Salmonella injects two bacterial proteins, SseF and SseG, into human gut cells to hijack the cell's internal membrane system and build a protected compartment where the bacteria can multiply. This matters because Salmonella causes serious food poisoning and systemic infections, yet the precise molecular steps it uses to remodel host cell membranes remain unknown. Without that knowledge, researchers cannot design drugs that block the infection at its earliest stage—before bacteria have a safe haven to replicate. This project is fundamental science. It will map exactly how SseF and SseG latch onto the host protein ACBD3, how that interaction pulls the Salmonella-containing vacuole close to the Golgi apparatus, and which lipids and proteins are diverted to the vacuole. The team will also test whether the bacteria selectively capture passing vesicles, using an experiment that anchors the bacterial proteins to mitochondria to see if they redirect membrane traffic there. If successful, the work will produce the first comprehensive molecular description of the Salmonella-containing vacuole. That catalogue of hijacked host components could reveal new drug targets. Similar fundamental studies of bacterial secretion systems have previously led to vaccines and anti-virulence compounds now in clinical development.
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Fundamental to the infection mechanism of Salmonella is its ability to survive and replicate within intestinal epithelial cells. This requires modification of its membrane-bound compartment, known as the Salmonella-containing vacuole, transforming it into a novel organelle with a unique biochemical composition that supports Salmonella replication. Changes in organelle composition require recruitment of cytoplasmic proteins or alterations in vesicular trafficking. Despite its importance for Salmonella infection, it remains unclear how Salmonella coopts these host processes to modify the Salmonella-containing vacuole and enable Salmonella replication. Crucial to this process are two highly-conserved secreted Salmonella virulence proteins, called SseF and SseG, and their interaction with the host Golgi-associated protein ACBD3. All three proteins are required for efficient intracellular Salmonella replication and for maintaining close proximity between Salmonella-containing vacuoles and the Golgi. In this proposal we will apply advanced cell biological techniques to elucidate the molecular mechanisms underlying this host-pathogen interaction. Firstly, we will combine biochemistry, microscopy and molecular cell biology to characterise the molecular interface between SseF, SseG and ACBD3 and explore how the association between the Golgi and Salmonella-containing vacuoles is mediated. This will determine the role of Golgi proximity in Salmonella infection. Next, we will determine how the composition of Salmonella-containing vacuoles depends on SseF, SseG and ACBD3. In a targeted approach, we will focus on membrane-modifying enzymes recruited to the Golgi by ACBD3, testing whether these proteins are diverted during infection to modify the composition of Salmonella-containing vacuoles. In an unbiased approach, we will use subcellular proteomics and lipidomics to provide a comprehensive characterisation of the protein and lipid composition of the Salmonella-containing vacuole. Finally, we will use kinetic trafficking assays to investigate how host components are redirected to the Salmonella-containing vacuole during infection. To test the hypothesis that SseF and SseG are involved in selective vesicle capture, we will anchor their cytoplasmic domains to mitochondria. This in-depth characterisation of how two key Salmonella virulence proteins modify membrane dynamics to enable Salmonella replication is critical to understand the mechanisms by which Salmonella causes disease. Furthermore, by producing a comprehensive description of the Salmonella-containing vacuole composition and how it is modified, we will uncover new therapeutic targets for combatting Salmonella infection.
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