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CombaT7

Uncovering bacteria’s secret weapons

An ERC-funded consortium decoding the type VII secretion system — the molecular machinery behind mycobacterial infection and microbial warfare.

EU Horizon Europe
Newcastle University Universitätsklinikum Hamburg-Eppendorf EPFL Vrije Universiteit Amsterdam
The Project

A bacterial weapon hidden in plain sight

For years, scientists thought specialised secretion systems were exclusive to Gram-negative bacteria. But Gram-positive bacteria — including harmful pathogens like Mycobacterium tuberculosis — have a powerful exception: the type VII secretion system (T7SS).

This complex machinery does not just export proteins involved in infection; it also plays a surprising role in microbial warfare between bacteria. The ERC-funded CombaT7 project brings together top researchers to decode the mysteries of T7SS in important mycobacterial pathogens like M. tuberculosis and M. abscessus. Using cutting-edge tools like cryo-EM and lung-on-a-chip models, the team will map the system’s structure, identify new protein targets, and uncover how it influences both disease and bacterial competition — laying the groundwork for new ways to fight infection.

Objectives

Four routes to a mechanistic understanding of mycobacterial T7SSs

Uniting leading experts in microbiology, structural biology, cell biology, and biophysics to spearhead research on T7SSs and their roles in both interbacterial and host–pathogen interactions.

i

Define the apparatus

Map the full trans-envelope T7SS by atomic force microscopy and cryo-electron microscopy.

ii

Decode transport

Study the mechanism of secretion by trapping translocation intermediates in the act.

iii

Expand the substrates

Discover new T7SS substrates through extensive proteomics and bioinformatics analysis.

iv

Watch warfare unfold

Visualise T7SS in bacterial warfare and host–pathogen interactions using microfluidics, lung-on-a-chip models and time-lapse microscopy.

The Consortium

Principal investigators

Prof. John McKinney

Prof. John McKinney

EPFL
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Single-cell microbiology, host–pathogen dynamics and time-lapse imaging.

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Prof. Georg Fantner

Prof. Georg Fantner

EPFL
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Atomic force microscopy and nanoscale bioimaging of the cell envelope.

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Prof. Tracy Palmer

Prof. Tracy Palmer

Newcastle University
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Bacterial protein secretion and the molecular biology of the T7SS.

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Prof. Thomas Marlovits

Prof. Thomas Marlovits

UKECSSBDESY
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Cryo-EM structural analysis of bacterial secretion machines.

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Prof. Wilbert Bitter

Prof. Wilbert Bitter

VU Amsterdam
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Mycobacterial pathogenesis and the genetics of ESX secretion systems.

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Prof. Edith Houben

Prof. Edith Houben

VU Amsterdam
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Assembly and substrate recognition of mycobacterial T7SSs.

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Researchers

Researchers

Select a researcher to read about their role in the project.

Théo Aspert

Théo Aspert, PhD

EPFL
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ORCID

Research interests: Human tissue models, microfabrication, microfluidics, timelapse microscopy, host–pathogen interactions.

To fully understand the T7SS's role in both bacterial warfare and host–pathogen interactions, we require dynamic and controlled models. Microfluidic systems are essential as they allow for precise visualization of bacteria–bacteria antagonism and, when integrated with platforms like the lung-on-a-chip, enable the study of complex host–bacteria interactions in an in vivo-like context. My efforts are concentrated on developing and utilizing these microfluidic models to observe and quantify the T7SS mechanisms in action.

Pit Engling

Pit Engling, PhD

EPFL
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LinkedIn

Research interests: Interbacterial antagonism, bacterial secretion systems, mycobacterial pathogenesis, timelapse microscopy.

My work focuses on the mechanistic characterization of ESX-4–mediated interbacterial antagonism in mycobacteria and on identifying predator–prey interaction dynamics at single-cell level. Central to this effort is timelapse imaging at single-cell resolution, supported by machine-learning–based image analysis. This enables us to resolve the mode of action, sequence of events, and dynamic outcomes of ESX-4-driven cell–cell antagonism. To achieve this, we incorporate custom-made microfluidic and lung-on-chip platforms providing controlled environments and physiologically relevant contexts for these single-cell mechanistic studies.

Luca Schlotheuber

Luca Schlotheuber, PhD

EPFL
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LinkedIn

As a crucial resident immune cell in the alveolus of the lung, macrophages represent the first line of defense against tuberculosis. During infection, however, the lung pathogen TB can infect, hijack and kill macrophages in a complex interplay between secreted proteins of the T7 secretion system, host receptors, and intracellular factors. As part of CombaT7 I am investigating this interplay and the mechanisms that drive the killing of macrophages and the dissemination of mycobacteria in the lung.

Rory Hennell James

Rory Hennell James, PhD

UKECSSBDESY
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LinkedIn ORCID

Research interests: Cryo-EM, cryo-ET, secretion systems, cellular structure, microbiology.

I use cryo-electron microscopy and tomography to resolve the architecture of the T7SS apparatus at near-atomic detail, revealing how its components assemble across the mycobacterial cell envelope.

Robin Lissner

Robin Lissner, PhD

VU Amsterdam
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LinkedIn ORCID

Research interests: Mycobacteria, cell envelope, membrane proteins, protein secretion systems, microbial pathogens.

My research focuses on the mechanics of substrate translocation within the mycobacterial Type VII secretion system. Specifically, I utilize molecular and biochemical techniques to investigate the fundamental processes of substrate recognition and the pathways of transport across the inner membrane. This work is critical for understanding how mycobacteria survive and cause infection, ultimately aiding the development of targeted therapeutics.

Sam Benedict

Sam Benedict, PhD

Newcastle University
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Research interests: Cell wall homeostasis, interbacterial interactions, bacterial secretion systems.

I am a Postdoctoral Research Associate specialising in mycobacterial cell envelope biogenesis and interbacterial competition. With a PhD in cell wall protein biochemistry, my research focuses on the structural and functional characterisation of novel antimicrobial toxins and glycoside hydrolases. Using structural, molecular, and biochemical approaches, I am investigating cell wall-targeting Type VII secreted effectors to decipher how mycobacteria deliver antibacterial effectors and to identify vulnerable structural targets for new therapeutic strategies.

Manon Oudejan

Manon Oudejan

VU Amsterdam
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Research interests: Mycobacteria, protein secretion, membrane proteins.

My research focuses on the ESX-1 Type VII secretion system in mycobacteria, with an emphasis on the secretion and function of the virulence-associated Esp proteins. Using molecular and biochemical techniques, I contribute to studies investigating how these proteins are exported, and their role in hemolysis and infection. Through supporting a range of research projects, my work helps advance our understanding of mycobacterial secretion systems and the mechanisms that enable infection.