Immunological and Pathological Landscape of Dengue Serotypes 1-4 Infections in Immune-Competent Mice

Abstract

Dengue virus (DENV), a Flavivirus, causes a broad spectrum of disease in humans with key clinical signs including thrombocytopenia, vascular leakage and hemorrhaging. A major obstacle to understanding DENV immunity has been the lack of a validated immune-competent mouse model. Here, we report the infection profiles of human clinical isolates of DENV serotypes 1-4 in an immune-competent mouse model. We detected replicating DENV in the peritoneal cells, liver and the spleen that was generally resolved within 2 weeks. The DENV target cell types for infection were monocytes/macrophages, dendritic cells, endothelial cells, and we identified a novel DENV cellular target, fibroblast reticular cells of the spleen. We observed gross pathologies in the spleen and liver that are consistent with dengue disease, including hemorrhaging as well as transcriptional patterns suggesting that antiviral responses and tissue damage were induced. Key clinical blood parameters that define human DENV disease such as hemoconcentration, leukopenia and reduced number of platelets were also observed. Thus, immune-competent mice sustain replicating infection and experience signs, such as hemorrhaging, that define DENV disease in humans. This study thoroughly characterizes DENV1-4 infection in immune-competent mice and confirms the wild-type mouse model as a valid and reproducible system for investigating the mechanisms of DENV pathogenesis.

Discrepant Activation Pattern of Inflammation and Pyroptosis Induced in Dermal Fibroblasts in Response to Dengue Virus Serotypes 1 and 2 and Nonstructural Protein 1

“…Importantly, DENV-2 induced high levels of expression of these transcripts in 24 to 72 h of infection; however, in the case of DENV-1, excess levels of these transcripts were observed after 72 h of infection. These data are partly supported by an infection model in immunocompetent wild-type mice, which show a stronger IFN-associated innate immune response to DENV-2 infection but weaker response to DENV-1 infection at the early infection phase ( 28 ). Our data might reflect the pathogenic differences between DENV-1 and DENV-2 infections.…”

Dengue virus infection modifies mosquito blood-feeding behavior to increase transmission to the host

“…To evaluate virus multiplication and transmission, we quantified DENV in the skin and draining lymph nodes 24 h postprobing. Importantly, we used immuno-competent mice (wild-type C57BL/6) that we previously used to evaluate immune response to DENV inoculation ( 44 , 45 ) but not as a model for virus transmission by mosquitoes. As DENV is susceptible to the murine immune response, its infectivity is usually evaluated in an immuno-compromised mouse model ( 46 ).…”

Role of glycolysis in myeloid cells during dengue infection

“…In order to address this, some groups started to use immunocompetent mice with type I IFN receptors knocked out only in specific cell types (295,296). Zust mice infected with strains from EDEN (298) had viral load in peritoneum, spleen and liver (299). They also showed DENV-infected WT mice thrombocytopenia, leukopenia and increase hematocrit which resembles DENV-infection in humans.…”