Cellular immunity and genetic restriction of Influenza, Hepatitis C virus infection and Hepatitis B associated heptocellular carcinoma.
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
Human infections, cancer development and the course of disease are mainly influenced by T cell responses. While a robust and appropriate T cell response is beneficial to the host, a weak or inappropriate response can be ineffective or even have a detrimental effect. Numerous factors influence the quality of the T cell response to viral infections or cancer development, predominant among them being the microenvironment of the infection site, the type of cells affected and in the case of infection, the variability of the virus. By understanding the key factors required for efficient control by the T cell response in a number of different viral infections and viral associated cancers, in particular HBV associated HCC, we aim to identify targets to augment and control the immune response as a way of improving the outcome of in several important human diseases.
While my group's main focus is T cell responses, a subset of the group focus on the important anti-viral restriction factor IFITM3, which is known to restrict >15 RNA viruses including Influenza A virus, HIV and Hepatitis C virus, however the mechanism of restriction is still unknown. Little conclusive data on IFITM3 is published due to its high homology to other IFITM family members. A single nucleotide polymorphism (SNP) within IFITM3 is known to prevent its viral restriction but again the mechanism for this is unknown. This interesting protein leaves us with several unanswered questions and we aim to characterise this protein using novel reagents in order to elucidate the mechanism by which viral restriction occurs.
While my group's main focus is T cell responses, a subset of the group focus on the important anti-viral restriction factor IFITM3, which is known to restrict >15 RNA viruses including Influenza A virus, HIV and Hepatitis C virus, however the mechanism of restriction is still unknown. Little conclusive data on IFITM3 is published due to its high homology to other IFITM family members. A single nucleotide polymorphism (SNP) within IFITM3 is known to prevent its viral restriction but again the mechanism for this is unknown. This interesting protein leaves us with several unanswered questions and we aim to characterise this protein using novel reagents in order to elucidate the mechanism by which viral restriction occurs.
Technical Summary
Influenza remains a global threat. The avian influenza H7N9 outbreak in China has a high death rate and is able to transmit from human-to-human. We recently established that people with a particular genetic variant of IFITM3-rs12252-C are six times more likely to suffer from severe influenza infection than those without. This variant gene is very rare in Northern European populations, but is common in the Chinese population. The IFITM3 protein is known to inhibit the entry of many RNA viruses including influenza virus into cells and it is assumed that the variant is unable to do this. The first aim of our program is to assess if a lower level of IFITM3 expression is responsible for this association and determine which immune signalling pathway and proteins are affected. The impact of this genetic variation on the efficacy of the seasonal influenza and live attenuated vaccinations will also be evaluated.
HBV-associated Hepatocellular Carcinoma (HCC) is one of the leading causes of death from cancer worldwide. Of the 1 million new cases of liver cancer cases globally every year, 50% are in China. The second aim is to address whether differences in HCC microenvironment modulate the quality of HCC-specific T cells and if this is affected by the presence or absence of chronic infection by HBV.
To pursue these aims, we will continue to use the cohorts established through collaborations in China and will expand to include additional cohorts in the UK and abroad. Overall, we anticipate that the two main components of our programme - to study the impact of virus restriction by IFITM3 on the nature and risk of severe influenza infection and on HCV infection, and to explore new ways of manipulating tumour associated antigen-specific (TAA) T cells in HBV-associated HCC as well as HPV and EBV associated cancers, including viral and non-viral antigens –will inform vaccine development and therapeutic intervention.
HBV-associated Hepatocellular Carcinoma (HCC) is one of the leading causes of death from cancer worldwide. Of the 1 million new cases of liver cancer cases globally every year, 50% are in China. The second aim is to address whether differences in HCC microenvironment modulate the quality of HCC-specific T cells and if this is affected by the presence or absence of chronic infection by HBV.
To pursue these aims, we will continue to use the cohorts established through collaborations in China and will expand to include additional cohorts in the UK and abroad. Overall, we anticipate that the two main components of our programme - to study the impact of virus restriction by IFITM3 on the nature and risk of severe influenza infection and on HCV infection, and to explore new ways of manipulating tumour associated antigen-specific (TAA) T cells in HBV-associated HCC as well as HPV and EBV associated cancers, including viral and non-viral antigens –will inform vaccine development and therapeutic intervention.
