A Lethal Murine Infection Model for Dengue Virus 3 in AG129 Mice Deficient in Type I and II Interferon Receptors Leads to Systemic Disease

Sarathy, Vanessa V.; White, Mellodee; Li, Li; Gorder, Summer R.; Pyles, Richard B.; Campbell, Gerald A.; Milligan, Gregg N.; Bourne, Nigel; Barrett, Alan D.T.

doi:10.1128/jvi.01320-14

Cited by 77 publications

(123 citation statements)

References 39 publications

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“…Liver sections contained hepatocytes with nuclear pleomorphism and areas of necrosis, similar to the D2Y98P, C0360/94 and 703-4 models (Tan et al, 2010;Sarathy et al, 2015;Milligan et al, 2015). Also, TVP-376 statistical significance (asterisks) between 1 and 2 days p.i.…”

Section: Discussionmentioning

confidence: 60%

“…D2Y98P, D2S10, 703-4 and TVP-376 cause a time-dependent increase of TNF-a, but C0360/94 induces high levels of TNF-a beginning at 1 day p.i. (Tan et al, 2010;Shresta et al, 2006;Milligan et al, 2015;Sarathy et al, 2015). Neutralization of TNF-a in TVP-376-infected mice increased the median survival time from 5 to 13 days p.i.…”

Section: Discussionmentioning

confidence: 95%

“…TNF-a contributes to lethal infection in humans and in AG129 mouse models of DENV-2 (Srikiatkhachorn & Green, 2010;Atrasheuskaya et al, 2003;Shresta et al, 2006;Sarathy et al, 2015). Administration of anti-TNF-a antibody or isotype control (groups of five mice) into AG129 mice infected with TVP-376 resulted in 20 and 0 % survival, respectively; although the treatment increased the median survival time from 5 to 13 days, it was not statistically significant (P50.3383) (Fig.…”

Section: Ag129 Mice Infected With Tvp-376 Develop Increasing Circulatmentioning

confidence: 94%

“…DENV-4 TVP-376 was tested in AG129 mice (6-8 weeks old) at doses comparable with those used for the other AG129 DENV models (Shresta et al, 2006;Sarathy et al, 2015;Milligan et al, 2015). With an inoculum of 10 7.0 p.f.u.…”

Section: Denv-4 Tvp-376 Is Lethal In Ag129 Micementioning

confidence: 99%

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Characterization of lethal dengue virus type 4 (DENV-4) TVP-376 infection in mice lacking both IFN-α/β and IFN-γ receptors (AG129) and comparison with the DENV-2 AG129 mouse model

Sarathy

Infante

et al. 2015

Journal of General Virology

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Dengue is a mosquito-borne disease caused by four related but distinct dengue viruses, DENV-1 to DENV-4. Dengue is endemic in most tropical countries, and over a third of the world's population is at risk of being infected. Although the global burden is high, no vaccine or antiviral is licensed to combat this disease. An obstacle complicating dengue research is the lack of animal challenge models that mimic human disease. Advances in immunocompromised murine infection models resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice, which are deficient in both the IFN-a/b receptor (IFN-a/bR) and the IFN-c receptor (IFN-cR). These models mimic features of dengue disease in humans. Here, we characterized lethal infection of AG129 mice by DENV-4 strain TVP-376 and found that AG129 mice developed clinical signs of illness and high viral loads in multiple tissues and succumbed 5 days after infection. Moreover, the splenic and hepatic histopathology of TVP-376-infected mice demonstrated the presence of cell activation and destruction of tissue architecture. Furthermore, infected mice had heightened levels of circulating cytokines. Comparison of the virulence phenotypes of DENV-4 strain TVP-376 and DENV-2 strain D2S10 revealed that TVP-376-induced mortality occurred in the absence of both IFN-a/bR and IFN-cR signalling, but not with intact signalling from the IFN-cR, whereas D2S10 required the absence of IFN-a/bR signalling only, indicating that it is more virulent than TVP-376. In conclusion, TVP-376 is lethal in AG129 mice, and this model provides a useful platform to investigate vaccine candidates and antivirals against DENV-4.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 95%

Section: Ag129 Mice Infected With Tvp-376 Develop Increasing Circulatmentioning

confidence: 94%

Section: Denv-4 Tvp-376 Is Lethal In Ag129 Micementioning

confidence: 99%

See 2 more Smart Citations

Characterization of lethal dengue virus type 4 (DENV-4) TVP-376 infection in mice lacking both IFN-α/β and IFN-γ receptors (AG129) and comparison with the DENV-2 AG129 mouse model

Sarathy

Infante

et al. 2015

Journal of General Virology

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“…We previously reported the development of AG129 mouse models of lethal disseminated infection using a non-mouse adapted DENV-3 strain, C0360/94 [20], and DENV-4 strains 703/4 and TVP376 [21,22]. To extend the utility of the AG129 mouse for dengue research we describe here the characterization of a model of disseminated lethal DENV-1 disease produced by the non-mouse-adapted DENV-1 strain, West Pacific 74 (WP 74) [23].…”

