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

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 people
died whereas The Black Death (ca 1348-1351) is believed to have killed between 1/3 to 1/2 of the
24 million people living in Europe. Its 'success' as a pathogen is attributed to the fact that it is
highly contagious and death can occur in as little as 1-2 days. The genus Yersinia therefore
occupies a prominent place in the story of microbiology influencing human history and civilisation
possibly to a greater extent than any other bacterium. Outbreaks and subsequent deaths still occur
in both developed and third world locations where infections present as bubonic, pneumonic or
septicaemic plague. Untreated, mortality rates are extremely high and in the case of primary
pulmonary plague this can approach 100% if untreated, and up to 50 % following the use of
appropriate antibiotics. Person-to-person pneumonic plague is rare due to the limited number of
cases at any given time but is highly infectious with 10 to 100 bacteria being sufficient to cause
infection. Infection can also be through oral, intradermal, subcutaneous, or intravenous routes.
Transmission is greatly exacerbated because Y. pestis is a zoonotic infection using secondary
mammalian and insect hosts.
Yersinia enterocolitica and Yersinia pseudotuberculosis (from which Y. pestis recently evolved) are
also highly adaptable primary human pathogens, which in contrast to Y. pestis cause gastric
infections which are usually non-lethal. All three possess a type three secretion (T3S) system
which delivers effector proteins into the cytosol of eukaryotic cells through a macromolecular
needle-like structure known as the injectisome causing disruption of host cell signalling systems,
triggering cytoskeletal rearrangement and inducing apoptosis. All the structural components of the
injectisome, along with the effectors are encoded on a virulence plasmid where expression is
regulated by temperature.
These human pathogens have evolved sophisticated molecular networks that facilitate migration
between 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 phenotypes
including motility, biofilm formation, aggregation, N-acetylglucosamine metabolism and T3S. These
virulence-related phenotypes represent novel targets for the control of virulence which is of
particular importance in the context of the consequences of the re-emergence of a multi-drug
resistant Y. pestis strain.
Iron-sulphur cluster-containing proteins are a group of regulators with a range of functions
including sensing of molecular oxygen, stress response, and iron regulation. The iron sulphur
cluster regulator IscR is involved in a homeostatic mechanism believed to regulate Fe-S
cluster biogenesis in Escherichia coli and in Y. pseudotuberculosis it has been shown to be
involved 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 the
molecular regulatory mechanisms which link these three systems together. Y. pseudotuberculosis
and Y. pestis will be used for this work and the project will also investigate the Y. pestis response in
our Caenorhabditis elegans (nematode worm), Xenopsylla cheopis (oriental rat flea) and Pediculus
humanus humanus (human body louse) model systems.