People |
ORCID iD |
Tao Dong (Principal Investigator) |
Publications
Abd Hamid M
(2020)
Self-Maintaining CD103+ Cancer-Specific T Cells Are Highly Energetic with Rapid Cytotoxic and Effector Responses.
in Cancer immunology research
Alifu M
(2018)
HLA-A*30:01 and HLA-A*33:03 are the protective alleles while HLA-A*01:01 serves as the susceptible gene for cervical cancer patients in Xinjiang, China.
in Journal of cancer research and therapeutics
Asciak R
(2021)
Pleural Fluid Has Pro-Growth Biological Properties Which Enable Cancer Cell Proliferation
in Frontiers in Oncology
Barrett JR
(2021)
Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses.
in Nature medicine
Chen X
(2018)
The Early Antibody-Dependent Cell-Mediated Cytotoxicity Response Is Associated With Lower Viral Set Point in Individuals With Primary HIV Infection.
in Frontiers in immunology
De Silva TI
(2021)
The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.
in iScience
Dejnirattisai W
(2021)
The antigenic anatomy of SARS-CoV-2 receptor binding domain.
in Cell
Dejnirattisai W
(2021)
Antibody evasion by the P.1 strain of SARS-CoV-2
in Cell
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00008/1 | 01/04/2017 | 31/03/2023 | £2,738,000 | ||
MC_UU_00008/2 | Transfer | MC_UU_00008/1 | 01/04/2017 | 31/03/2023 | £1,821,000 |
MC_UU_00008/3 | Transfer | MC_UU_00008/2 | 01/04/2017 | 31/03/2023 | £2,257,000 |
MC_UU_00008/4 | Transfer | MC_UU_00008/3 | 01/04/2017 | 31/03/2023 | £1,459,000 |
MC_UU_00008/5 | Transfer | MC_UU_00008/4 | 01/04/2017 | 31/03/2023 | £1,346,000 |
MC_UU_00008/6 | Transfer | MC_UU_00008/5 | 01/04/2017 | 31/03/2023 | £1,660,000 |
MC_UU_00008/7 | Transfer | MC_UU_00008/6 | 01/04/2017 | 31/03/2023 | £401,000 |
MC_UU_00008/8 | Transfer | MC_UU_00008/7 | 01/04/2017 | 31/03/2024 | £2,876,000 |
MC_UU_00008/9 | Transfer | MC_UU_00008/8 | 01/04/2017 | 31/03/2023 | £2,568,000 |
MC_UU_00008/10 | Transfer | MC_UU_00008/9 | 01/04/2017 | 31/03/2023 | £2,060,000 |
MC_UU_00008/11 | Transfer | MC_UU_00008/10 | 01/04/2017 | 31/03/2023 | £1,477,000 |
Description | CO-CONNECT Advisory Steering Committee |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | UK-India COVID-19 partnership initiative |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
Description | UKRI Future Leaders Fellowships Scheme |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | CAMS Oxford Institute |
Amount | £26,416,931 (GBP) |
Organisation | Chinese Academy of Medical Sciences (CAMS) |
Sector | Academic/University |
Country | China |
Start | 01/2019 |
End | 12/2023 |
Description | DSHC NDM Grant |
Amount | £2,382,979 (GBP) |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 10/2021 |
End | 04/2023 |
Description | Janssen Pharmaceutical - Characterising HBV specific T cells in HBV associated liver disease |
Amount | $500,000 (USD) |
Organisation | Janssen Research & Development |
Sector | Private |
Country | Global |
Start | 03/2019 |
End | 03/2020 |
Description | Monkeypox Rapid Research Response |
Amount | £666,656 (GBP) |
Funding ID | BB/X011607/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2022 |
End | 05/2023 |
Description | Mosaic RBD nanoparticles to protect against a new pandemic caused by emergent zoonotic SARS-like betacoronavirus |
Amount | $30,000,000 (USD) |
Organisation | Coalition for Epidemic Preparedness Innovations |
Sector | Learned Society |
Country | Norway |
Start | 06/2022 |
End | 05/2026 |
Description | CAMS Oxford Institute |
Organisation | Chinese Academy of Medical Sciences (CAMS) |
Country | China |
Sector | Academic/University |
PI Contribution | Jointly set up the CAMS Oxford Institute, collaborative research - Immunity to infection and cancer |
Collaborator Contribution | Jointly set up the CAMS Oxford Institute, collaborative research - Immunity to infection and cancer CAMS Innovation fund provided £20million |
Impact | None yet |
Start Year | 2018 |
Description | CSC-COI Scholarship partnership |
Organisation | Chinese Scholarship Council |
Country | China |
Sector | Charity/Non Profit |
PI Contribution | MD PhD Scholarship to host around 50 students over 5 years at the University of Oxford |
Collaborator Contribution | MD PhD Scholarship to provide funding for 50 students over 5 years |
Impact | None yet |
Start Year | 2018 |
Description | Simcere collaboration |
Organisation | Simcere Diagnostics |
Country | China |
Sector | Private |
PI Contribution | Research collaboration partners |
Collaborator Contribution | Funding contribution for research |
Impact | None yet |
Start Year | 2020 |
Title | POLYPEPTIDE PANELS AND USES THEREOF |
Description | The present invention relates to one or more polypeptides derived from SARS-CoV-2 and their use in detecting early stage or previous infection in a subject |
IP Reference | 2011652.1 |
Protection | Patent application published |
Year Protection Granted | |
Licensed | No |
