Completed Infection & Immunity Cells, Biochemistry & Physiology

Use of the cytoskeleton to control Shigella infection

Funder Wellcome Charity-funded
Recipient organisation Imperial College London
Funding £1.9M
Period Jul 2018 — Jul 2023

In plain English

AI plain-English summary

When *Shigella* bacteria invade human cells, the cell’s own internal skeleton—a network of protein filaments called the cytoskeleton—can assemble into cage-like structures that trap the bacteria and mark them for destruction. The researcher recently discovered that mitochondria, the cell’s power plants, help build these cages, which are made of proteins called septins. But exactly how the cages form, and whether septins play other roles in fighting infection, remains unknown. This matters because *Shigella* causes severe diarrhoeal disease, and antibiotic resistance is rising. Understanding how cells naturally imprison the bacteria could reveal new ways to boost the immune system without drugs. The researcher will use zebrafish larvae, whose transparent bodies allow real-time observation of infection at the single-cell level—a resolution impossible in mammals. This is fundamental science: the work aims to uncover basic mechanisms of septin biology and cellular immunity. If successful, it could eventually inform strategies to treat not only bacterial infections but also other diseases—such as certain cancers and neurodegenerative conditions—where septins have been implicated.

View original technical description
The cytoskeleton occupies a central role in innate immunity by promoting bacterial sensing and executing antibacterial functions. We recently discovered that mitochondria promote septin assembly into cages that entrap Shigella for antibacterial autophagy, highlighting new roles for the cytoskeleton in host defence. However, the processes underlying septin cage assembly, and the breadth of roles for septins in bacterial infection control, remain to be established. To investigate the cell biology of Shigella infection in vivo we developed zebrafish infection models which provide unprecedented opportunities to follow innate immunity at a resolution that cannot be achieved using any other animal model. I will now exploit the novelty of septin biology, and its direct link to host defence, as the foundation for this research programme. Using Shigella I will: (1) Discover new roles for the cytoskeleton in host defence against bacterial infection, and (2) Investigate the role of septin-mediated host defence mechanisms in vivo using zebrafish models of infection. The results generated from this research programme will provide fundamental advances in understanding septin biology and cellular immunity. They could also suggest the development of new strategies aimed at combating infectious diseases, and possibly other human diseases in which septins have been implicated.

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Researchers

Serge Mostowy (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Septins: from bacterial entrapment to cellular immunity
New roles for the cytoskeleton in cell-autonomous immunity to mycobacteria
Identification and manipulation of factors that control Shigella flexneri entrapment in septin cages.
In vitro reconstitution and single cell analysis of the Shigella-septin cage.
Controlling persistent infection and antimicrobial resistance in Shigella

Original classification

Senior Research Fellowship Basic

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