Interleukin‐33 contributes to disease severity in Dengue virus infection in mice

Abstract

The excessive inflammation often present in patients with severe dengue infection is considered both a hallmark of disease and a target for potential treatments. Interleukin-33 (IL-33) is a pleiotropic cytokine with pro-inflammatory effects whose role in dengue has not been fully elucidated. We demonstrate that IL-33 plays a disease-exacerbating role during experimental dengue infection in immunocompetent mice. Mice infected with dengue virus serotype 2 (DENV2) produced high levels of IL-33. DENV2-infected mice treated with recombinant IL-33 developed markedly more severe disease compared with untreated mice as assessed by mortality, granulocytosis, liver damage and pro-inflammatory cytokine production. Conversely, ST2 mice (deficient in IL-33 receptor) infected with DENV2 developed significantly less severe disease compared with wild-type mice. Furthermore, the increased disease severity and the accompanying pathology induced by IL-33 during dengue infection were reversed by the simultaneous treatment with a CXCR2 receptor antagonist (DF2156A). Together, these results indicate that IL-33 plays a disease-exacerbating role in experimental dengue infection, probably driven by CXCR2-expressing cells, leading to elevated pro-inflammatory response-mediated pathology. Our results also indicate that IL-33 is a potential therapeutic target for dengue infection.

Accuracy of the SD BIOLINE Dengue Duo for rapid point-of-care diagnosis of dengue

“…In our study, dengue confirmed cases were outpatients with mild disease. In contrast, the majority of the other studies were conducted on hospitalized patients, which usually manifest greater disease severity and duration, consequently influencing the intensity of inflammatory and immune response [22–24]. Yet, a previous evaluation of this RDT in Cambodia, enrolling children hospitalized due to a febrile illness of no clear source, showed an overall low sensitivity (57.8%) [21].…”

Rousette Bat Dendritic Cells Overcome Marburg Virus-Mediated Antiviral Responses by Upregulation of Interferon-Related Genes While Downregulating Proinflammatory Disease Mediators

“…IL-33 is centrally important in dengue virus infection and is strongly upregulated in mice that develop disease. The addition of recombinant exogenous IL-33 in dengue virus-infected mice resulted in severe disease with proinflammatory cytokine production and liver damage; thus, neutralization of IL-33 has been proposed as a target for therapeutics (36). The release of IL-33 is also important for responses to malaria and hepatotropic viruses, where high levels of IL-33 correlate with hepatic damage in humans (37).…”

Dengue mouse models for evaluating pathogenesis and countermeasures

“…Moreover, vascular leakage is not observed in these DENV-infected immunocompetent mice. Although one group has reported a model of severe systemic disease in wild-type mice after infection with mouse-adapted DENV-2 and DENV-3 strains and used it to define mechanisms of immune control [29][30][31][32], these results have not been confirmed by independent groups. Thus, the utility of immunocompetent mice for studying DENV infection, pathogenesis, and disease remains limited.…”