amount of IFN-␤ being synthesized (11,12). If a marked activation of IFN-␤ gene expression is required to efficiently set up the appropriate response to an external aggression, such as virus infection, this response needs to be adjusted in order to limit its pathological side effects.As expected for a gene with pleiotropic functions, its transcriptional state is regulated at different levels. At the cellular level, only a stochastic fraction of the infected cells produces 14) as a way to avoid an exacerbated and uncontrolled IFN response. At the nuclear level, one IFN-␤ allele localizes within interchromosomal regions rich in NF-B DNA binding sites before and after infection (15), whereas the other allele localizes next to pericentromeric heterochromatin (PCH) clusters in the absence of infection and dissociates from PCH clusters during infection (16). The monoallelic characteristic of these particular subnuclear localizations suggests that a yet undeciphered regulatory mechanism exists at the chromosome level. Finally, at the promoter level, the coordinated action of several transcription factors and chromatin-remodeling complexes (17-21) regulates the...

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“…Even though studies have shown that NSs blocks the transcription of type I IFN (Bouloy et al, 2001), it appears that infection of MBT/Pas mice with pathogenic RVFV does lead to small amounts of IFN secretion (do Valle et al, 2010;Le May et al, 2008). do Valle et al (2010) suggested that the slightly stronger IFN response in BALB/cByJ mice is one of the factors contributing to longer survival after infection with RVFV when compared with the MBT/Pas mice. Endogenous IFN levels contribute to host survival even in the presence of RVFV mediated inhibition of ISG transcription (Bouloy et al, 2001;Le May et al, 2008;Morrill et al, 1989Morrill et al, , 1990.…”

Section: Introductionmentioning

confidence: 99%

Cytokine response in mouse bone marrow derived macrophages after infection with pathogenic and non-pathogenic Rift Valley fever virus

Roberts

Hill

Davis

et al. 2015

Journal of General Virology

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Rift Valley fever virus (RVFV) is the most pathogenic member of the genus Phlebovirus within the family Bunyaviridae, and can cause severe disease in humans and livestock. Until recently, limited information has been published on the cellular host response elicited by RVFV, particularly in macrophages and dendritic cells, which play critical roles in stimulating adaptive and innate immune responses to viral infection. In an effort to define the initial response of host immunomodulatory cells to infection, primary mouse bone marrow derived macrophages (BMDM) were infected with the pathogenic RVFV strain ZH501, or attenuated strains MP-12 or MP-12 based Clone13 type (rMP12-C13 type), and cytokine secretion profiles examined. The secretion of T helper (Th)1-associated antiviral cytokines, chemokines and various interleukins increased rapidly after infection with the attenuated rMP12-C13 type RVFV, which lacks a functional NSs virulence gene. In comparison, infection with live-attenuated MP-12 encoding a functional NSs gene appeared to cause a delayed immune response, while pathogenic ZH501 ablates the immune response almost entirely. These data demonstrate that NSs can inhibit components of the BMDM antiviral response and supports previous work indicating that NSs can specifically regulate the type I interferon response in macrophages. Furthermore, our data demonstrate that genetic differences between ZH501 and MP-12 reduce the ability of MP-12 to inhibit antiviral signalling and subsequently reduce virulence in BMDM, demonstrating that viral components other than NSs play a critical role in regulating the host response to RVFV infection.

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A New Mouse Model Reveals a Critical Role for Host Innate Immunity in Resistance to Rift Valley Fever

Cited by 60 publications

References 43 publications

The Rift Valley fever accessory proteins NSm and P78/NSm-G _N are distinct determinants of virus propagation in vertebrate and invertebrate hosts

The Rift Valley fever accessory proteins NSm and P78/NSm-G _N are distinct determinants of virus propagation in vertebrate and invertebrate hosts

β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites

Cytokine response in mouse bone marrow derived macrophages after infection with pathogenic and non-pathogenic Rift Valley fever virus

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A New Mouse Model Reveals a Critical Role for Host Innate Immunity in Resistance to Rift Valley Fever

Cited by 60 publications

References 43 publications

The Rift Valley fever accessory proteins NSm and P78/NSm-G N are distinct determinants of virus propagation in vertebrate and invertebrate hosts

The Rift Valley fever accessory proteins NSm and P78/NSm-G N are distinct determinants of virus propagation in vertebrate and invertebrate hosts

β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites

Cytokine response in mouse bone marrow derived macrophages after infection with pathogenic and non-pathogenic Rift Valley fever virus

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The Rift Valley fever accessory proteins NSm and P78/NSm-G _N are distinct determinants of virus propagation in vertebrate and invertebrate hosts

The Rift Valley fever accessory proteins NSm and P78/NSm-G _N are distinct determinants of virus propagation in vertebrate and invertebrate hosts