Human Cellular Genetics of Innate Immunity
Research type
Research Study
Full title
Human Cellular Genetics of Innate Immunity
IRAS ID
200648
Contact name
Sarah Teichmann
Contact email
Duration of Study in the UK
3 years, 7 months, 2 days
Research summary
Summary of Research
When cells get infected with viruses, they elicit a rapid immune response for their own defence and for alerting other cells, which is master regulated by interferon - a protein whose expression results in dramatic changes in the cell.
Here we plan to study two main questions, which are pivotal to our understanding of how different individuals resist various pathogens:
(1) How does the interferon response vary between different human individuals with different genetic backgrounds?
(2) How do different individual cells respond to a danger signal that should elicit interferon, and how do they respond to a direct interferon stimulus?We plan to use skin cells (fibroblasts) from Cambridge BioResource volunteers, to carry out our research. We may also use cell-lines made at the Sanger Institute as part of the HIPSCI project (Human Induced Pluripotent Stem Cells Initiative, http://www.hipsci.org/). The HIPSCI project was funded by the Wellcome Trust and Medical Research Council (MRC) to create a catalogue of high-quality induced pluripotent stem cells (iPS cells) for use by both academia and industry.
We will generate a wide range of molecular, including whole genome, and cellular
data that will enable us to understand the function of genes in great detail.We will share the results of our work by producing scientific publications, presenting at conferences and we will distribute the results of the genetic analysis to other researchers through a managed access system via the European Genome-phenome Archive (EGA) operated by the EMBL-European Bioinformatics Institute.
Summary of Results
All cells in the body can mount a so-called innate immune response. The innate immune response is triggered by danger signals, molecules that are associated with bacterial and viral infections, and is a critical component in our defence against pathogens. In this study, we harnessed the power of single cell sequencing to understand how much variability exists in this innate immune response between cells of the same cell type, between different cell types and between species (Hagai et al. Nature, 2018). We found that some of the effector genes, such as immune stimulating factors such as cytokines, show high variability, whilst regulators of the innate responses are more similar. In addition, the promoters of the genes with high variability had unique structural features. The implications of this study are that there are evolutionary benefits to high variability, allowing organisms to mount an optimal response, whilst at the same time minimising tissue damage. This knowledge will be useful when trying to modulate immune responses therapeutically.
A second study probed the innate immune system by mimicking viral and bacterial infections in a set of fibroblasts with very well documented genetic variation (Kumasaka et al Nature Genetics in press). Again, single cell sequencing was employed and computational methods developed to obtain insights from our data, harnessing the ability to computationally model response pathways. In particular, it allowed us to understand genetic variation that had no effect in resting cells but changed the behaviour of cells under specific conditions. For example, we found a genetic variant that exerted its effect after SARS-CoV-2 stimulation. Understanding such variants is important for understanding who is most at risk from infection, and highlights pathways that can potentially be modulated by drugs.REC name
East of Scotland Research Ethics Service REC 1
REC reference
16/ES/0034
Date of REC Opinion
26 Feb 2016
REC opinion
Favourable Opinion