The impact of IFITM3 genetic variation on virus infection, immune responses and disease outcome

Supervisors: Prof Tao Dong and Dr Dannielle Wellington

Project overview
IFITM3 is an IFN-induced transmembrane protein found within the endosomal compartment of cells. Other members of the IFITM family include IFITM1 and IFITM2, which differ from IFITM3 by 30 and 16 amino acids, respectively. The IFITM3 protein is known to inhibit the entry of many RNA viruses, including influenza virus, HIV, Hanta virus and Hepatitis C Virus into cells. It is thought that the IFITM3 protein restricts influenza A virus entry into cells by preventing fusion of the viral envelope with cellular membranes in acidic endosomes, however this mechanism of action is still being investigated. Others and we have shown that a SNP variant, rs12252-C, which is common in Asian populations, is greatly increased in patients with severe acute influenza, HIV infection and Hanta virus infection. This SNP does not generate an amino acid change and is thus unlikely to alter the protein structure in any way. However, how this synonymous SNP alters viral restriction is still unknown.

The aim of this D.Phil project is to understand how the IFITM3 rs12252-C variant differs from the more common T variant in its ability to restrict entry of virus into cells (i.e. influenza, HIV and HCV), and to determine which immune signalling pathways and proteins are affected. Progress in this project will be greatly aided by the unique set of reagents we have recently generated in our laboratory, including CRISPR/Cas9 knock out/in cell lines and an IFITM3-specific antibody which is not commercially available. In addition, we have access to unique patient and healthy control cohorts from China, which are available for the study.

Training Opportunities
This project will be based in the MRC Human Immunology Unit at the Weatherall Institute of Molecular Medicine, with access to state-of-the-art facilities. The project provides an opportunity for training in a broad range of different techniques, including cell culture, Western blot, fluorescence imaging, flow cytometry, RNAseq analysis, molecular biology and bioinformatic analysis.

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.

Publications

  1. Zhang YH, et al. Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals.2013 Nat Commun 
  2. Makvandi-Nejad et al. Lack of truncated IFITM3 transcripts in cells homozygous for the rs12252-C variant that is associated with severe influenza infection. 2017. JID accepted 
  3. Zhang Y et al. Interferon-induced transmembrane protein-3 rs12252-C is associated with rapid progression of acute HIV-1 infection in Chinese MSM cohort. 2015, AIDS 
  4. Wilkinson TM, et al. Preexisting influenza-specific CD4 + T cells correlate with disease protection against influenza challenge in humans 2012, Nature Medicine

For further information, please contact: Prof Tao Dong