New Mouse Model for Dengue Virus Vaccine Testing

Johnson, Alison J.; Roehrig, John T.

doi:10.1128/jvi.73.1.783-786.1999

Cited by 309 publications

(157 citation statements)

References 28 publications

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“…Treatment with either IFN-␣ or IFN-␤ suppressed the replication of both DENV (49) and CHIKV (50) in cell culture. Moreover, infection of mice lacking IFNAR led to a significantly higher lethality after DENV (51) or CHIKV infection (52,53). Among the viral RNA sensors, RIG-I, MDA5, and TLR3 are activated upon DENV infection and are essential for host defense against the virus (54).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Dengue and Chikungunya Virus Infections by RIG-I-Mediated Type I Interferon-Independent Stimulation of the Innate Antiviral Response

Olagnier

Scholte

Chiang

et al. 2014

J Virol

118

108

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RIG-I is a cytosolic sensor critically involved in the activation of the innate immune response to RNA virus infection. In the present study, we evaluated the inhibitory effect of a RIG-I agonist on the replication of two emerging arthropod-borne viral pathogens, dengue virus (DENV) and chikungunya virus (CHIKV), for which no therapeutic options currently exist. We demonstrate that when a low, noncytotoxic dose of an optimized 5=triphosphorylated RNA (5=pppRNA) molecule was administered, RIG-I stimulation generated a robust antiviral response against these two viruses. Strikingly, 5=pppRNA treatment before or after challenge with DENV or CHIKV provided protection against infection. In primary human monocytes and monocyte-derived dendritic cells, the RIG-I agonist blocked both primary infection and antibody-dependent enhancement of DENV infection. The protective response against DENV and CHIKV induced by 5=pppRNA was dependent on an intact RIG-I/MAVS/TBK1/IRF3 axis and was largely independent of the type I IFN response. Altogether, this in vitro analysis of the antiviral efficacy of 5=pppRNA highlights the therapeutic potential of RIG-I agonists against emerging viruses such as DENV and CHIKV. IMPORTANCEDENV and CHIKV are two reemerging mosquito-borne viruses for which no therapeutic options currently exist. Both viruses overlap geographically in tropical regions of the world, produce similar fever-like symptoms, and are difficult to diagnose. This study investigated the inhibitory effect of a RIG-I agonist on the replication of these two viruses. RIG-I stimulation using 5=pppRNA before or after DENV or CHIKV infection generated a protective antiviral response against both pathogens in immune and nonimmune cells; interestingly, the protective response against the viruses was largely independent of the classical type I interferon response. The antiviral efficacy of 5=pppRNA highlights the therapeutic potential of RIG-I agonists against emerging viruses such as DENV and CHIKV.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Dengue and Chikungunya Virus Infections by RIG-I-Mediated Type I Interferon-Independent Stimulation of the Innate Antiviral Response

Olagnier

Scholte

Chiang

et al. 2014

J Virol

118

108

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“…In particular, the knockout mouse strain AG129 defective of interferon alpha/beta and gamma receptors has been a widely utilized model to test the in vivo efficacy of norovirus polymerase inhibitors (Rocha-Pereira et al, 2013). This particular strain of mice is also used as model for dengue and Zika virus infection (Aliota et al, 2016;Johnson and Roehrig, 1999;Zmurko et al, 2016). Smallanimal models have also been developed to study HuNoV infection.…”

Section: In Vivo Modelsmentioning

confidence: 99%

Structure(s), function(s), and inhibition of the RNA-dependent RNA polymerase of noroviruses

Deval¹,

Zhang²,

Chuang

et al. 2017

Virus Research

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Noroviruses belong to the Caliciviridae family of single-stranded positive-sense RNA viruses. The genus Norovirus includes seven genogroups (designated GI-GVII), of which GI, GII and GIV infect humans. Human noroviruses are responsible for widespread outbreaks of acute gastroenteritis and represent one of the most common causes of foodborne illness. No vaccine or antiviral treatment options are available for norovirus infection. The RNA-dependent RNA polymerase (RdRp) of noroviruses is a key enzyme responsible for transcription and replication of the viral genome. Here, we review the progress made in understanding the structures and functions of norovirus RdRp and its use as a target for small molecule inhibitors. Crystal structures of the RdRp at different stages of substrate interaction have been determined, which shed light on its multi-step catalytic cycle. The in vitro assays and in vivo animal models that have been developed to identify and characterize inhibitors of norovirus RdRp are also summarized, followed by an update on the current antiviral research targeting different regions of norovirus RdRp. In the future, structure-based drug design and rational optimization of known nucleoside and non-nucleoside inhibitors of norovirus RdRp may pave the way towards the next generation of direct-acting antivirals.

