BBSRC DTP targeted studentship - The role of RNA elements that control protein synthesis during host pathogen interaction

Understanding host responses to pathogen infection is critical for guiding the development of intervention strategies. Changes in gene expression are commonly observed upon infection, as exemplified by numerous transcriptomic studies. However, techniques to analyse genome-wide responses at the level of protein synthesis have only recently become available with ribosome profiling, permitting a more sophisticated interrogation of host-pathogen interaction at the level of translation. This project will focus on the synthesis of flagellin in the food-borne enteric pathogen Salmonella enterica. Flagellin is a major virulence factor as it helps the bacterium swim to its preferred site of infection inside the host and is also a key antigen for the host innate immune system. The major structural component of flagella consists of thousands of copies of flagellin monomer protein and Salmonella undergoes phase-switching to produce two types of flagellin - FljB or FliC - allowing the pathogen to evade the host immune s system. Indeed, it was shown that FljB phase 2 flagellin is involved in the intestinal stage of infection but the bacterium switches to FliC phase 1 flagellin synthesis for systemic infection [Ikeda et al 2001 Infection and Immunity]. This alternative expression of the two flagellins is achieved by control of the fljBA operon encoding FljB and FljA, a repressor protein that controls expression of the distally located FliC through direct binding of the FliC 5’UTR, thus directly impeding FliC protein synthesis [Aldridge et al 2006 PNAS]. However, how this switch occurs in the context of infection is less clear and whether FljA regulates other mRNAs in a similar manner is unknown. The candidate will acquire tailored high-throughput next generation sequencing techniques, both experimentally and computationally to identify translationally regulated targets in response to stresses that modulate flagella synthesis (i.e. infection and different osmotic stresses), followed by a wide range of RNA-biochemistry to characterise the mechanisms utilised for this process.

The student will be supervised by Dr Betty Chung, in collaboration with Dr Gillian Fraser, both in the Division of Micribiology and Parasitology and Dr Andrew Firth in the Division of Virology.