Inflammasomes, Toll-like receptors and dengue virus

Associate Professor Kate Stacey, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane

Activation of the innate immune system via receptors for pathogen molecules as well as self "danger" signals is essential for subsequent development of acquired immune responses, and also contributes to a wide range of inflammatory pathologies. My laboratory works on several such receptor systems, including Toll-like receptors (TLR) and inflammasomes. Toll-like receptor 4 (TLR4) is responsible for mediating inflammatory effects of lipopolysaccharide (LPS), the major constituent of the Gram-negative bacterial cell wall. An increasing number of reports also show activation of TLR4 by diverse viral infections including Ebola, influenza, Japanese encephalitis virus and respiratory syncytial virus. We have shown that the dengue virus secreted lipoprotein NS1 activates TLR4. The serious complications of dengue virus infection include hemorrhage 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 pathway potentially provides an explanation for similarity between dengue and bacterial-mediated shock. Another class of innate immune pathway with involvement in a wide range of inflammatory and infectious disease is the inflammasome. Inflammasomes are large protein complexes mediating activation of caspase-1 and caspase-8, resulting in release of inflammatory cytokines and cell death. This is an extremely rapid response with massive protein oligomerisation and cell death within minutes of stimulus. We are studying the dynamics of this response and requirements for caspase activation and inactivation. I will discuss aspects of both of these projects.

Kate Stacey’s research interest is pathogen receptors of the innate immune system, including toll-like receptors (TLR) and inflammasome proteins. She pioneered work on macrophage activation by foreign (“CpG”) DNA, recognised via TLR9, and more recently focussed on inflammasome activation by AIM2 recognition of DNA in the cytosol. Her group has shown that the inflammasome is a novel platform for activation of caspase-8. She also investigates innate immune responses in viral infection, and is currently investigating the importance of TLR4 recognition of dengue virus NS1 protein in disease pathology.