TLR4 as an inflammatory key to severe dengue disease

Modhiran N, Vajjhala PR, Watterson D, Young PR and Stacey KJ

Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Qld 4072.

Toll-like receptor 4 (TLR4) is the pattern recognition receptor responsible for mediating inflammatory effects of lipopolysaccharide (LPS), the major constituent of the Gram-negative bacterial cell wall. We have shown that the dengue virus secreted non-structural protein NS1 also activates TLR4, inducing the release of inflammatory cytokines from myeloid cells and loss of endothelial monolayer integrity. The serious complications of dengue virus infection include haemorrhage and shock, indicating a critical role for disruption of the endothelial barrier. We find that inhibition of TLR4 responses in dengue virus-infected mice substantially reduces vascular leak and is thus a potential therapeutic avenue. This suggests that at least in the later stages of infection, the host does not benefit from recognition of infection via TLR4. The striking similarities in cellular responses to LPS and NS1 via TLR4 suggest that NS1 is a viral counterpart of bacterial endotoxin. Similar to the role of LPS in septic shock, NS1 may contribute to vascular leak in dengue patients. A role for TLR4 in dengue infection opens up new therapeutic avenues for decreasing the severity of dengue pathology using established antagonists.