Impact | n/a |
Description | BBC Radio Science - CrowdScience radio/podcast episode |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | The episode focussed on COVID-19: The importance of scientific collaboration with China, vaccine development, and antiviral use |
Year(s) Of Engagement Activity | 2020 |
Description | Career talk at sixth form school |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Career talk at sixth form school in Abingdon. Spoke to ~70 16-17year olds about my career progression and options for their future. |
Year(s) Of Engagement Activity | 2018 |
Description | Designed an activity for the MRC festival of research |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Designed an activity for the MRC festival of research based on the gene editing work by the Rehwinkel lab. The MRC festival of research reached ~500 members of the public across 6 days throughout Oxfordshire. |
Year(s) Of Engagement Activity | 2018 |
Description | Freeland Primary School Science Day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Helped run a range of activities at the primary schools science day that were designed to explain aspects of the immune system. |
Year(s) Of Engagement Activity | 2022 |
Description | GTEC Podcast - Research during the COVID-19 pandemic |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | The episode focused on the challenges of research during the COVID-19 pandemic and was part of a Pandemic preparedness-focused podcast series which aims to educate on the importance of immunology and T cell research for current and future pandemics. |
Year(s) Of Engagement Activity | 2021 |
Description | Hosted work experience students |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Hosted two work experience students aged 17 years old. |
Year(s) Of Engagement Activity | 2018 |
Description | Immune System disorders EDI Seminar |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Dannielle Wellington gave a talk over Zoom on the basics of the immune system and what goes wrong in immunocompromise and autoimmune disease. There were 40 Oxford University researchers on Zoom and 150 people watched the livestream on YouTube. This video has now had 430 views |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.youtube.com/watch?v=yvQyrarGLD0&t=167s |
Description | Northway Church; "Superdads" playgroup |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Event for children aged 3-9 and their fathers. Title: "The Blood Factory" Info sent to parents prior to event: "Come and learn about the different types of cells in your blood, from those that make it red to magic cells that have the potential to become anything they want. Plus learn how one group of cells in our bodies are constantly working together to stop you from feeling sick with our fun dress-up game. Will you be a Detective dendritic cell, Ninja Killer T cell, Macrophage maid or Fibroblast Builder?" Props used: Soft toy blood cells; colouring in sheets; dress up as cells Activities: brief introduction; drawing blood cells; game to find infected cell Verbal feedback at/after the event was very positive and several text / WhatsApp messages were received afterwards saying it was a special event. |
Year(s) Of Engagement Activity | 2019 |
Description | Nursery Visit |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Spoke to ~30 age 3-4 children about the components of blood and function of the immune system. Received excellent feedback from key workers at the nursery. |
Year(s) Of Engagement Activity | 2018 |
Description | Oxford IF stand on Fighting Viral Infections |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Dannielle Wellington led the design and implementation of a new stand with 3 activities targeted at explaining to children aged 7-12 how viruses are sensed, degraded and killed by T cells. We spent two days exhibiting at Templars Square Shopping Centre, Oxford, and spoke to ~200 people. Delaney Dominey-Foy and Zixi Yin volunteered at the event. This stand was sponsored by BSI. |
Year(s) Of Engagement Activity | 2021 |
Description | Oxford Open Doors |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Range of activities to explain gene editing and CRISPR, in the context of genome editing to treat diseases etc. Sparked a range of discussions about how gene editing works and what situations it is ethically appropriate to use it etc. |
Year(s) Of Engagement Activity | 2022 |
Description | Oxford Wellcome Integrative Neuroimaging centre EDI Seminar |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | gave a talk on the basics of the immune system and what goes wrong in immunocompromise and autoimmune disease. 40 people on Zoom and 150 live on YouTube. YouTube video has now been viewed 393 times |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.youtube.com/watch?v=yvQyrarGLD0&feature=youtu.be |