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“…In most of the cases, in vivo DENV studies classically involve immunodeficient mouse strains such as AG129 which do not express IFN-α/β and IFN-γ receptors. These mice are highly susceptible to DENV infection and generally die within two weeks after injection [166][167][168]. Following advancement of the knowledge about host-pathogen interactions and the advent of novel technologies (e.g., by CRISPR/Cas9 gene editing), a paradigm shift can be anticipated.…”

Section: Immunocompetent Mouse Model For Denv Vaccine Researchmentioning

confidence: 99%

The Interplay between Dengue Virus and the Human Innate Immune System: A Game of Hide and Seek

et al. 2019

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With 40% of the world population at risk, infections with dengue virus (DENV) constitute a serious threat to public health. While there is no antiviral therapy available against this potentially lethal disease, the efficacy of the only approved vaccine is not optimal and its safety has been recently questioned. In order to develop better vaccines based on attenuated and/or chimeric viruses, one must consider how the human immune system is engaged during DENV infection. The activation of the innate immunity through the detection of viruses by cellular sensors is the first line of defence against those pathogens. This triggers a cascade of events which establishes an antiviral state at the cell level and leads to a global immunological response. However, DENV has evolved to interfere with the innate immune signalling at multiple levels, hence dampening antiviral responses and favouring viral replication and dissemination. This review elaborates on the interplay between DENV and the innate immune system. A special focus is given on the viral countermeasure mechanisms reported over the last decade which should be taken into consideration during vaccine development.Vaccines 2019, 7, 145 2 of 21 serotypes (1-4) in one given restricted geographic area [4,5]. While there is an unmet medical need regarding strategies against dengue, the incidence of this disease is expected to geographically expand in the future considering that the arthropod vector is colonizing northern European and American territories with temperate climates. Clinical ManifestationDENV infection is characterized by a mixed clinical presentation that ranges from an asymptomatic disease to a mild febrile prodrome all the way to a severe hemorrhagic fever and shock syndrome. All infected individuals, asymptomatic or not, can transmit DENV to Aedes mosquitoes during a blood meal, making it difficult to precisely estimate the actual size of the reservoir at any given time. DENV infection severity is classified according to the World Health Organization (WHO) 1997 and 2009 guidelines [6]. Dengue "without warning signs" (or dengue fever) regroups at-risk individuals with fever and at least two of the following signs and symptoms: nausea/vomiting, rash, headaches, eye pain, muscle aches, joint pain, leukopenia, or positivity at the tourniquet test. Dengue "with warning signs of severe infection" (or dengue hemorrhagic fever) includes in addition to the previous signs and symptoms abdominal pain, persistent vomiting, ascites, pleural effusion, mucosal bleeding, lethargy or restlessness, hepatomegaly, and an increase in hematocrit paired with rapid decrease in platelet count. Lastly, severe dengue (or dengue shock) occurs when the infection leads to severe plasma leakage, massive bleeding, and multiple organ failures. As of now, the therapeutic arsenal against DENV infection is fairly limited and only consists of supportive care and intravenous fluid therapy.From a host-pathogen interaction point of view, it is interesting to note that, in the majority of DENV-...

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New Mouse Model for Dengue Virus Vaccine Testing

Cited by 309 publications

References 28 publications

Inhibition of Dengue and Chikungunya Virus Infections by RIG-I-Mediated Type I Interferon-Independent Stimulation of the Innate Antiviral Response

Inhibition of Dengue and Chikungunya Virus Infections by RIG-I-Mediated Type I Interferon-Independent Stimulation of the Innate Antiviral Response

Structure(s), function(s), and inhibition of the RNA-dependent RNA polymerase of noroviruses

The Interplay between Dengue Virus and the Human Innate Immune System: A Game of Hide and Seek

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