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Precision Medicine DTP - Establishing the role of pathogenetic mechanisms in the evolution of epidemic K. pneumoniae lineages


College of Medicine and Veterinary Medicine

About the Project

Background

The rising rates of antibiotic resistance limit the efficacy of life-saving antibiotics against all deadly infections but particularly against those caused by Gram-negative pathogens such as Klebsiella pneumoniae (KPN). KPN is a major nosocomial pathogen, driven by its’ ability to acquire and transmit antimicrobial resistance (AMR); where according to the CDC and WHO poses a critical threat to human health(1,2,3). Critically, KPN has emerged as a predominant pathogen associated with secondary bacterial infections in COVID-19 pneumoniae (unpublished, 4) underscoring its relevance as a major pathogen. Multiple studies now show that antibiotic pressure has led to the expansion of highly successful epidemic lineages which exhibit a combination of high levels of antimicrobial resistance and immune evasive phenotypes. As such, there are two main underdeveloped research strategies which require biological and mechanistic validation to limit KPN infection; the first, is detailed systematic bioinformatics-driven biological analyses of epidemic KPN lineages and the second, is the exploitation of these analytics in the rationalisation of antibiotic use. In this proposal, we will focus on the ubiquitously distributed ST15 KPN epidemic lineage. Preliminary phlyogenomic analyses suggests that ST15 strains have closely expanded with AMR gene acquisition in tandem with mutations resulting in the upregulation of the transcriptional regulator RamA. In previous work, we demonstrate that elevated RamA levels confer both reduced antibiotic susceptibility and immune evasive phenotypes through the modification of lipopolysaacharide. As such, we hypothesise that the successful dissemination of the ST15 epidemic lineage is linked to elevated RamA levels.

Aims

Aim 1: Phylogenomic-Analyses of Epidemic lineages of KP. Using existing genome sequences we will undertake a population level genomic and phylogenetic analyses of RamR mutations in different epidemic and ST15 lineages with temporal and geographic data to identify (i) additional mutational events (ii) emerging epidemic sub-lineages with advantageous mutations and (iii) map the potential drivers of mutational events.

Aim 2: Undertake comparative genomics of the RamA regulon in ST15 and non-ST15 epidemic lineages. Using data derived from the bioinformatic analyses, we will identify the relevant strains to undertake established transcriptomic and ChIP-seq based analyses, to ascertain the regulatory cascade and binding interactions of RamA. This data will be critical in defining the regulatory impact of RamA and facilitate mechanistic analyses of how these changes hostpathogen interactions in the ST15 epidemic lineage.

Aim 3: Establish the infection dynamics of ST15 (RamA overexpressed) and ST15R (RamA overexpression is repaired using genetic manipulation) in specific murine models which mimic systemic infection. Using the murine model of infection, in addition to assessing the viability of these strains in the presence of antibiotics, we will establish the immune checkpoints which are relevant to counter the infection of ST15 and ST15R variants. These data will be utilised in collaboration with Prof. David Dockrell in existing SHIELD consortium screens to establish innate immune responses as tools for diagnosis or treatment of KPN infection.

Training Outcomes

The expected training outcomes will enable the student to train and gain expertise in molecular bacteriology, immunology and in vivo work. This project addresses a key strategic priority area in strengthening AMR expertise, where the candidate will be trained in both bioinformatics and cutting edge molecular techniques. All supervisors have well-resourced labs and extensive experience in supervising and mentoring PhD students, which will provide for both the scientific and pastoral development of the candidate.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2021

Qualifications criteria: Applicants applying for an MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area. The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,285 (UKRI rate 2020/21).

Full eligibility details are available: View Website

Enquiries regarding programme:

References

1. https://academic.oup.com/femsre/article/41/3/252/3830265.

2. https://www.sciencedirect.com/science/article/pii/S1369527418300225.

3. https://www.pnas.org/content/112/27/E3574.

4. https://mbio.asm.org/content/11/4/e01806-20.

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