A Nuclear Transport Inhibitor That Modulates the Unfolded Protein Response and Provides In Vivo Protection Against Lethal Dengue virus Infection

Fraser, Johanna E.; Watanabe, Sumio; Wang, Chunxiao; Chan, Wing Ki; Maher, Belinda; López-Denman, Adam J.; Hick, Caroline A.; Wagstaff, Kylie M.; Mackenzie, Jason M.; Sexton, Patrick M.; Vasudevan, Subhash G.; Jans, David A.

doi:10.1093/infdis/jiu319

Cited by 89 publications

(111 citation statements)

References 49 publications

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“…Although 4-HPR is known to affect several different cellular pathways, the recent study by Fraser et al (62) showing that 4-HPR inhibits the interaction of the DENV NS5 protein with nuclear importin-␣/␤1 in a biochemical assay and also activates the unfolded protein response in DENV-infected cells (62) is particularly noteworthy. Preliminarily, our observation of the immunofluorescence of the nuclear NS5 protein in cells treated with 4-HPR (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…While our study focused on quantifying the effect of 4-HPR on DENV replication in vivo, the study by Fraser et al (62) documented the effect of 4-HPR on survival in another murine model of DENV infection without measuring the effect of the compound on viremia or viral burden. Although neither study (50 mg/kg) as an oral suspension to AG129 mice infected with DENV-2 D2Y98P.…”

Section: Discussionmentioning

confidence: 99%

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The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication

Carocci

Hinshaw

Rodgers

et al. 2015

Antimicrob Agents Chemother

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Dengue virus (DENV) is a mosquito-borne pathogen that is the causative agent of dengue fever. Severe dengue virus infection is potentially fatal due to hemorrhaging, plasma leakage, and pulmonary shock. The four serotypes of DENV (DENV-1 to DENV-4) are defined by antigenic differences on the viral envelope protein, E, and together, they comprise a species within the Flavivirus genus of the Flaviviridae family. This family of small enveloped viruses with positive-sense RNA genomes encompasses other human pathogens, including West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), and hepatitis C virus (HCV). A recent evidence-based study suggests that approximately 300 million DENV infections occur annually (1), and no vaccine or specific antiviral drug is currently available to treat it. DENV vaccine development is a major challenge due to the antibody-dependent enhancement of infection, a phenomenon in which neutralizing antibodies against one DENV serotype can exacerbate disease upon subsequent infection with another serotype (2, 3). A parallel exploration of antiviral strategies to combat DENV infection is therefore crucial.Resistance to antiviral drugs that act against viral targets occurs rapidly due to the intrinsically high mutation rate of RNA virus polymerases. Host-targeted antivirals that can complement these more traditional antivirals may make the acquisition of resistance to antiviral drugs much less likely and may also offer broad-spectrum activity against phylogenetically related viruses. The interactions between DENV and host lipid biosynthetic, metabolic, trafficking, and signal transducing pathways represent a rich and largely unexplored class of targets for host-targeted antiviral strategies. DENV and other RNA viruses rely entirely on host lipids to supply the membranes essential for the viral replication cycle, and the interaction of viruses with lipid-related processes in the host cell is highlighted by recent studies documenting specific perturbations of these pathways by viruses (4). In addition, so-called bioactive lipids can regulate cellular processes by modulating signal transduction cascades that may impinge on viral infection. Thus, small molecules that act on host-cell lipid signaling and metabolism are attractive as potential anti-DENV compounds.To pursue the strategy of targeting host lipid metabolic and signaling pathways important for DENV infection, we screened a panel of bioactive lipids and small-molecule inhibitors of lipid metabolism for activity against DENV. We chose a library enriched for compounds with known safety and bioavailability profiles to increase our likelihood of identifying clinically useful anti-DENV compounds. We present here the identification of the bioactive lipid 4-hydroxyphenyl retinamide (4-HPR) as an inhib-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication

