A model of DENV-3 infection that recapitulates severe disease and highlights the importance of IFN-γ in host resistance to infection.
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.
Laboratório de Interação Microrganismo-Hospedeiro, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Vivian V
VV
Costa
Caio T
CT
Fagundes
Deborah F
DF
Valadão
Daniel
D
Cisalpino
Ana Carolina F
AC
Dias
Kátia D
KD
Silveira
Lucas M
LM
Kangussu
Thiago V
TV
Ávila
Maria Rosa Q
MR
Bonfim
Daniela
D
Bonaventura
Tarcília A
TA
Silva
Lirlândia P
LP
Sousa
Milene A
MA
Rachid
Leda Q
LQ
Vieira
Gustavo B
GB
Menezes
Ana Maria
AM
de Paula
Alena
A
Atrasheuskaya
George
G
Ignatyev
Mauro M
MM
Teixeira
Danielle G
DG
Souza
D000220:Adaptation, Biological; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003715:Dengue / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology* / Q000472:pathogenicity*; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000276:immunology; D016019:Survival Analysis
D016207:Cytokines; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse