Investigating innate immune signalling with CRISPR-Cas9 screens

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.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

Generic skills training is offered through the Medical Sciences Division’s Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.