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Background: Platelet Activating Factor (PAF) has been shown to be an important mediator of vascular
leak in acute dengue. Antibody dependent enhancement (ADE) and microbial translocation has also
shown to contribute to severe dengue. Since monocytes are one of the primary targets of the dengue
virus (DENV) we sought to investigate if monocytes were a source of PAF, and the effect of ADE and
microbial endotoxin (LPS) on DENV infected monocytes.
Methods: PAF and cytokine levels were evaluated in serial blood samples, in patients with acute dengue
infection. The effect of ADE and LPS in production of PAF and cytokines from DENV infected primary
human monocytes derived macrophages (MDM8) was assessed. Gene expression analysis was undertaken to investigate mechanisms by which LPS potentiates PAF and cytokine production by DENV
infected MDM6.
Results: Serum PAF levels significantly correlated with both TNF-a (p < 0.0001) and 1L-1P (p < 0.0001) in
patients with acute DENV infection. Although primary human MDM8 produced inflammatory cytokines
following infection with the DENV, they did not produce PAF following in vitro DENV infection alone, or
in the presence of dengue immune serum. Levels of PAF produced by DENV infected MDM8 co-cultured
with LPS was significantly higher than uninfected MDM8s co-cultured with LPS. Although TLR-4 was
upregulated in uninfected MDMBs co-cultured with LPS, this upregulation was not significant in DENV
infected MDM6. Only expression of RIG-1 was significantly up regulated (p < 0.05) when DENV infected
MDM8 were co-cultured with LPS.
Conclusion: LPS acts synergistically with the DENV to induce production of PAF and other inflammatory
cytokines, which suggests that microbial translocation that has shown to occur in acute dengue, could
contribute to dengue disease severity.
