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MRC Precision Medicine DTP: Limiting infection: Identifying factors for the in vivo dissemination of themajor nosocomial pathogen Klebsiella pneumoniae


Project Description

Background
The zebrafish infection model (Danio rerio) is a reliable verterbrate model which harbors a mammalian-like innate immune system. D. rerio has successfully been used to elucidate factors necessary for host-pathogen interactions1. The success of this model rests on the non- invasive live-cell imaging techniques allowing mechanistic details for tissue-tropism and pathogen-specific survival mechanisms to be established.
In this project, we seek to establish and implement a zebrafish model to study the infective process and the subsequent immune response of the major human pathogen Klebsiella pneumoniae (KPN). KPN is a major nosocomial pathogen, driven by its ability to acquire and transmit antimicrobial resistance (AMR), that according to the CDC and WHO poses a critical threat to human health. As such, there are two main underdeveloped research strategies which require biological and mechanistic validation to limit KPN infection; the first, is detailed systematic high-throughput genome-based analyses of KPN infection and the second, is the exploitation of host-driven diagnostics for rationalisation of antibiotic use. Given that antimicrobial resistance is a critical healthcare issue, the understanding of in-vivo transmission and survival is necessary in the identification, stratification and use of antimicrobial therapy
against Klebsiella.
Whilst, studies that describe KPN-D. rerio infection models exist2, these do not provide a systematic assessment of both bacterial and host factors necessary for infection. Therefore, the overriding aim of this proposal is to establish and implement an in-vivo infection model to identify the specific roles of key innate cells such as macrophages3 which can be mapped to specific Klebsiella characteristics. As such, the key aims of this proposal are to firstly, establish the molecular parameters of a Klebsiella-D. rerio in vivo infection model, and secondly, identify specific-innate immune signatures for diagnostic or therapeutic exploitation.
Aim 1: Establish and Implement a Klebsiella-D. rerio infection model system. To implement further studies into the pathogen-host response we will first parameterise with factors such as types of KPN infection routes2 e.g. yolk sac vs otic vesicle, bacterial inoculum, time of colonisation to infection, rates of bacterial transmission with tagged and untagged strains of Klebsiella pneumoniae.
Aim 2: Establish the pathogen factors necessary for KPN infection in D.rerio. With the model developed in Aim 1, where using a Tn-seq approach, transposon mutant pools of candidate KPN strain(s), will be used to establish the genetic factors necessary for in vivo infection. This data is critical in identifying novel genes relevant to infection but also in validating the model against previously identified bacterial factors in murine and human infection models.
Aim 3: Establish the infection dynamics of WT KPN in a macrophage depleted model of D. rerio. The current MRC AMR strategy underscores the exploitation of the innate immune response as a treatment alternative against antibiotic-resistant bacteria. In collaboration with Prof Dockrell and the MRC-funded SHIELD consortium (https://shieldamrresearch.org/about/), we will use the macrophage depleted transgenic D.rerio model3 to characterise the effects of KPN infection. Comparative analyses of data derived from Aim 2and 3 will allow the mapping of specific KPN-macrophage responses and validate pathogen and host factors for systemic spread and tissue trophism. This data will be utilised in existing SHIELD consortium screens to establish macrophage responses as tools for diagnosis or treatment of KPN infection4.
The expected training outcomes will enable the student to train and gain expertise in molecular bacteriology, immunology, the development and implementation of an animal model and bioinformatics. This project addresses a key strategic priority area of AMR and in targeting efforts to reduce antibiotics. 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.
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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:

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 should contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2019

Qualifications criteria: Applicants applying for a 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 qualifications, in an appropriate science/technology area.

Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £14,777 (RCUK rate 2018/19) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: View Website

Enquiries regarding programme:

References

1. https://www.sciencedirect.com/science/article/pii/S1074761304000846 2. https://www.frontiersin.org/articles/10.3389/fcimb.2018.00030/full
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717010/
4. https://mbio.asm.org/content/9/3/e00874-18

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