CISBIC Sub-project 3: Innate Immune Signalling
This project addresses issues related to the innate immune response. In a fundamental process that is conserved between plants, insects and mammals, the initial encounter between host and pathogen involves recognition of conserved microbial components by a set of pattern recognition receptors (PRRs; including the "toll-like receptors", mannose receptor, and scavenger receptors) on the surface of the host cell. Signals from these receptors are integrated by the host cell, triggering an innate response customised to reflect the degree of “danger” posed by the particular pathogen.
Importantly, it is becoming clear that any one pathogen triggers both pro- and anti-inflammatory cascades by ligating different PRRs, possibly even through differentially glycosylated forms of the same signalling ligand. By altering their repertoire of surface-expressed ligands, therefore, pathogens can influence the nature of the immune response in a way that may allow them to evade effective immunity.
An important additional component of the infection-associated signalling cascade has been demonstrated at Imperial College and by others. The Notch receptor and Notch ligand families are expressed by cells of the immune system and fundamentally influence the outcome of immune stimulation. Triggering of Notch receptors on T cells by the Delta-like1 ligand expressed on antigen-presenting cells converts a normally IFNg-dominated response to an IL-10-dominated response, for example, and the pattern of Notch ligands on antigen-presenting cells is in turn regulated by TLR signalling. The Notch pathway therefore represents a direct link between TLR signalling and the adaptive immune response. There are 4 mammalian Notch receptors and 5 ligands; little is known about the differential regulation of their expression on cells of either innate or adaptive immune systems.
This sub-project will use a systems biology approach to study how signals from multiple PRRs are combined within an antigen-presenting cell, and how this is integrated with Notch signalling to shape the subsequent adaptive response. A limited amount of modelling has been done for TLR signalling and transcription factors such as NFkB. We will build on this by a combination of experimental and modelling approaches. The experimental approach undertaken within the current exemplar will focus on a mammalian cell model, but the project will be closely linked with parallel research efforts in other systems. Comparative biology across plant, insect and animal kingdoms has been highly informative in investigation of innate immune mechanisms and we anticipate synergy between this project and the strong research programme of Profs Fotis Kafatos and Bob Sinden in the area of insect immunity and the plant pathogenesis group at Imperial College.
Organisms:
- Mus musculus
Funding:
- BBSRC Research Grant: BB/C519670/1
For more information about the outputs from this project or to discuss data reuse please contact bsshelp@imperial.ac.uk