Nitric oxide synthase expression correlates with death in an experimental mouse model of dengue with CNS involvement
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- 作者：Kátia Paulino Ribeiro de Souza (1)
Emanuele Guimar?es Silva (1)
Eliseu Soares de Oliveira Rocha (1)
Leandra Barcelos Figueiredo (1)
Camila Megale de Almeida-Leite (1)
Rosa Maria Esteves Arantes (1)
Juliana de Assis Silva Gomes (1)
Gustavo Portela Ferreira (2)
Jaquelline Germano de Oliveira (3)
Erna Geessien Kroon (1)
Marco Ant?nio Campos (3) - 关键词：Dengue virus ; Murine model ; Neurovirulence ; Neuropathogenesis ; Immunopathogenesis ; Encephalitis ; Nitric oxide synthase 2 ; Nitric oxide ; Interferon gamma
- 刊名：Virology Journal
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：10
- 期：1
- 全文大小：407KB
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Emanuele Guimar?es Silva (1)
Eliseu Soares de Oliveira Rocha (1)
Leandra Barcelos Figueiredo (1)
Camila Megale de Almeida-Leite (1)
Rosa Maria Esteves Arantes (1)
Juliana de Assis Silva Gomes (1)
Gustavo Portela Ferreira (2)
Jaquelline Germano de Oliveira (3)
Erna Geessien Kroon (1)
Marco Ant?nio Campos (3)
1. Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
2. Universidade Federal do Piauí, Parnaíba, Piauí, Brazil
3. Centro de Pesquisas René Rachou, Funda??o Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil - ISSN：1743-422X
文摘
Background The clinical presentation of dengue is classified by the World Health Organization into dengue without warning signs, dengue with warning signs and severe dengue. Reports of neurological disease caused by Dengue virus (DENV) are becoming frequent, with symptoms that include reduced consciousness, severe headache, neck stiffness, focal neurological signs, tense fontanelle and convulsions. However, the immune mechanisms involved in neurovirulence remain poorly understood. Here we present a mouse model in which one genotype of DENV is inoculated by the intracranial route and infects C57/BL6 mice and replicates in the brain, causing death of mice. Methods Mice were infected with different serotypes/genotypes of DENV by the intracranial route to evaluate viral replication, host cytokine and nitric oxide synthase 2 (Nos2) expression in the brain via real-time PCR. Histological analysis of the brain tissues was also performed. An analysis of which cells were responsible for the expression of cytokines and Nos2 was performed using flow cytometry. Survival curves of infected animals were also generated Results DENV 3 genotype I infected mice and replicated in the brain, causing death in our murine model. The increased levels of NOS2 could be the cause of the death of infected mice, as viral replication correlates with increased Nos2 and cytokine expression in the brain of C57BL/6 mice. In Nos2 ??/sup> mice that were infected with DENV, no clinical signs of infection were observed and cytokines were expressed at low levels, with the exception of interferon gamma (Ifng). Additionally, the Ifng ??/sup> mice infected with DENV exhibited a severe and lethal disease, similar to the disease observed in C57BL/6 mice, while the DENV- infected Nos2 ??/sup> mice did not display increased mortality. Analyses of the brains from infected C57BL/6 mice revealed neuronal degeneration and necrosis during histopathologic examination. IFNg and NOS2 were produced in the brains of infected mice by CD4+ T cells and macrophages, respectively. Conclusion The neurovirulence of DENV 3 genotype I is associated with a deleterious role of NOS2 in the brain, confirming this murine model as an appropriate tool to study DENV neurovirulence.