Description | Pint of Science Beautiful Mind Evening |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Dannielle Wellington was part of the team that organised and co-ordinated this evening, presenting a series of talks and interactive games with audiences through YouTube Live. Event was aimed at the general public and attracted ~100 people live. YouTube video has now had 655 views |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.youtube.com/watch?v=xY1YvHGD29o |
Description | Radio 4 episode - World This Weekend |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | The episode focussed on COVID-19 and the research being performed in Oxford |
Year(s) Of Engagement Activity | 2020 |
Description | Ran a stand at Oxford IF Science Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Ran a stand at Oxford IF Science Festival. Blood factory stand explaining the components of blood and functions of the immune system. Targeted at high school children and members of the public. Spoke to ~250 people. Received great feedback from event organisers. |
Year(s) Of Engagement Activity | 2018 |
Description | S3E1: Research during the COVID-19 pandemic Global T cell Expert Consortium Podcast |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Tao Dong discusses the impact of the coronavirus disease outbreak on the research community and highlight the importance of T cells in understanding more about COVID-19 immunology. |
Year(s) Of Engagement Activity | 2021 |
URL | https://podcasts.apple.com/gb/podcast/global-t-cell-expert-consortium/id1545133200?i=1000511373893 |
Description | School visits for British science week |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Directly spoke to 60 students aged 11 and then hosted a stand at a drop in session where we spoke to ~80-100 students age 5-11 years. Explained the various components of the blood with a demonstration of the distinct functions of cells of the immune system. Received excellent feedback from the students as well as their teachers. |
Year(s) Of Engagement Activity | 2018 |
Description | Science Oxford Live Lab, Family Day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Had a stall at an event to explain how our T cells, a special type of immune cell, are able to find and kill germs that invade our body. Using pH colour change and pipetting the children taking part in the activity get to identify what kind of germs their T cells were able to kill. This activity sparked discussions about the immune system and how our body works to protect us from getting sick. Was invited back for a second event later in the year. |
Year(s) Of Engagement Activity | 2022 |
Description | Science in the supermarket, MRC Festival 2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Ran a stall in a supermarkets in Didcot, Reading and Oxford as part of the MRC Science Festival 2019. Families including adults and children took part. |
Year(s) Of Engagement Activity | 2019 |
Description | Session on Vaccines for Work Experience students |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Run a session on vaccines. 16-17 year old work experience students played the role of scientists, government and pharmaceutical companies, as they decided on which vaccine research to invest. |
Year(s) Of Engagement Activity | 2019 |
Description | Swindon Science Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Science Festival to introduce the general public to science. Stickers were given to each visitor. Stickers given out on Friday = 282 Stickers given out on Saturday = 307 Total stickers distributed = 589 |
Year(s) Of Engagement Activity | 2020 |
Description | T cell article on University College, Oxford of Oxford Website |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Undergraduate students |
Results and Impact | An article giving information on the study into T cell responses in patients recovered from COVID-19 |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.univ.ox.ac.uk/news/t-cell-update/ |
Description | Westminster Higher Education Forum policy conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Delivered a keynote address at the Westminster Higher Education Forum policy conference, which focussed on the future of the UK's research partnerships with the international research community, discussing the outcomes from the Smith-Reid Review, the UKRI review into international research and retaining research talent within the UK. |
Year(s) Of Engagement Activity | 2020 |
Description | Work experience student |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Hosted an 18 year old work experience student for a week. |
Year(s) Of Engagement Activity | 2020 |
Description | Work experience student |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Hosted a 17 year old work experience student for a week |
Year(s) Of Engagement Activity | 2019 |