A Model of DENV-3 Infection That Recapitulates Severe Disease and Highlights the Importance of IFN-gamma in Host Resistance to Infection

作者：Costa Vivian V^*; Fagundes Caio T; Valadao Deborah F; Cisalpino Daniel; Dias Ana Carolina F; Silveira Katia D; Kangussu Lucas M; Avila Thiago V; Bonfim Maria Rosa Q; Bonaventura Daniela; Silva Tarcilia A; Sousa Lirlandia P; Rachid Milene A; Vieira Leda Q; Menezes Gustavo B; de Paula Ana Maria; Atrasheuskaya Alena; Ignatyev George; Teixeira Mauro M; Souza Danielle G

来源：PLoS Neglected Tropical Diseases, 2012, 6(5): e1663.

DOI：10.1371/journal.pntd.0001663

There are few animal models of dengue infection, especially in immunocompetent mice. Here, we describe alterations found in adult immunocompetent mice inoculated with an adapted Dengue virus (DENV-3) strain. Infection of mice with the adapted DENV-3 caused inoculum-dependent lethality that was preceded by several hematological and biochemical changes and increased virus dissemination, features consistent with severe disease manifestation in humans. IFN-gamma expression increased after DENV-3 infection of WT mice and this was preceded by increase in expression of IL-12 and IL-18. In DENV-3-inoculated IFN-gamma(-/-) mice, there was enhanced lethality, which was preceded by severe disease manifestation and virus replication. Lack of IFN-gamma production was associated with diminished NO-synthase 2 (NOS2) expression and higher susceptibility of NOS2(-/-) mice to DENV-3 infection. Therefore, mechanisms of protection to DENV-3 infection rely on IFN-gamma-NOS2-NO-dependent control of viral replication and of disease severity, a pathway showed to be relevant for resistance to DENV infection in other experimental and clinical settings. Thus, the model of DENV-3 infection in immunocompetent mice described here represents a significant advance in animal models of severe dengue disease and may provide an important tool to the elucidation of immunopathogenesis of disease and of protective mechanisms associated with infection.

• 出版日期2012-5