Investigating innate immune signalling with CRISPR-Cas9 screens

Supervisor: Associate Prof Jan Rehwinkel

Project Overview
Genome editing using CRISPR-Cas9 is a powerful system to study gene function and can be used in genome-wide screens. This project will make use of this transformative technique to identify novel regulators of innate immune responses. Our group is interested in signalling pathways that allow cells to detect invading viruses. Indeed, detection of virus presence by the innate immune system is a crucial event mediated by germ-line encoded receptors inside cells. These sensors of virus presence signal for the induction of innate immune response genes, such as those encoding type I interferons. Many of these receptors sense viral nucleic acids. For example, RIG-I recognizes the RNA genomes of viruses such as influenza A virus (Rehwinkel et al., Cell 2010) and cGAS detects viral DNA. In addition to their roles in virus infection, these sensors are also important in some autoinflammatory diseases and in cancer.

We have recently established several reporter cell lines for the induction of type I interferons by virus-sensing receptors. Furthermore, we have established CRISPR-Cas9 screening protocols in these cells that can now be applied to genome-wide sgRNA libraries.

The successful candidate will contribute to and extend these studies. In particular, we will (i) perform several screens for RNA and DNA sensing pathways with the intention of identifying new molecular players in these signalling cascades, (ii) validate hits using secondary screens and (iii) analyse in-depth the role of selected candidates in the detection of virus infection, and in models of autoimmune disease and cancer. As such, the project has basic and translational research components and may lead to identification of new genes involved in innate immunity.

Training Opportunities
Based in the MRC Human Immunology Unit at the Weatherall Institute of Molecular Medicine, with access to state-of-the-art facilities, this project provides an opportunity for training in a broad range of different techniques, including cell culture, molecular biology, immunology, virology and mouse models. This project will additionally benefit from close collaboration with many scientists. The successful candidate will be supervised by Jan Rehwinkel and additional day-to-day supervision will be provided by an experienced member of the Rehwinkel lab.

Molecular Biology

For further information, please contact Prof Jan Rehwinkel