How particle shape determines phagocytic uptake: a systems-biology analysis

点击翻译按钮获取中文摘要

Phagocytosis is the fundamental cellular process by which our immune cells bind, engulf, and destroy unwanted bacteria and particles that enter our bodies. This process is complex, relying on an estimated 1000 different signalling molecules inside the cell, making it difficult to build a mathematical or computer model that includes all of these regulatory components. However, despite the signalling complexity, phagocytosis also depends on simple biophysical parameters; the process is sensitive to particle shape and stiffness. A simple analogy would be the difficulty in wrapping a soft toy compared to a book. It costs the cell different amounts of energy to bend and stretch its membrane around particles of regular shapes compared to irregular soft particles. The influence of shape on phagocytosis is clearly important for our immune response as bacteria exist in various shapes, ranging from round spheres, to rods, and even spiral forms. Particle shape is also important for efficient drug delivery, in determining whether or not drugs remain outside cells, or are taken up by cell in order to reach their targets. For instance, tuberculosis starts with an infection of cells in the lung and could be targeted efficiently by aerosolised drugs, transmitted in the form of micro-sized particles of optimal shape for phagocytosis by cells in our lungs. Recently, phagocytosis-like engulfment processes were also found in bacteria themselves, such as during the formation of spores. This points to the universal importance of cells being able to engulf particles. Despite the tremendous importance of engulfment in biology, little is known about the biophysical aspects of uptake. Recent work by us and others described some of the early events in phagocytic engulfment using simple mathematical equations to describe the forces for engulfment. However, these studies did not address the sensing of rod- or spiral-shaped bacteria, nor the stiffness of the particles. Furthermore, these models do not sufficiently include signalling and force generation in the cell interior, and hence are unable to explain the dynamics of cellular proteins and mechanosensitivity. In particular, motor proteins are important to contract the cell membrane around the particle to complete internalisation. Here, integrated into the rich research activities at Imperial College London and its interdisciplinary centres, we aim to develop a quantitative biophysical model for phagocytosic engulfment focussing on explaining the importance of particle-shape on uptake. Our proposed simulations will be more realistic and specifically include aspects of signalling and contraction by motor proteins. In order to determine if our model describes phagocytosis correctly, we will conduct high-resolution imaging experiments to see where key proteins localize in the cell, and what the cell shape and dynamics of uptake look like. Additional collaborations and contacts with industry are being initiated to ensure relevance to improving health, and the economy.