NHMRC Research Fellowship (SRF A): Toll-like receptors and innate immunity: genes and pathways regulating infectious and inflammatory diseases (2011–2015)
Cells of the innate immune system such as macrophages recognize danger signals from invading pathogens (e.g. conserved structures present on microorganisms) and/or endogenous host ligands (e.g. products released from necrotic cells) through several families of pattern recognition receptors (PRRs). Consequently, PRRs are essential for the control of infectious diseases, but also contribute to pathology in inflammatory diseases. Toll-like Receptors (TLRs) are the most widely studied PRRs. TLR ligands such as bacterial lipopolysaccharide (LPS) and CpG-containing DNA initiate immediate changes in macrophage function, as well as delayed changes through gene regulation. TLR-regulated genes have diverse roles in immune function including anti-microbial responses, inflammation, cell survival/apoptosis and antigen presentation. I focus on understanding the role of TLR signalling pathways and TLR target genes in anti-microbial and inflammatory pathways.
At the signalling level, I focus on the role of protein acetylation in TLR-initiated inflammation. The first proteins found to be regulated by lysine acetylation were histones, but it is now clear that many proteins are subject to this post-translational modification. Histone deacetylases (HDACs) catalyse the deacetylation of proteins, and HDAC inhibitors are therapeutic in many inflammatory disease models. I focus on identifying how HDAC inhibitors target TLR-initiated inflammatory pathways, the specific HDACs that promote inflammation, and small molecule inhibitors selective for such HDACs. In infectious disease, I focus on the role of specific TLR target genes in anti-microbial responses against Salmonella enterica Serovar Typhimurium (a classical intracellular pathogen that survives within macrophages), and uropathogenic Escherichia coli (an important human pathogen recently found by my laboratory to survive within macrophages). I also have a research program in characterizing the functions of novel TLR-target genes.