Identifying focal points and functional relevance of host-microbe communication during tissue injury and repair

Project offered for Ker Memorial PhD Studentship in Infectious Diseases

Tissue repair is critical for a eukaryotic host to return to homeostasis following acute injuries. As part of this reparative process, injury‑induced regulated cell death signals to the surrounding tissue to raise the alarm. Traditionally, the focus of regenerative biology has been on the growth factors that promote stem cell differentiation and/or epithelial cell proliferation. Recent work from the Anderson and Lucas labs has independently shown that dying epithelial cells secrete soluble metabolites that promote bacterial growth within the intestinal tract (Anderson lab) as well as macrophage‑mediated epithelial repair within the lung (Lucas lab). Interestingly, both host and microbe seem to be using the same death‑dependent signals for their own purpose. These paradigm‑shifting findings raise the exciting question: is cross‑species competition for these signalling molecules impacting host tissue repair?

To answer this question, the PhD project will:

1. Visualize fluorescently labelled bacteria and host immune cells and quantify their interaction during tissue injury and repair using a model of zebrafish tail wounding.
2. Perform unbiased RNA sequencing (bulk and single cell) on bacterial isolates and host macrophages to identify relevant response pathways within each species.
3. Utilize advanced bacterial genetics and mammalian genetic + pharmacological approaches to block target pathways.
4. Apply these findings to models of injury including zebrafish tail wounding and mouse intestinal and lung infections.
5. Assist with translation of these findings to human‑derived cell and tissue samples.
6. Test the relevance of these findings to bacterial competition using germ free mice. 

The PhD student will be trained in the following inter‑disciplinary methodologies:

1. Fluorescence-based microscopy.
2.  Flow cytometry.
3. Fundamental molecular biology.
4. Bioinformatic analyses of RNA sequencing datasets.
5. in vitro culturing of cells from multiple organisms (bacteria, zebrafish, mouse, human).
6. Bacterial mutagenesis.
7. in vivo injury models (zebrafish and mouse) across multiple tissue systems (skin, lung, intestine).

 The findings from this PhD studentship will be used to identify novel therapeutic targets aimed at limiting harmful bacterial growth while promoting reparative epithelial cell-macrophage communication. New relationships with third party companies to commercialize these findings will be pursued as necessary.

• https://www.ed.ac.uk/inflammation-research/people/principal-investigators/dr-cj-anderson
• https://www.ed.ac.uk/inflammation-research/people/principal-investigators/dr-christopher-lucas

Training and skills development

An equal emphasis will be placed on the training and development of the PhD student as scientific discovery. This cutting-edge PhD studentship will uniquely prime the candidate for future career endeavours within academia (ie postdoctoral fellowship) or outside of academia (ie industry, science policy, science communication, etc). The PhD student will benefit from acquiring diverse, and highly marketable, technical skills across the major disciplines of microbiology and immunology, including advanced bioinformatics. Further, the student will gain hands-on experience in multiple model organisms (bacteria, zebrafish, mice) and in multiple tissue systems (skin, lung, intestine) that would be largely applicable in any future career in academia or industry.

The Anderson lab is supported by a Wellcome Trust Career Development Award (2023-2031) and the Lucas lab is supported by an MRC Clinician Scientist Fellowship (2023-2028) and an MRC programme grant (2022-2027). As part of this support, the PhD student will receive the following career development opportunities:

1. International travel to New York City (approximately 1-2 weeks) to receive expert training in RNA sequencing analysis at Memorial Sloan Kettering under the supervision of Prof. Justin Perry.
2. International travel to Ghent, Belgium (approximately 1 month) to receive expert training and perform infections in germ free mice at the VIB-UGent Center for Inflammation Research under the supervision of Prof. Lars Vereecke.
3. Public speaking, writing, and leadership training offered by grant-funded courses and additional external learning tools (ex: MasterClass) to supplement hands-on training provided by the supervisors.
4. The opportunity to present their work within the department, at domestic conferences (ex: BSI), and at international conferences