Investigating the molecular mechanisms underpinning the quorum sensing dependent regulation of key virulence descriptors in Yersinia spp

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Yersinia pestis is probably responsible for more human deaths than any other microorganism.During the first major outbreak (pandemic), the plague of Justinian, around 80-100 million peopledied whereas The Black Death (ca 1348-1351) is believed to have killed between 1/3 to 1/2 of the24 million people living in Europe. Its 'success' as a pathogen is attributed to the fact that it ishighly contagious and death can occur in as little as 1-2 days. The genus Yersinia thereforeoccupies a prominent place in the story of microbiology influencing human history and civilisationpossibly to a greater extent than any other bacterium. Outbreaks and subsequent deaths still occurin both developed and third world locations where infections present as bubonic, pneumonic orsepticaemic plague. Untreated, mortality rates are extremely high and in the case of primarypulmonary plague this can approach 100% if untreated, and up to 50 % following the use ofappropriate antibiotics. Person-to-person pneumonic plague is rare due to the limited number ofcases at any given time but is highly infectious with 10 to 100 bacteria being sufficient to causeinfection. Infection can also be through oral, intradermal, subcutaneous, or intravenous routes.Transmission is greatly exacerbated because Y. pestis is a zoonotic infection using secondarymammalian and insect hosts.Yersinia enterocolitica and Yersinia pseudotuberculosis (from which Y. pestis recently evolved) arealso highly adaptable primary human pathogens, which in contrast to Y. pestis cause gastricinfections which are usually non-lethal. All three possess a type three secretion (T3S) systemwhich delivers effector proteins into the cytosol of eukaryotic cells through a macromolecularneedle-like structure known as the injectisome causing disruption of host cell signalling systems,triggering cytoskeletal rearrangement and inducing apoptosis. All the structural components of theinjectisome, along with the effectors are encoded on a virulence plasmid where expression isregulated by temperature.These human pathogens have evolved sophisticated molecular networks that facilitate migrationbetween the environment and their animal hosts and we have shown that the quorum sensing cellto-cell signalling systems of Yersinia spp. regulates a number of virulence related phenotypesincluding motility, biofilm formation, aggregation, N-acetylglucosamine metabolism and T3S. Thesevirulence-related phenotypes represent novel targets for the control of virulence which is ofparticular importance in the context of the consequences of the re-emergence of a multi-drugresistant Y. pestis strain.Iron-sulphur cluster-containing proteins are a group of regulators with a range of functionsincluding sensing of molecular oxygen, stress response, and iron regulation. The iron sulphurcluster regulator IscR is involved in a homeostatic mechanism believed to regulate Fe-Scluster biogenesis in Escherichia coli and in Y. pseudotuberculosis it has been shown to beinvolved in the regulation of the T3S system via the T3S system regulator LcrF.Given that QS and IscR regulates the T3S system this project will focus on investigating themolecular regulatory mechanisms which link these three systems together. Y. pseudotuberculosisand Y. pestis will be used for this work and the project will also investigate the Y. pestis response inour Caenorhabditis elegans (nematode worm), Xenopsylla cheopis (oriental rat flea) and Pediculushumanus humanus (human body louse) model systems.