Carocci

Hinshaw

Rodgers

et al. 2015

Antimicrob Agents Chemother

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“…As this model clearly showed the effect of ADE in vivo, we used this mouse system for the study of DENV pathogenesis (33) and the evaluation of therapeutic candidates (34)(35)(36). In the present study, in order to address the relationship between the neutralizing activity of Abs and dengue disease severity, we take a reductionist approach to examine the conditions where neutralizing levels of Abs at the time of infection cause severe disease progression in mice.…”

Section: Inoculation With Highly Neutralized Ics Causes Lethal Diseasmentioning

confidence: 99%

Dengue Virus Infection with Highly Neutralizing Levels of Cross-Reactive Antibodies Causes Acute Lethal Small Intestinal Pathology without a High Level of Viremia in Mice

Watanabe

Chan

Wang

et al. 2015

J Virol

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107

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Severe dengue virus (DENV)-associated diseases can occur in patients who have preexisting DENV antibodies (Abs) through antibody-dependent enhancement (ADE) of infection. It is well established that during ADE, DENV-antibody immune complexes (ICs) infect Fc␥ receptor-bearing cells and increase the systemic viral burden that can be measured in the blood. For protection against infection with DENV serotypes 1 to 4, strongly neutralizing Abs must be elicited to overcome the effect of ADE. Clinical observations in infants who have maternal DENV Abs or recent phase II/III clinical trials with a leading tetravalent dengue vaccine suggested a lack of correlation between Ab neutralization and in vivo disease prevention. In addressing this gap in knowledge, we found that inoculation of ICs formed with serotype cross-reactive Abs that are more than 98% neutralized in vitro promotes high mortality in AG129 mice even though peak viremia was lower than that in direct virus infection. This suggests that the serum viremia level is not always correlated with disease severity. We further demonstrated that infection with the ICs resulted in increased vascular permeability, specifically in the small intestine, accompanied with increased tissue viral load and cytokine production, which can be suppressed by anti-tumor necrosis factor alpha (anti-TNF-␣) Abs. Flow cytometric analysis identified increased infection in CD11b int CD11c int/hi CD103 ؊ antigen-presenting cells by IC inoculation, suggesting that these infected cells may be responsible for the increase in TNF-␣ production and vascular permeability in the small intestine that lead to mortality in mice. Our findings may have important implications for the development of dengue therapeutics. IMPORTANCEWe examined the relationship between the neutralizing level of Abs at the time of infection and subsequent disease progression in a mouse model in order to understand why patients who are shown to have a neutralizing quantity of Abs still allow sufficient DENV replication to induce severe dengue manifestations, which sometimes do not correlate with viremia level. Strikingly, we found that high mortality was induced in AG129 mice by the increase in TNF-␣-induced vascular permeability accompanied by an increased viral load, specifically in the small intestine, even when the initial infection level is suppressed to less than 5% and the peak viremia level is not enhanced. This suggests that ADE overcomes the protective efficacy of Abs in a tissue-dependent manner that leads to severe small intestinal pathology. Our findings may serve to address the pathogenic role of Abs on severe dengue disease and also help to develop safe Ab-based therapeutic strategies. D engue virus (DENV) infection with any of the 4 related viral serotypes (DENV1 to DENV4) causes a variety of clinical manifestations, ranging from self-limiting febrile illness, known as dengue fever (DF), to the life-threatening severe diseases, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), charac...

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“…Non-nucleoside inhibitors bind to an allosteric sites away from the active site and affect the enzymatic activity of RdRp (Niyomrattanakit et al, 2010). Nonnucleoside inhibitors could also inhibit viral replication through blocking the binding between RdRp and other viral replication components as well as host factors (Fraser et al, 2014). In the case of HCV, several allosteric sites (such as Palm I, Palm II, Thumb I and Thumb II sites) have been identified and explored for the development of non-nucleoside inhibitors (Beaulieu 2009).…”

Section: Introductionmentioning

confidence: 99%