Antibodies Against Modified NS1 Wing Domain Peptide Protect Against Dengue Virus Infection

Lai, Yu-Cheng; Chuang, Yung Chun; Liu, Ching Chuan; Ho, Tzong Shiann; Lin, Yee Shin; Anderson, Robert; Yeh, Trai Ming

doi:10.1038/s41598-017-07308-3

Cited by 72 publications

(84 citation statements)

References 54 publications

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“…Lack of protective NS1 immunity is independent of mouse background Previous studies that reported NS1-mediated protection were conducted in mouse strains such as IFNAR −/− ; Beatty et al, 2015) and STAT1 −/− (Wan et al, 2017;Lai et al, 2017), both on the C57BL/6 background. We thus questioned whether the discrepancy between our observations and the earlier studies could be explained by a difference in mouse background.…”

Section: Resultsmentioning

confidence: 99%

Relative contribution of nonstructural protein 1 in dengue pathogenesis

Lee

Ting

Boey

et al. 2020

Journal of Experimental Medicine

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Dengue is a major public health concern in the tropical and subtropical world, with no effective treatment. The controversial live attenuated virus vaccine Dengvaxia has boosted the pursuit of subunit vaccine approaches, and nonstructural protein 1 (NS1) has recently emerged as a promising candidate. However, we found that NS1 immunization or passive transfer of NS1 antibodies failed to confer protection in symptomatic dengue mouse models using two non–mouse-adapted DENV2 strains that are highly virulent. Exogenous administration of purified NS1 also failed to worsen in vivo vascular leakage in sublethally infected mice. Neither method of NS1 immune neutralization changed the disease outcome of a chimeric strain expressing a vascular leak-potent NS1. Instead, virus chimerization involving the prME structural region indicated that these proteins play a critical role in driving in vivo fitness and virulence of the virus, through induction of key proinflammatory cytokines. This work highlights that the pathogenic role of NS1 is DENV strain dependent, which warrants reevaluation of NS1 as a universal dengue vaccine candidate.

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Section: Resultsmentioning

confidence: 99%

Relative contribution of nonstructural protein 1 in dengue pathogenesis

Lee

Ting

Boey

et al. 2020

Journal of Experimental Medicine

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“…Consequently, NS1 may represent an important viral factor that causes vascular leakage and glycocalyx degradation during DENV infection. Indeed, antibodies against NS1 have been shown to be protective against DENV infection in mice [ 17 , 51 , 52 ]. Furthermore, MIF may represent the primary host factor that mediates NS1-induced glycocalyx degradation.…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability

et al. 2018

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Vascular leakage is one of the salient characteristics of severe dengue. Nonstructural protein 1 (NS1) of dengue virus (DENV) can stimulate endothelial cells to secrete endothelial hyperpermeability factor, macrophage migration inhibitory factor (MIF), and the glycocalyx degradation factor heparanase 1 (HPA-1). However, it is unclear whether MIF is directly involved in NS1-induced glycocalyx degradation. In this study, we observed that among NS1, MIF and glycocalyx degradation-related molecules, the HPA-1, metalloproteinase 9 (MMP-9) and syndecan 1 (CD138) serum levels were all increased in dengue patients, and only NS1 and MIF showed a positive correlation with the CD138 level in severe patients. To further characterize and clarify the relationship between MIF and CD138, we used recombinant NS1 to stimulate human cells in vitro and challenge mice in vivo. Our tabulated results suggested that NS1 stimulation could induce human endothelial cells to secrete HPA-1 and immune cells to secrete MMP-9, resulting in endothelial glycocalyx degradation and hyperpermeability. Moreover, HPA-1, MMP-9, and CD138 secretion after NS1 stimulation was blocked by MIF inhibitors or antibodies both in vitro and in mice. Taken together, these results suggest that MIF directly engages in dengue NS1-induced glycocalyx degradation and that targeting MIF may represent a possible therapeutic approach for preventing dengue-induced vascular leakage.

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“…To quantify the monocyte infiltration in brain tissues, the slices of brain tissues were first received immunohistochemistry (IHC) staining with anti-Ly6C antibody (Abcam), and then the degree of monocytes infiltration was digitally quantified by ImageJ software [ 45 – 47 ]. In brief, the staining patterns of Ly6C were detected by EVOS FL Cell Imaging System (Thermo Fisher Scientific), and the blot signals from the digital images were further analyzed by Image J software (NIH, USA).…”

Section: Methodsmentioning

confidence: 99%

ICR suckling mouse model of Zika virus infection for disease modeling and drug validation

Tseng

Lin

et al. 2018

PLoS Negl Trop Dis

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BackgroundZika virus (ZIKV) infection causes diseases ranging from acute self-limiting febrile illness to life-threatening Guillain–Barré Syndrome and other neurological disorders in adults. Cumulative evidence suggests an association between ZIKV infection and microcephaly in newborn infants. Given the host-range restrictions of the virus, a susceptible animal model infected by ZIKV must be developed for evaluation of vaccines and antivirals. In this study, we propose a convenient mouse model for analysis of neurological disorders caused by ZIKV.MethodologySix-day-old immunocompetent ICR suckling mice were used in the experiment. Different inoculum virus concentrations, challenge routes, and challenge times were assessed. Viremic dissemination was determined in the liver, spleen, kidney, and brain through Western blot assay, plaque assay, absolute quantification real-time PCR, and histological observation. Azithromycin, a well-characterized anti-ZIKV compound, was used to evaluate the ICR suckling mouse model for antiviral testing.ConclusionsSigns of illness and neurological disease and high mortality rate were observed in mice injected with ZIKV intracerebrally (102 to 105) and intraperitoneally (103 to 105). Viremic dissemination was observed in the liver, spleen, kidney, and brain. ZIKV transmitted, rapid replicated, and induced monocyte infiltration into the brain approximately 5 to 6 days post inoculum. Azithromycin conferred protection against ZIKV-caused neurological and life-threatening diseases. The developed model of ZIKV infection and disease can be used for screening drugs against ZIKV and discovering the underlying mechanism of ZIKV pathogenesis.

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Antibodies Against Modified NS1 Wing Domain Peptide Protect Against Dengue Virus Infection

Cited by 72 publications

References 54 publications

Relative contribution of nonstructural protein 1 in dengue pathogenesis

Relative contribution of nonstructural protein 1 in dengue pathogenesis

Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability

ICR suckling mouse model of Zika virus infection for disease modeling and drug validation

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