Dr. Peter Bond, Principal investigator, Bioinformatics Institute, Agency for Technology and Research (A*STAR) Singapore

Elucidating the Cascade of Interactions in the Innate Immune Response to Bacterial Lipids

Bacterial infections are a significant threat to human health. The outer membranes of Gram-negative bacteria contain lipopolysaccharide (LPS), which is both a barrier to antibiotic therapy and a key player in the mammalian innate immune response to bacterial infections. The latter involves a relay of specialized protein complexes culminating in transfer of immunostimulatory LPS molecules from CD14 to Toll-like receptor 4 (TLR4) on the cell surface, leading to activation of cytoplasmic signal transduction and downstream inflammatory responses.

Accurate computational models of bacterial membranes, the associated immune receptors, and their interplay in LPS recognition would contribute to an improved understanding of bacterial infections and help in the search for novel approaches to antimicrobial therapy, sepsis, inflammatory conditions, and adjuvant formulation. To this end, we have used computational modelling and simulations to identify the allosteric switch in TLR4 activation, supported by accurate predictions of lipid binding affinities to the receptor, providing a quantitative means to unravel the complex structure-activity relationships associated with the innate immune response to LPS. This has enabled us to investigate a host of endotoxic ligands, and to challenge the long-accepted notion that obesity, chronic inflammation, and insulin resistance are linked via this receptor.

Building on this work, multiscale approaches are helping us to understand the structural basis for systems-level function. Using coarse-grained models, we are now able to trace the complete endotoxin recognition cascade, starting with extraction and transfer of lipid from a model bacterial envelope, through membrane-anchored CD14, to the TLR4 receptor complex. This provides us with a first molecular glimpse into the LPS exchange process at the plasma membrane surface. 

Host: Professor Birgit Schiøtt, Department of Chemistry, AU

Bio
Peter Bond is Principal Investigator at the Bioinformatics Institute (BII) A*STAR, Singapore, where he runs the Multiscale Simulation, Modeling and Design group. His research interests include host-pathogen interactions, receptor signaling, and virus dynamics. Following his graduation in Biochemistry at the University of Oxford in 2001, Peter moved to the Laboratory of Molecular Biophysics to read for a DPhil, supported by a Wellcome Trust Prize Studentship. He was awarded an EMBO Long-Term Fellowship in 2007 to carry out research at the Max Planck Institute of Biophysics in Frankfurt. In 2010, he became a University Lecturer and Group Leader in the Department of Chemistry, University of Cambridge, before moving to Singapore in late 2013. 

Coffee, tea, and bread will be served in front of the auditorium from 10:00.