A model of DENV-3 infection that recapitulates severe disease and highlights the importance of IFN-γ in host resistance to infection.

• Main Authors: Vivian V Costa, Caio T Fagundes, Deborah F Valadão, Daniel Cisalpino, Ana Carolina F Dias, Kátia D Silveira, Lucas M Kangussu, Thiago V Ávila, Maria Rosa Q Bonfim, Daniela Bonaventura, Tarcília A Silva, Lirlândia P Sousa, Milene A Rachid, Leda Q Vieira, Gustavo B Menezes, Ana Maria de Paula, Alena Atrasheuskaya, George Ignatyev, Mauro M Teixeira, Danielle G Souza
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2012-01-01
• Series: PLoS Neglected Tropical Diseases
• Online Access: http://europepmc.org/articles/PMC3362616?pdf=render
• ISSN: 1935-2727; 1935-2735

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-γ 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-γ(-/-) mice, there was enhanced lethality, which was preceded by severe disease manifestation and virus replication. Lack of IFN-γ 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-γ-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.