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ERC

PPHPI Report Summary

Project ID: 280492
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Final Report Summary - PPHPI (Physical principles in host-pathogen interactions)

In this project we combined theoretical physics, mathematical modeling, computation, and quantitative biology, to gain novel insights into the principles of host-pathogen interactions. In its simplest form, such host-pathogen interactions include bacteria (the pathogen) and eukaryotic cells (the immune cells), both of which are motile and can follow chemical signals (chemotaxis). Furthermore, when an immune cell catches a bacterium, the bacterium is engulfed and destroyed (phagocytosis). All these cellular programs are highly complicated and involve hundreds of molecular species, most of which are little understood. In fact, we even know surprisingly little about the environments cells live in. Cells certainly don’t live in petri dishes in sterile labs but in complex chemical micro-environments, e.g. in the human gut or in the blood. How can a physicist’s approach contributed understanding to traditional biology problems? We believe physics and its laws impose strict constraints and that biology found ways to operate as close as possible at the physical possible limits. Understanding these limits and the physical principles at work also helps us understand the biological problem – these are two sides of the same coin.

Aim 1 was about bacteria. As bacteria are relatively simple, there is good understanding of signaling pathways and excellent data e.g. from FRET experiments. Using this information and further developing concepts from information theory allowed us to predict the inaccessible chemical environments bacteria such as E. coli live in. It also allowed us to understand puzzles e.g. why biological dose-response curves are often very steep, despite limiting information transmission to only 1 bit. For instance, bacteria circumvent this problem by having multiple flagellated rotary motors for swimming, which enhances information transmission to the level of the receptors.

Aim 2 was about eukaryotic cells, which are much more complicated and much less understood. Here basic understanding of the physical limits of chemical sensing as set by ligand diffusion allowed us to predict the cell shapes and behaviors for implementing a strategy for approaching the physical limits. These physical limits are key parameters of our immune response where accuracy matters. Once we understood single cells, we were able to build a multiscale model to describe cell-cell communication at a much larger scale. We basically found that cells achieve long-range communication due to a critical-like state known from second-order (disorder-order) phase transitions in physical systems such as ferromagnets.

Aim 3 was about both bacteria and eukaryotes, in particular how bacteria of various shapes are engulfed and destroyed. Using concepts from first-order phase transitions (e.g. the melting of ice), we could predict what bacterial shapes and orientations are better engulfed than others, which may also aid the rational drug particle design. Our approach was even able to include active signaling mechanisms in addition to basic physics. To generalize our understanding of engulfment, we also worked on bacteria. For instance, during sporulation, the mother cell engulfs the spore for spore maturation. We discovered the mechanism of such engulfment, which in the end was not that different from phagocytosis in eukaryotes. However, one key difference is that bacteria have a cell wall, which needs to be remodeled during engulfment, while eukaryotic cells have an acto-myosin cytoskeleton, which pushes the membrane around the bacterium.

In conclusion, our work pushed the limits of our understanding of biology forward, demonstrating that all scientific disciplines need to be combined to solve the truly challenging problems. This pioneer spirit makes working in interdisciplinary science so exciting.

Reported by

IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
United Kingdom
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