Improving our understanding how virus-induced fusion works

The mechanisms by which certain biological cells fuse together is currently poorly understood. The aim of my project is to develop and optimise a microfluidic system that can be used to study how viral infections can cause the cells of their host to fuse together.

There are an untold number of biological processes which contribute to sustaining all the different types of life that exist on Earth, with one of the most widely-known and fundamentally important being cell division (or mitosis and meiosis, in multicellular organisms such as humans). However, a process of similarly massive significance is that of cell fusion, in which simple single-nucleus cells come together to form larger, more complex cells, known as syncytia.

Cell fusion occurs in numerous different contexts. Some of these are beneficial – such as forming the placenta in pregnant women, or the creation of cells that detect damage to our bone tissue – whilst others represent means by which diseases can propagate, such as during the progression of cancer, or fusion induced by viruses.

This project will be focused on improving our understanding how the latter-most of these examples – virus-induced fusion – works. Viruses employ a family of proteins, known as fusogens, in order to accelerate the fusion of cell membranes through a variety of different methods. Numerous classes of fusogen exist, with several different pathogens employing them, including: HIV, Ebola, rabies, Zika virus, and others. The viruses commonly encourage the fusion of viral cells with cells from the host organism; however, they can also use their fusogens to encourage host cells to fuse with one another. Regardless of the specific manner in which they work, fusogens play a crucial role in viral infection, making them of keen interest in medicinal research.

Several methods of studying cell fusion have already been developed. However, a large number of these methods are relatively crude, unable to offer the confinement necessary to study individual cells coming together. To solve this issue, we can use microfluidics: a rapidly expanding and interdisciplinary field based on examining how tiny amounts of fluid (so small that they’re almost invisible to the naked eye) interact throughout channels as wide as a human hair. So-called microfluidic ’chips’ are made from materials such as rigid polymers or glass, with microscopic channels of varying length, shapes, and layouts being engineered throughout to facilitate the flow of fluid. Microfluidics have been used for numerous applications, ranging all the way from studying nuclear reactor waste to searching for evidence of extraterrestrial life – however, applications in cellular biology are of the greatest interest to us.

By developing a microfluidic chip capable of mixing two separate streams of cells together under finely-tuned conditions, we can study the fusion processes on a scale so small that individual cells can be probed. The project seeks to develop and optimise this setup for the study of fusionassociated
small transmembrane (FAST) proteins – a unique class of fusogens found in a mostly non-pathogenic group of viruses known as reoviruses – in order to better understand how fusogens work.

Charles Seymour

NanoDTC PhD Student, c2023