Section: Introductionmentioning

confidence: 99%

A lethal model of disseminated dengue virus type 1 infection in AG129 mice

Milligan

Sarathy

White

et al. 2017

Journal of General Virology

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The mosquito-borne disease dengue is caused by four serologically and genetically related flaviviruses termed DENV-1 to DENV-4. Dengue is a global public health concern, with both the geographical range and burden of disease increasing rapidly. Clinically, dengue ranges from a relatively mild self-limiting illness to a severe life-threatening and sometimes fatal disease. Infection with one DENV serotype produces life-long homotypic immunity, but incomplete and short-term heterotypic protection. The development of small-animal models that recapitulate the characteristics of the disseminated disease seen clinically has been difficult, slowing the development of vaccines and therapeutics. The AG129 mouse (deficient in interferon alpha/beta and gamma receptor signalling) has proven to be valuable for this purpose, with the development of models of disseminated DENV-2,-3 and -4 disease. Recently, a DENV-1 AG129 model was described, but it requires antibody-dependent enhancement (ADE) to produce lethality. Here we describe a new AG129 model utilizing a non-mouse-adapted DENV-1 strain, West Pacific 74, that does not require ADE to induce lethal disease. Following high-titre intraperitoneal challenge, animals experience a virus infection with dissemination to multiple visceral tissues, including the liver, spleen and intestine. The animals also become thrombocytopenic, but vascular leakage is less prominent than in AG129 models with other DENV serotypes. Taken together, our studies demonstrate that this model is an important addition to dengue research, particularly for understanding the pathological basis of the disease between DENV serotypes and allowing the full spectrum of activity to test comparisons for putative vaccines and antivirals.

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Fingolimod (FTY720), an FDA‐approved sphingosine 1‐phosphate (S1P) receptor agonist, restores endothelial hyperpermeability in cellular and animal models of dengue virus serotype 2 infection

Modak,

Mishra,

Awasthi

et al. 2023

IUBMB Life

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Extensive vascular leakage and shock is a major cause of dengue‐associated mortality. At present, there are no specific treatments available. Sphingolipid pathway is a key player in the endothelial barrier integrity; and is mediated through the five sphingosine‐1‐phosphate receptors (S1PR1‐S1PR5). Signaling through S1PR2 promotes barrier disruption; and in Dengue virus (DENV)‐infection, there is overexpression of this receptor. Fingolimod (FTY720) is a specific agonist that targets the remaining barrier‐protective S1P receptors, without targeting S1PR2. In the present study, we explored whether FTY720 treatment can alleviate DENV‐induced endothelial hyperpermeability. In functional assays, in both in vitro systems and in AG129 animal models, FTY720 treatment was found effective. Upon treatment, there was complete restoration of the monolayer integrity in DENV serotype 2‐infected human microvascular endothelial cells (HMEC‐1). At the molecular level, the treatment reversed activation of the S1P pathway. It significantly reduced the phosphorylation of the key molecules such as PTEN, RhoA, and VE‐Cadherin; and also, the expression levels of S1PR2. In DENV2‐infected AG129 mice treated with FTY720, there was significant improvement in weight gain, in overall clinical symptoms, and in survival. Whereas 100% of the DENV2‐infected, untreated animals died by day‐10 post‐infection, 70% of the FTY720‐treated animals were alive; and at the end of the 15‐day post‐infection observation period, 30% of them were still surviving. There was a significant reduction in the Evan's‐blue dye permeability in the organs of FTY720‐treated, DENV‐2 infected animals; and also improvement in the hemogram, with complete restoration of thrombocytopenia and hepatic function. Our results show that the FDA‐approved molecule Fingolimod (FTY720) is a promising therapeutic intervention in severe dengue.

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A Lethal Murine Infection Model for Dengue Virus 3 in AG129 Mice Deficient in Type I and II Interferon Receptors Leads to Systemic Disease

Cited by 77 publications

References 39 publications

Characterization of lethal dengue virus type 4 (DENV-4) TVP-376 infection in mice lacking both IFN-α/β and IFN-γ receptors (AG129) and comparison with the DENV-2 AG129 mouse model

Characterization of lethal dengue virus type 4 (DENV-4) TVP-376 infection in mice lacking both IFN-α/β and IFN-γ receptors (AG129) and comparison with the DENV-2 AG129 mouse model

A lethal model of disseminated dengue virus type 1 infection in AG129 mice

Fingolimod (FTY720), an FDA‐approved sphingosine 1‐phosphate (S1P) receptor agonist, restores endothelial hyperpermeability in cellular and animal models of dengue virus serotype 2 infection

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