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Nanofibres induce remodelling of cell membranes

A nanometre-scale mechanism has been proposed to explain how bacteria improve their grip on human cells. The findings have implications for drug discovery, and might inspire biomimetic applications such as adhesives.
John R. Dutcher is in the Department of Physics and the Biophysics Interdepartmental Group, University of Guelph, Ontario N1G 2W1, Canada.
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Biological membranes serve as the barrier between cells and their surrounding environment, and regulate the transfer of ions and small molecules into and out of cells. Because of their central role in proper cellular operation, membranes are a target for many disease-causing microorganisms1. Writing in Nature Communications, Charles-Orszag et al.2 propose a previously unknown mechanism by which one such pathogenic bacterium, Neisseria meningitidis (also known as meningococcus), rearranges the outer plasma membrane of host cells to improve its adhesion to the cells. Achieving improved cell adhesion is a key step in host infection, which in humans can lead to septic shock and meningitis3.

A key challenge for N. meningitidis is how to stick to and colonize the endothelial cells that line blood vessels without being swept away by flowing blood. The interaction between the bacterial and endothelial-cell surfaces is not strong enough to withstand the forces exerted by blood flow4, and so N. meningitidis uses extremely thin (6-nanometre-diameter) protein filaments called type IV pili (T4P) to increase its grip on the cell membrane. T4P can be extended and retracted through the cell wall in a variety of bacteria, and have crucial roles in the microbes’ life cycle, allowing them to stick to and move across surfaces and to infect or damage other cells5.

The interaction between N. meningitidis cells and endothelial cells results in the formation of protrusions on the endothelial-cell membrane4, and it has been shown that proteins in T4P are essential for protrusion formation6, and that they interact with specific receptors in the endothelial cells7. However, the molecular mechanism underlying the interaction of T4P with host cells was not understood. Charles-Orszag and co-workers now shed light on this mechanism by combining in vivo and in vitro studies with a simple theoretical model.

The theoretical model is one of the strengths of the new study, and describes a previously unknown mechanism for wetting (the spreading of a deformable substance such as a liquid on the surface of another substance8). Wetting is key to many aspects of everyday life, from the spreading of ink on paper to the beading of water droplets on spider webs or freshly waxed cars, and it typically occurs in two dimensions. However, in the case of a very thin fibre in contact with a soft membrane, the membrane cannot wrap around (wet) the fibre, because too much energy is required to accommodate the large curvature around the fibre’s cross-section.

Charles-Orszag et al. use their model to show that it can be energetically more favourable for a narrow tube to be drawn out from the membrane, along the fibre, than wrapped around it (Fig. 1). This mechanism for forming membrane protrusions, which the authors call one-dimensional wetting, is driven by adhesion between the membrane and the fibre. The membrane protrusions could help to anchor a bacterium to a host cell as its T4P extend and retract, without breaking the adhesive interactions between the T4P and the membrane — thus maintaining the dynamic nature of the fibres.

Figure 1 | Enhancing adhesion between a bacterium and an endothelial cell. The bacterium Neisseria meningitidis attaches itself to the endothelial cells that line blood vessels in host organisms. The bacterium uses fibres known as type IV pili (T4P) to induce the formation of protrusions from endothelial-cell membranes. These protrusions strengthen the bacterium’s hold on the membrane, helping it to colonize cells without being swept away by the surrounding blood flow. Charles-Orszag et al.2 propose that the adhesion of T4P to the membrane drives a process called one-dimensional wetting, in which the protrusions are drawn along the T4P fibres (red arrows). (Adapted from Fig. 5 of ref. 2.)

Because the remodelling of endothelial-cell membranes by N. meningitidis had previously been observed only for cultured cells, the researchers studied blood vessels in human skin grafted onto mice to confirm that remodelling also occurs in vivo. They then complemented those experiments with in vitro studies to explore the mechanism involved. Unfortunately, the in vitro experiments did not examine the interaction of isolated T4P with model membranes, because this would have required the appropriate receptor proteins to be introduced into the membranes. Instead, Charles-Orszag et al. studied two model systems: artificial cells (known as giant unilamellar vesicles) interacting with filaments of a protein called actin through adhesion between the filaments and molecules attached to the cells; and endothelial-cell membranes interacting with mimics of the fibres found in the extracellular matrix around cells.

The authors show that 1D wetting does indeed occur in these systems, and that it can be understood quantitatively using their model. Their in vitro observations highlight the essential feature of this phenomenon: the presence of adhesion between a deformable membrane and a nanoscale fibre. Their observations also suggest that 1D wetting could occur more generally for physiologically important interactions of human cells with other biological nanofibres, and that it could have a major role in cell migration.

Further work is needed to understand 1D wetting in more detail. Systematic studies in which the fibre radius, strength of the adhesive interaction and surface tension of the membrane are varied would improve our understanding. In addition, further developments in microscopy will lead to better visualization of the structure and dynamics of the protrusions involved in 1D wetting.

Charles-Orszag and co-workers’ results reveal opportunities for biomimetic strategies for wetting synthetic nanofibres and for producing strong adhesives, and new ways of moving nanoscale objects. Their findings also imply that reducing or disabling the 1D wetting of N. meningitidis T4P would limit the bacterium’s ability to colonize and infect host cells, opening up a potential avenue for drug discovery. More generally, 1D wetting might enable cell function and health to be manipulated through interactions of cells with nanofibres to which biologically active molecules have been attached.

doi: 10.1038/d41586-018-07261-9
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