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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.
