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

Abstract

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.

Markers of dengue severity: a systematic review of cytokines and chemokines

“…Reports from humans and from animal models suggest that IFNg controls infections through viral clearance and limiting virus replication (Costa et al, 2012;Horras et al, 2011;Pal et al, 2014;Shresta et al, 2004). Notably, dengue viral titres correlate with disease severity (Endy et al, 2004;Vaughn et al, 2000), but are plausibly influenced by DENV type and infection status (Duyen et al, 2011).…”

“…Levels of IFNg can be attenuated by IL-10 through SOCS-3 blockage of STAT1-IFNg receptor interaction in intrinsic ADE-DENV infection (Chareonsirisuthigul et al, 2007;Ubol et al, 2010). Indeed, the absence of IFNg in a mouse model of dengue led to primary dengue-infection-induced lethality (Costa et al, 2012). Thus, depending on the infection status and DENV type, in combination with timing of IL-10 production, IFNg levels may be affected, leading to altered viral clearance, prolonged infection and consequently determining disease severity.…”

“…One promising example is TNFa, which was reported to induce endothelial cell apoptosis and was also noted in this review as an elevated cytokine in DHF. Other potential circulating markers of dengue severity, such as proteases (Koraka et al, 2010;St John et al, 2013;van de Weg et al, 2014), soluble adhesion molecules (Cardier et al, 2006) or metabolites (Cui et al, 2013(Cui et al, , 2016, may show potential as alternative soluble prognostic markers of SD, but face similar challenges in the extensive demands of large study cohorts. Capturing soluble factors that correlate and potentially foretell pathognomonic symptoms may not only increase the specificity and sensitivity of prognosing SD, but also avoid the non-specific 'cytokine storms' observed in other acute infectious diseases, such as influenza and malaria (Clark, 2007).…”

Subversion of early innate antiviral responses during antibody-dependent enhancement of Dengue virus infection induces severe disease in immunocompetent mice

“…the hybridoma of mab clone 2.4g2 from atCC was purchased from the rio de Janeiro cell Bank, grown in serumfree medium (Cultilab) and purified as described previously. For in vivo experiments, Denv-2 and Denv-3 strains previously adapted to mice [34,35], respectively, were propagated in vero cells, and the supernatants of infected cells were harvested, filtered, tittered by plaque assay in vero cells and stored at −70 °C until use. all in vivo studies with the infectious viruses were performed in a Bsl-2 facility of the laboratório de Interação Microrganismo-Hospedeiro-ICB-UFMg.…”

“…We conducted experiments in mice infected with adapted strains of Denv-2 and Denv-3 that were previously shown to induce in immunocompetent mice a disease that resembles the severe dengue manifestations found in humans [33][34][35]. We demonstrate that, although B cells are pivotal for host resistance to primary Denv infection, passive transfer of anti-Denv-immune serum or subneutralizing monoclonal antibodies leads to the enhancement of Denv infection and replication as well as the occurrence of severe disease manifestations in mice.…”