Modulation of Dengue Virus Infection in Human Cells by Alpha, Beta, and Gamma Interferons

Diamond, Michael S.; Roberts, T. Guy; Edgil, Dianna; Lu, Betty; Ernst, Joel D.; Harris, Eva

doi:10.1128/jvi.74.11.4957-4966.2000

Cited by 301 publications

(242 citation statements)

References 45 publications

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“…In cell culture, DENV is sensitive to type I IFN (29) (Fig. 1F), and type I and II IFN receptor-deficient mice are highly susceptible to DENV infection (22) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dengue reporter viruses reveal viral dynamics in interferon receptor-deficient mice and sensitivity to interferon effectors in vitro

Schoggins

Dorner

Feulner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

172

175

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Dengue virus (DENV) is a global disease threat for which there are no approved antivirals or vaccines. Establishing state-of-the-art screening systems that rely on fluorescent or luminescent reporters may accelerate the development of anti-DENV therapeutics. However, relatively few reporter DENV platforms exist. Here, we show that DENV can be genetically engineered to express a green fluorescent protein or firefly luciferase. Reporter viruses are infectious in vitro and in vivo and are sensitive to antiviral compounds, neutralizing antibodies, and interferons. Bioluminescence imaging was used to follow the dynamics of DENV infection in mice and revealed that the virus localized predominantly to lymphoid and gut-associated tissues. The high-throughput potential of reporter DENV was demonstrated by screening a library of more than 350 IFN-stimulated genes for antiviral activity. Several antiviral effectors were identified, and they targeted DENV at two distinct life cycle steps. These viruses provide a powerful platform for applications ranging from validation of vaccine candidates to antiviral discovery. Flaviviridae family that causes significant morbidity and mortality worldwide. Each year, over 50 million people are affected by dengue fever, and ∼500,000 are hospitalized with the more severe dengue hemorrhagic fever (1). The virus is endemic to tropical environments in Southeast Asia, the Pacific, and the Americas, and has recently reemerged as far north as southern Florida (2). Currently, no vaccines or antivirals have been approved for prevention or treatment of DENV infection.Four genetically and antigenically distinct DENV serotypes circulate, and each can be isolated from infected human sera and propagated in cell culture. The pathogenesis and immune response to patient-derived virus can be studied in vitro and in vivo by quantifying viral genomes or antigens. These detection methods are also used to study the molecular virology of DENV with reagents such as virus-like particles (VLPs) and subgenomic replicons. In some cases, VLPs and subgenomic replicons have been engineered to take advantage of reporter proteins, such as luciferase, which can be used in high-throughput screening platforms for discovery of inhibitors of viral entry or replication (3). A caveat to these tools is the inability to fully recapitulate the entire viral life cycle. This can be overcome by launching virus production from full-length infectious molecular clones, which have been generated for DENV serotypes 1, 2, and 4 (4-6).Full-length flavivirus infectious clones are often difficult to work with, largely due to instability in various bacterial cell lines and the inability to rescue sufficient quantities of DNA for downstream applications (7). Additionally, mutagenesis of viral sequences may result in disruption of the various long-range interactions required for establishment of a productive replication complex (8-10). Thus, strategies to generate infectious viruses expressing heterologous sequences have to contend with both sub...

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“…In cell culture, DENV is sensitive to type I IFN (29) (Fig. 1F), and type I and II IFN receptor-deficient mice are highly susceptible to DENV infection (22) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dengue reporter viruses reveal viral dynamics in interferon receptor-deficient mice and sensitivity to interferon effectors in vitro

Schoggins

Dorner

Feulner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

172

175

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“…IFNs are classically known as antiviral molecules and some reports confirm that flaviviruses are susceptible to these molecules (Roers et al 1994, Diamond et al 2000. Indeed, these viruses stimulate IFN-α production (Libraty et al 2001, Deauvieau et al 2007, Palmer et al 2007, Querec et al 2009), although IFN-α induction was not compared between viruses in previous reports.…”

Section: Discussionmentioning

confidence: 96%

Dengue-2 and yellow fever 17DD viruses infect human dendritic cells, resulting in an induction of activation markers, cytokines and chemokines and secretion of different TNF-α and IFN-α profiles

Gandini

Reis

Torrentes-Carvalho

et al. 2011

Mem. Inst. Oswaldo Cruz

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Flaviviruses cause severe acute febrile and haemorrhagic infections, including dengue and yellow fever and the pathogenesis of these infections is caused by an exacerbated immune response. Dendritic cells (DCs) are targets for dengue virus (DENV) and yellow fever virus (YF) replication and are the first cell population to interact with these viruses during a natural infection, which leads to an induction of protective immunity in humans. We studied the infectivity of DENV2 (strain 16681), a YF vaccine (YF17DD) and a chimeric YF17D/DENV2 vaccine in monocytederived DCs in vitro with regard to cell maturation, activation and cytokine production. Higher viral antigen positive cell frequencies were observed for DENV2 when compared with both vaccine viruses. Flavivirus-infected cultures exhibited dendritic cell activation and maturation molecules. CD38 expression on DCs was enhanced for both DENV2 and YF17DD, whereas OX40L expression was decreased as compared to mock-stimulated cells, suggesting that a T helper 1 profile is favoured. Tumor necrosis factor (TNF)-α production in cell cultures was significantly higher in DENV2-infected cultures than in cultures infected with YF17DD or YF17D/DENV. In contrast, the vaccines induced higher IFN-α levels than DENV2. The differential cytokine production indicates that DENV2 results in TNF induction, which discriminates it from vaccine viruses that preferentially stimulate interferon expression. These differential response profiles may influence the pathogenic infection outcome.Key words: cytokines -dendritic cells -dengue virus -yellow fever vaccine -flavivirus dendritic cell activation by flavivirus • Mariana Gandini et al.

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“…If the viruses do not grow well or form plaques, the best measuring tests are quantitative RT-PCR of viral RNA or flow cytometry of infected cells [3]. Three studies have demonstrated that dengue virus isolates vary in their capacity to infect the same cell type in vitro, depending on virus genotype and passage history [4][5][6]. The first targets of dengue virus replication, after mosquito bite, were postulated to be monocytes or macrophages and numerous studies focused on this cell lineage.…”

Section: In Vitro Modelsmentioning

confidence: 99%

Models of dengue virus infection

Bente

Rico-Hesse

2006

Drug Discovery Today: Disease Models

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The need for models of dengue disease has reached a pinnacle as the transmission of this mosquitoborne virus has increased dramatically. Little is known about the mechanisms that lead to dengue fever and its more severe form, dengue hemorrhagic fever; this is owing to the fact that only humans show signs of disease. In the past 5 years, research has better identified the initial target cells of infection, and this has led to the development of models of infection in primary human cell cultures. Mouse-human chimeras, containing these target cells, have also led to progress in developing animal models. These advances should soon end the stalemate in testing antivirals and vaccine preparations that had necessarily been done in incomplete or irrelevant models.

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Modulation of Dengue Virus Infection in Human Cells by Alpha, Beta, and Gamma Interferons

Abstract: A role for interferon (IFN) in modulating infection

Cited by 301 publications

References 45 publications

Dengue reporter viruses reveal viral dynamics in interferon receptor-deficient mice and sensitivity to interferon effectors in vitro

Dengue reporter viruses reveal viral dynamics in interferon receptor-deficient mice and sensitivity to interferon effectors in vitro

Dengue-2 and yellow fever 17DD viruses infect human dendritic cells, resulting in an induction of activation markers, cytokines and chemokines and secretion of different TNF-α and IFN-α profiles

Models of dengue virus infection

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