Abstract
ABSTRACTThere are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors. DENV infections can lead to vascular complications, hemorrhage, and shock due to the ability of DENV to infect a variety of immune and nonimmune cell populations. Increasingly, studies have implicated the host response as a major contributor to severe disease. Inflammatory products of various cell types, including responding T cells, mast cells (MCs), and infected monocytes, can contribute to immune pathology. In this study, we show that the host response to DENV infection in immunocompetent mice recapitulates transcriptional changes that have been described in human studies. We found that DENV infection strongly induced metabolic dysregulation, complement signaling, and inflammation. DENV also affected the immune cell content of the spleen and liver, enhancing NK, NKT, and CD8+ T cell activation. The MC-stabilizing drug ketotifen reversed many of these responses without suppressing memory T cell formation and induced additional changes in the transcriptome and immune cell composition of the spleen, consistent with reduced inflammation. This study provides a global transcriptional map of immune activation in DENV target organs of an immunocompetent host and supports the further development of targeted immunomodulatory strategies to treat DENV disease.IMPORTANCE Dengue virus (DENV), which causes febrile illness, is transmitted by mosquito vectors throughout tropical and subtropical regions of the world. Symptoms of DENV infection involve damage to blood vessels and, in rare cases, hemorrhage and shock. Currently, there are no targeted therapies to treat DENV infection, but it is thought that drugs that target the host immune response may be effective in limiting symptoms that result from excessive inflammation. In this study, we measured the host transcriptional response to infection in multiple DENV target organs using a mouse model of disease. We found that DENV infection induced metabolic dysregulation and inflammatory responses and affected the immune cell content of the spleen and liver. The use of the mast cell stabilization drug ketotifen reversed many of these responses and induced additional changes in the transcriptome and immune cell repertoire that contribute to decreased dengue disease.
Highlights
There are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors
We found that DENV2 infection resulted in the differential expression of 320 genes in the liver on day 1 but that the response in this organ was mostly resolved by day 3, when only 9 differentially expressed (DE) genes were detected (Fig. 1A and B)
DENV2 infection induced the upregulation of interferon-stimulated genes (ISGs) such as IFIT3 (IFNinduced protein with tetratricopeptide repeats 3), ISG15, and OAS (2=-5=-oligoadenylate synthetase 1) (Fig. 1C)
Summary
There are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors. It was thought that productive DENV infections were restricted to humans and other primates and could not occur in immunocompetent mice This led to the development of several immunodeficient mouse models of infection, which have improved our understanding of some aspects of dengue disease but have not allowed us to investigate the contribution of the host response in the context of an intact innate immune response [22, 23]. We recently described an immunocompetent model of dengue disease in which C57BL/6 mice infected intraperitoneally (i.p.) with a DENV clinical isolate, EDEN2, showed symptoms such as thrombocytopenia, increased hematocrit values, vascular leakage, and viral replication in the spleen and liver, which are reminiscent of human disease [24, 25]
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