Structural Infection Biology
Manipulation of human host cells is a fundamental challenge for all pathogens. This task is accomplished by the controlled secretion and delivery of effector proteins into the host cell. Through genetic and proteomic studies many effector proteins have been identified, providing topographic maps of the most prominent subversive strategies.
In many Gram-negative bacteria, the main virulence machinery that contributes to bacterial pathogenesis is the type three secretion system (T3SS). This system is a membrane-embedded macromolecular complex that allows the translocation of effector proteins directly from the bacterial cytosol to our body to invade the host and propagate infection. The structural core of the T3SS is a 3.5 megadalton nanosyringe-like complex assembled from more than twenty components that spans the double membrane of Gram-negative bacteria.
The current challenge we face now is to understand how this system works and how protein secretion is regulated. Our research focuses on the structural and functional analysis of this nanomachine and investigates the rules for effector protein secretion, transport dynamics and regulation of the T3SS.
We use biological (molecular genetics, protein biochemistry, cellular invasion and secretion assays) and advanced structural biology techniques (X- crystallography, electron and fluorescence microscopy), in combination with biophysical methodologies (light scattering, calorimetry, CD- and fluorescence spectroscopy) for a comprehensive structure-function analysis of the T3SS during infection. We aim to gain a predictable understanding of the mechanistic details of the T3SS transport adopted during the course of an infection at the atomic level to be used as an antibacterial target for both developing improved therapies for fatal Gram-negative infections and lightening the burden of antibiotic resistance.
The World Health Organization estimates that diseases caused by Gram-negative pathogens such as gastroenteritis (Shigella flexneri), typhoid fever (Salmonella typhi), food poisoning (Escherichia coli spp) and bubonic plague (Yersinia pestis) affect more than 100 million people worldwide causing several million death each year.
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