Centre for Innate Immunity Immunity and Infectious Disease

Toll-like receptor signalling laboratory

Laboratory head: Dr Ashley Mansell

Within the innate immune system, there are mechanisms to recognize and respond to both foreign and self danger signals. These signals may be bacterial or viral infections, or dead or stressed cells in the host. Without these responses, we would die.

As recently as a few years ago, immunology textbooks covered innate immunity in generic terms, before going into expansive detail on adaptive immunity. However, the discovery of the pattern recognition receptor family Toll-like receptors (TLRs) in the late 1990s changed all that. Today, TLRs constitute a group of three pattern recognition receptors (PRRs) superfamilies, which also include the NOD-like receptors (NLRs) and RIG-I-like helicases (RLHs).

TLRs are implicated not only in infectious diseases, but also a broad range of ‘self’ diseases such as chronic obstructive pulmonary disease (COPD) and autoimmune diseases such as atherosclerosis, asthma, lupus, diabetes, arthritis and cancer.

Dr Mansell’s TLR Signaling Laboratory uses a range of cellular and molecular biology methods, combined with powerful bioinformatics and array technologies, to provide a molecular understanding of innate immunity. They are interested in three main research themes related to the TLR superfamily of receptors:

What are the signal transduction pathways from TLRs to the initiation of the pro-inflammatory response?
Dr Mansell’s team aims to characterize and identify novel signaling mediators of these pathways that pass the message from receptor recognition of danger to activation of transcription factors, such as NF-kB and IRF3, which initiate the inflammatory response.

Too much of a good thing is bad for you
Negative regulation of such a powerful inflammatory response must be as carefully controlled as initiated. Building on their successful identification of SOCS-1 as a negative regulator of TLR signaling, Dr Mansell and his team are gaining a strong molecular understanding by identifying novel negative regulators of innate immunity.

Immunomodulation of these pathways
In a constant arms race, bacteria and viruses have developed mechanisms to target the immune response, expressing homologues and inhibitors that target the PRR superfamily of immune responders. Dr Mansell is currently investigating how viruses such as hepatitis B may evade immune responses by targeting these signaling pathways.

Dr Mansell and his team apply their TLR-related research to a range of diseases including:

• Infectious diseases
• Septic shock/severe sepsis
• Hepatitis B
• COPD
• Asthma
• Stomach inflammation (in conjunction with Associate Professor Brendan Jenkins )

Dr Mansell’s research is supported by National Health and Medical Research Council (NHMRC), Cancer Council Australia and the Association for International Cancer Research.