Peripheral effects induced in BALB/c mice infected with DENV by the intracerebral route

Abstract

The lack of an immunocompetent animal model for dengue mimicking the disease in humans is a limitation for advances in this field. Inoculation by intracerebral route of neuroadapted dengue strains in mice is normally lethal and provides a straightforward readout parameter for vaccine testing. However, systemic effects of infection and the immune response elicited in this model remain poorly described. In the present work, BALB/c mice infected by the intracerebral route with neuroadapted DENV2 exhibited several evidences of systemic involvement. DENV-inoculated mice presented virus infective particles in the brain followed by viremia, especially in late stages of infection. Infection induced cellular and humoral responses, with presence of activated T cells in spleen and blood, lymphocyte infiltration and tissue damages in brain and liver, and an increase in serum levels of some pro-inflammatory cytokines. Data highlighted an interplay between the central nervous system commitment and peripheral effects under this experimental condition.

Intracranial Injection of Dengue Virus Induces Interferon Stimulated Genes and CD8+ T Cell Infiltration by Sphingosine Kinase 1 Independent Pathways

“…Following DENV-2 infection, as expected, WT and SK1 -/mice exhibited body weight loss and signs of neurovirulence compared to mock-infected mice. This reflects the pathogenicity and virulence of the DENV-2 MON 601 strain in mouse brain, as has been previously reported [29,34]. Similar to other studies of DENV ic infection, not all mice develop neurological symptoms [29,34].…”

“…This reflects the pathogenicity and virulence of the DENV-2 MON 601 strain in mouse brain, as has been previously reported [29,34]. Similar to other studies of DENV ic infection, not all mice develop neurological symptoms [29,34]. We have further shown here that symptomatic DENV-infection with body weight loss and neurological signs is positively associated with the level of DENV RNA in the brain with a lower level of DENV RNA in the brains of asymptomatic mice at 9-14 dpi.…”

“…We demonstrated a marked cell infiltrate in DENV-infected mouse brain by H&E staining and further characterised the nature of this cellular infiltrate as CD8+ but not CD4+ T-cells by RT-PCR analysis, although we did not analyse the presence of monocytes, a cell type also known to infiltrate the brain in WNV infection [59,60]. A prior study has shown both CD4+ and CD8+ T cells infiltration into the brain following DENV-3 challenge in C57BL/6 mice [25], or DENV-2 challenge in BALB/c mice [34]. Further, Hsieh et al showed predominant CD8+ compared to CD4+ T cell infiltration in DENV-infected mouse brain [38].…”

Desenvolvimento de modelo experimental de infecção pelo vírus da dengue em camundongos.

“…com o JHA1 e redução plaquetária transiente (principal marcador de dengue com sinais de alarme em humanos) JOHN;ABRAHAM;GUBLER, 2013;NOISAKRAN;PERNG, 2008). No entanto, não foram observados sinais de morbidade como arqueamento de coluna, paralisia de membros e letargia, como geralmente é visto em camundongos infectados com linhagens de DENV adaptadas para o hospedeiro murino OLIVEIRA et al, 2016;TAN et al, 2010 .…”

“…permanece como um obstáculo no sentido de aproximar o modelo a condições mais semelhantes àquelas observadas em condições naturais. De fato, como ressaltado por vários autores, a busca de modelos animais mais adequados para estudos com DENV ainda é considerada uma prioridade para a área (MARCOS et al, 2016;OLIVEIRA et al, 2016;SARATHY et al, 2015a). Deste modo, a realização do presente projeto teve como objetivo inicial contribuir para a geração de dados que auxiliem no desenvolvimento de um modelo experimental de infecção em camundongos imunocompetentes por DENV, sem a necessidade de adaptação do vírus ou administração de grandes quantidades de vírus.…”