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How does the protein LicB underpin infection by opportunistic bacteria?

  • Full or part time
  • Application Deadline
    Monday, November 25, 2019
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

The human body is colonized by trillions of bacteria. These are generally harmless but can become a serious threat to human health. This project will investigate, for the first time, a specific protein that supports bacterial residence in the nose and throat. This protein also helps these bacteria to invade the body and evade the immune system to cause dangerous infections. Understanding the activity of this protein provides new insights into pathogenic bacteria.

This project will investigate bacteria carried in the nose and throat that can cause life- threatening infections including pneumonia, meningitis and sepsis. These bacteria are also the dominant cause of acute respiratory infections that cause 100,000 hospital admissions and 5 million GP visits each year in the UK. Our focus is on the molecular interactions that underpin bacterial colonization and invasion. We wish to understand how a particular protein, known as LicB, contributes to these processes. LicB is found in major pathobionts of the human respiratory tract including Streptococcus, Haemophilus, Neisseria, and Moraxella spp. LicB is an integral membrane protein that is a choline permease, catalysing the transport of choline from the exterior to the interior of the cell. This is the critical first step of a short metabolic pathway that modifies the bacterial cell envelope with phosphorylcholine. The impacts of this modification are far-reaching, allowing bacteria to adhere to epithelial cells, invade the bloodstream and evade the immune system. The importance of LicB in the bacterial lifecycle is such that it has recently been identified as an essential gene in Streptococcus pneumoniae, the bacterium responsible for the pneumonococcal diseases that kill over 800,000 children worldwide every year. LicB thus plays a fundamental role in the biology of opportunistic pathogens and is a potential drug target. However, the sequence of LicB is unrelated to other choline transporters and the precise mechanism of choline binding and transport remain cryptic. We have applied bioinformatics methods to identify a novel sequence motif (AMxxNITYxxW) that is absolutely and uniquely conserved in LicB proteins, but the importance of this motif has not been experimentally verified. We now seek a GW4 BioMed student to pursue a pioneering interdisciplinary research project that will reveal the structure and function of LicB for the first time. One strand of this research project will use biochemical and biophysical methods to describe the activity of LicB in vitro. These measurements will build directly upon compelling preliminary data to determine the substrate affinity and substrate profile of LicB as well as the transport mechanism, energetics and kinetics. Specific mutations will be introduced into LicB to directly probe the role of each residue in the conserved LicB family motif. A concurrent research strand will enter purified LicB into crystal trials to enable structural determination by X-ray crystallography. A third research strand will establish a recombinant Streptococcus strain to verify our in vitro functional data, to assess the impacts of LicB mutations on phosphorylcholine production, and to relate this to bacterial invasion in a respiratory epithelial cell line. The outcomes will be the first comprehensive molecular study of this key bacterial protein, providing critical new knowledge to the field; an unprecedented understanding of the role of LicB in bacterial adherence and invasion; and novel experimental systems that could ultimately be used to screen for new antibiotics.

Funding Notes

Link to project: View Website

DEADLINE: 5.00 pm on Friday 25th NOVEMBER 2019
Please complete application to the GW4 BioMed MRC DTP for an ‘offer of funding’. You also need to make an 'offer to study' to your chosen institution(s) – details are on the website. View Website
A 3.5 year funded studentship by the GW4BioMed MRC Doctoral Training Partnership. Full UK/EU tuition fees, a stipend matching UK Research Council Minimum (£15,009 p.a. for 2019/20, updated each year).
Additional research training and support funding of up to £5,000 per annum is also available.

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