Characterization of lethal dengue virus type 4 (DENV-4) TVP-376 infection in mice lacking both IFN-α/ß and IFN-γ receptors (AG129) and comparison with the DENV-2 AG129 mouse model.
J Gen Virol
; 96(10): 3035-3048, 2015 Oct.
Article
em En
| MEDLINE
| ID: mdl-26296350
ABSTRACT
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-α/ß receptor (IFN-α/ßR) and the IFN-γ receptor (IFN-γR). 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 5âdays 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-α/ßR and IFN-γR signalling, but not with intact signalling from the IFN-γR, whereas D2S10 required the absence of IFN-α/ßR 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de Interferon
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Dengue
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Modelos Animais de Doenças
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Receptor de Interferon alfa e beta
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article