Lipopolysaccharide acts synergistically with the dengue virus to induce monocyte production of platelet activating factor and other inflammatory mediators

Abstract

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 (MDMθ) was assessed. Gene expression analysis was undertaken to investigate mechanisms by which LPS potentiates PAF and cytokine production by DENV infected MDMθ.

Results: Serum PAF levels significantly correlated with both TNF-α (p < 0.0001) and IL-1β (p < 0.0001) in patients with acute DENV infection. Although primary human MDMθ 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 MDMθ co-cultured with LPS was significantly higher than uninfected MDMθs co-cultured with LPS. Although TLR-4 was upregulated in uninfected MDMθs co-cultured with LPS, this upregulation was not significant in DENV infected MDMθ. Only expression of RIG-I was significantly up regulated (p < 0.05) when DENV infected MDMθ 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.

Keywords: Acute dengue; Inflammatory cytokines; Lipopolysaccharide; Monocytes; Platelet activating factor.