Every year, *Shigella* and *Salmonella* bacteria inject proteins into human gut cells to hijack the body’s defences, causing roughly 165 million cases of severe dysentery and 1 billion cases of food poisoning globally. These pathogens use a molecular syringe to deliver specific proteins—called effectors—that block the host’s ability to trigger inflammation or kill infected cells. Without these tricks, the bacteria cannot establish infection. This project aims to work out exactly how two families of effectors, EspO and NleF, bind to and manipulate key human proteins (Hax-1 and caspase-4) that control cell death and immune responses. This is fundamental science. There are currently no vaccines for *Shigella* or invasive *Salmonella*, and antibiotic-resistant strains are a growing threat. Understanding the precise molecular handshake between bacterial effectors and host proteins could reveal new targets for drugs that block infection at its earliest stage. Similar fundamental work on bacterial secretion systems has already led to experimental vaccines and anti-virulence therapies. A deeper grasp of these interactions may eventually help design treatments that let the body’s own defences clear the infection without relying on antibiotics.
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Escherichia coli is a bacterium that often inhabits the intestines of warm-blooded animals. Subsets of E. coli have evolved the ability to cause disease. One such group are enterohaemorrhagic E. coli (EHEC), which can cause bloody diarrhoea in humans. Infections can involve life-threatening complications affecting the kidneys and are frequently acquired via the food chain. Enteropathogenic E. coli (EPEC) strains are a related subset of bacteria that cause acute watery diarrhoea in infants in the developing world. Shigella strains, which are closely related to E. coli, cause bacillary dysentery (aka Shigellosis). Shigellosis, which is usually acquired by ingestion of contaminated food or water, remains a global endemic disease responsible for ca. 165 million cases of severe dysentery and 1 million deaths annually, particularly in children less than five years of age. Non-typhoidal Salmonella enterica (NTS) strains cause an estimated 1 billion cases of self-limiting foodborne gastroenteritis annually. More recently, multiple antibiotic-resistant strains have emerged as important causes of fatal invasive bacteraemia, particularly in sub-Saharan regions. Importantly, although considered high priority, no vaccines are yet available for either of these pathogens, the development of which relies on better understanding of their biology and infection strategies. EPEC, EHEC, Shigella and Salmonella rely on a 'molecular syringe' to colonise the intestines and produce disease. This syringe serves to inject a set of bacterial proteins termed effectors into cells lining the intestines. This process, known as Type III secretion (T3S), enables the bacteria to take control of processes inside host cells for their own benefit. Our research has shown that T3S is vital for adherence of EHEC and EPEC to the gut lining and to interfere with the induction of host responses that might otherwise resolve the infection. Infected hosts fight bacterial infection by mounting immune responses while infected cells might assist in clearing the pathogen by undergoing programme cell death (aka apoptosis). Importantly, low-level inflammation may assist the pathogens in establishing a foothold within the host as it modulates the gut physiology and the normal gut flora. It is therefore not surprising that the pathogenic E. coli, Shigella and Salmonella inject T3S effector proteins that subvert both inflammation and apoptosis. We recently found that the EPEC and EHEC T3SS effector NleF binds a host cell protein called caspase-4, which plays a role in both apoptosis and inflammation. Similarly, we found the effector EspO of EHEC, and it's family members in Shigella (OspE) and Salmonella (SopO) bind a host cell protein called Hax-1, which is a major inhibitor of apoptosis and has an indirect role in host immune responses. The broad aim of this work is to characterise the mechanism of action and to understand the role during infection of the EspO family members and NleF. In particular, our aim (which is also our strength) is to translate results obtained by biochemical and cell biology assays in vitro to pathogen-host interactions in vivo. The specific aims include: 1. Determine the structure of the EspO:Hax-1 and NleF:caspase-4 complexes 2. Determine the intracellular interactome of EspO family members and NleF 3. Dissect the EspO family members and NleF cell signalling pathways using cell culture models 4. Study the role of EspO, SopO and NleF and their host cell partner proteins in pathogen-host interaction in animal models in vivo
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