R(D)SVS: 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  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 in both humans and animals. The control of respiratory disease requires an understanding of the complexities and interaction between the pathogens and the host. A representative system that allows interrogation of the pathways involved in these disease processes has the potential to improve our understanding and reduce disease

Pulmonary Alveolar macrophages (PAMs), the most abundant antigen-presenting cells in the lungs, play a critical role in regulating immune responses to inhaled pathogens /allergens.

The project will combine the expertise of generating pig PSCdM (Burdon lab) and the PCLS culture system (McLachlan lab), building on preliminary studies showing that co-cultured PSCdM (ccPSCdM) can be recovered by enzymatic dissociation and cell-sorting. This system will be developed further to allow co-isolation of resident PAMs.

A comparison of ccPSCdMs with, naïve PSCdMs and resident PAMs will be performed using transcriptome sequencing and cell type markers to investigate the role of the tissue environment on macrophage phenotype. Preliminary data indicates upregulation of peroxisome proliferator-activated receptor- gamma (PPARg) expression which is highly expressed in PAMs.

To characterise the change in cell phenotype further we will also examine whether the co-culture period alters the response of the ccPSCdMs to LPS and/or pathogen challenge (PRRSV, Toxoplasma) through challenge either of the isolated ccPSCdM or directly on the PCLS co-cultures.

Demonstration that the ccPSCdM response more closely resembles that of the PAMs than the starting PSCdMs would highlight the utility of the model in such studies. This has the potential to produce an ex vivo model system to study the response to respiratory pathogens in a system where starting iPSCs can be genetically modified, through gene editing, to manipulate and interrogate immune regulatory pathways in derived ccPSCdM. This model system aligns to the NC3Rs mission to reduce animal usage.

Funding information and application procedures:

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. 

Application form can be downloaded via https://www.ed.ac.uk/sites/default/files/atoms/files/rdsvs_gaffs_roslin_foundation_studentship_application_form_2024-25.doc

Please send your completed Application Form to [Email Address Removed]

If you are applying for more than one studentship please submit a separate application with a closing date of noon on 8th January 2024 at https://www.ed.ac.uk/roslin/work-study/opportunities/studentships  

Biological Sciences (4)

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.

Where will I study?

 About the Project