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An ex vivo model system for understanding and manipulating host pathogen interactions in the lung


   College of Medicine and Veterinary Medicine

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  Dr G McLachlan, Dr T Burdon, Dr F Grey  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Infectious respiratory disease is one of the major global health concerns. Chronic respiratory disease is extremely common across species and is a significant burden in animal and human health. The control of respiratory disease requires an understanding of the complexities and interaction between the organisms that are present and the host. A representative system that allows interrogation of the pathways involved in the disease process between pathogen and the lung has the potential to improve our understanding and reduce disease.

Alveolar macrophages (AM), the most abundant antigen-presenting cells in the lungs, play a critical role in regulating pulmonary immune responses to inhaled pathogens /allergens and have a distinct phenotype compared to macrophages from other tissues.

This project will evaluate the co-culture of Pluripotent Stem Cell-derived pig macrophages (PSCdMs) with porcine precision cut lung slices (PCLS) as a system for modelling in vivo host - pathogen interactions.

The project will combine the expertise of generating pig PSCdM (Burdon lab) and the PCLS culture system (McLachlan lab). Initial studies will develop the PSCdM/PCLS co-culture and subsequent macrophage recovery system using GFP-expressing PSCdM, building on preliminary work to generate single cell suspensions from PCLS.

A comparison of co-cultured PSCdMs with, naïve PSCdMs and ex vivo/in vivo alveolar macrophages will be performed using transcriptome sequencing and cell type markers to investigate the role of the tissue environment on macrophage phenotype.

The project will then examine whether co-culture alters the response of the macrophages to pathogen infection of lung/and or macrophages using porcine respiratory pathogens such as PRRSV, Influenza Virus, Porcine respiratory coronavirus (PRCV).

The project will also test the role of candidate regulator/regulatory pathway(s) in controlling pathogen response in PSCdMs. This will involve generating gene edited macrophages and/or PCLS using CrispR/Cas gRNA delivery in collaboration with Finn Grey using existing gRNA libraries.


Funding Notes

This 3.5 year studentship opportunity is open to UK and international students and provides funding to cover stipend, tuition fees and consumable/travel costs. Applications including a statement of interest and full CV with names and addresses (including email addresses) of two academic referees, should be emailed to [Email Address Removed].
When applying for the studentship please state clearly the project title/s and the supervisor/s in your covering letter.
We would encourage applicants to list up to three projects of interest (ranked 1st, 2nd and 3rd choice) from those listed with a closing date of 4th January 2023 at https://www.ed.ac.uk/roslin/work-study/opportunities/studentships

References

Meek, S., Watson, T., Eory, L. et al. Stem cell-derived porcine macrophages as a new platform for studying host-pathogen interactions. BMC Biol 20, 14 (2022). https://doi.org/10.1186/s12915-021-01217-8  
Bryson, K.J., Garrido, D., Esposito, M. et al. Precision cut lung slices: a novel versatile tool to examine host–pathogen interaction in the chicken lung. Vet Res 51, 2 (2020). https://doi.org/10.1186/s13567-019-0733-0
Happle, Christine et al. “Pulmonary Transplantation of Human Induced Pluripotent Stem Cell–derived Macrophages Ameliorates Pulmonary Alveolar Proteinosis.” American journal of respiratory and critical care medicine. 198.3 (2018): 350–360.

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