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Regulation of danger signal secretion during bacterial infection

School of Medicine, Dentistry and Biomedical Sciences | PHD

Applications are now CLOSED
Funding
Funded
Reference Number
SMED-2241-1011
Application Deadline
23 January 2024
Start Date
1 October 2024

Overview

Bacterial gut pathogens are a leading cause of disease and death worldwide. To combat infection, our immune system mounts a protective inflammatory response. However, immune responses cause damage when they are uncontrolled, for example during inflammatory diseases. Therefore, an in-depth understanding of inflammatory mechanisms is required to harness the beneficial power of immunity during infection while counteracting debilitating inflammatory diseases with specific therapy. Extracellular ATP is a potent proinflammatory mediator. We are running an ambitious research programme studying how intestinal cells and microbes control the abundance of extracellular ATP and how they respond to it. This project aims at unravelling the molecular mechanisms controlling secretion of ATP during infection with pathogenic intestinal bacteria.

Background:

ATP has many essential functions inside cells, for example as energy currency and building block of nucleic acids. However, outside cells ATP is a signalling molecule. In fact, extracellular ATP is the archetypical endogenous danger and has long been known to regulate sterile inflammation, that is inflammation in the absence of infection.

Our pioneering work showed that ATP secretion by intestinal epithelial cells infected with pathogenic bacteria initiates acute intestinal inflammation upstream of proinflammatory cytokines and chemokines, revealing the importance of extracellular ATP during infection and its proinflammatory effect in the gut. This discovery bridges the molecular mechanisms between infection-induced and sterile inflammation.

Recently, we discovered that the characteristic actin-dependent plasma membrane ruffles, which engulf invasive bacteria such as Shigella flexneri, are a mechanical immune signal sensed by PIEZO1. PIEZO1 detects changes in lipid bilayer tension and mediates Ca2+ influx, which is necessary and sufficient for mechanically-driven ATP secretion. In addition, PIEZO1 triggers the proinflammatory transcription factor NF-κB and immune gene expression, providing an evolutionary advantage in early sensing of pathogens with strong immune evasion mechanisms. Together, this indicates that PIEZO1 functions in ways similar to immune sensors, but is driven by physical cues instead of chemical ligands.

About the project:

This project aims at elucidating how the mechanosensor PIEZO1 synergises with activation of classical immune sensors, the Pattern Recognition Receptors, to initiate the immune response against infection with Shigella flexneri and enteropathogenic Escherichia coli (EPEC) in the intestinal epithelium.

The project will be co-supervised by Prof. Jose Bengoechea. The successful candidate should be highly motivated and will acquire training in the fields of microbial pathogenesis, cellular signalling, innate immunity, mechanobiology, as well as in transferable skills such as supervision (of undergraduate students), scientific writing and presentation.

About the lab:

The Puhar Lab has recently relocated from The Laboratory for Molecular Infection Medicine Sweden (MIMS) – The Nordic EMBL Partnership for Molecular Medicine in Umea, Sweden to the Wellcome-Wolfson Institute for Experimental Medicine (WWIEM) of Queen’s University Belfast. We are located in a state-of-the-art centre with an interactive environment striving to improve people’s health through research. We are an international team performing high quality, hypothesis-driven research in infection biology, with projects studying the host, the microbes, and how they interact. To answer our questions, we use cutting edge techniques in bacteriology, cell biology, molecular biology, genome editing, omics and systems biology.

Key publications for the project:

Tadala L, Langenbach D, Dannborg M, Cervantes-Rivera R, Sharma A, Vieth K, Rieckmann LM, Wanders A, Cisneros DA, Puhar A (2022). Infection-induced membrane ruffling initiates danger and immune signaling via the mechanosensor PIEZO1. Cell Rep. 40: 111173

Puhar A, Tronchere H, Payrastre B, Tran Van Nhieu G, Sansonetti PJ (2013). A Shigella Effector Dampens Inflammation by Regulating Epithelial Release of Danger Signal ATP through Production of the Lipid Mediator PtdIns5P. Immunity 39: 1121-1131

Second Supervisor: Prof. Jose Bengoechea

Funding Information

Funded by the Department for the Economy (DfE). For UK domiciled students the value of an award includes the cost of approved tuition fees and maintenance support the 2024/25 rates are still to be confirmed (current rates for 2023/24 are Fees £4,712, Stipend £18,622). To be considered eligible you must have been ordinarily resident in the UK for the full 3-year period prior to the start of the studentship and you must be ordinarily resident in Northern Ireland on the first day of the start of the studentship. For further information about eligibility criteria please refer to the DfE Postgraduate Studentship Terms and Conditions at https://www.economy-ni.gov.uk/publications/student-finance-postgraduate-studentships-terms-and-conditions

Project Summary
Supervisor

Dr Andrea Puhar

Research Profile

Mode of Study

Full-time: 3 years

Funding Body
DfE
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