Pathogenesis of severe dengue infection

Abstract

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The pathogenesis of severe dengue (SD) is thought to be due to the complex interplay between the virus, host genes and the host immune response. As vascular leak, which is the hall mark of SD, occurs following the resolution of the viraemia, it was thought that an inappropriate immune response to the virus, was the main cause of SD. However, recent data shows that dengue NS1 alone activates monocytes through the TLR4 receptor, inducing inflammatory cytokine production and that NS1 was involved in vascular leak in acute dengue. We too have found that dengue NS1 stimulates IL-10 production from monocytes, which in turn could lead to suppression of dengue virus specific T cell responses and thereby contribute to disease severity. In our studies, which have investigated the kinetics of changes in inflammatory mediators, the degree of viraemia and the onset and extent of vascular leak, have shown that inflammatory mediators are significantly elevated in patients with SD, around day 4 to 5 of illness. Levels of both IL-10 and IL-17 and other cytokines were significantly elevated in patients with SD when compared to milder dengue, before the onset of vascular leak. Our previous studies had shown that platelet activating factor (PAF) was an important mediator of vascular leak. We found that although the dengue virus (DENV) or dengue immune serum did not induce PAF production by monocytes, lipopolysaccharide (LPS) acted synergistically with the DEN, in the production of PAF. Since LPS levels in serum have been found to be significantly elevated in SD, LPS could further contribute to disease pathogenesis and vascular leak. Mast cells are an important source of PAF and have shown to be important in disease pathogenesis in dengue mice models. We found that mediators such as tryptase and secretory phospholipase, which are produced exclusively by mast cells, are significantly elevated in patients with DHF, during early infection. Therefore, in summary, the events that lead to severe dengue appear to occur before the onset of vascular leak and the role of mast cells and viral proteins in the pathogenesis of SD should be further investigated.