Studentship: Autophagy and African swine fever virus
Lead Research Organisation:
THE PIRBRIGHT INSTITUTE
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Diseases of domestic livestock are an ever present threat to the challenge of feeding an increasing global population. African swine fever virus has existed in a natural cycle between warthogs and soft ticks for millennia, but causes a lethal, highly contagious, haemorrhagic fever in domestic swine and wild boar. In 2007, African swine fever was introduced into Georgia, probably through contaminated waste from a ship, and since has spread throughout most of European Russia and has now been reported in Poland, Lithuania, Latvia and Estonia. Effective vaccines against African swine fever are desperately needed.
Autophagy is a highly conserved intracellular pathway that has evolved to breakdown and recycle damaged cytoplasmic components by delivering them to lysosomes. Autophagy can also be induced in response to physiological stress, most notably that of starvation (The word autophagy literally means self-eat in Greek). Many important responses to infection are dependent on the autophagy pathway and pathogens have evolved mechanisms to manipulate autophagy for their own benefit. Recent experiments have demonstrated that disrupting the ability of viruses to inhibit autophagy can enhance immune responses. We have shown that African swine fever virus can block part of the autophagy pathway, raising the possibility that deletion of viral proteins that inhibit autophagy may enhance the immunogenicity of a live attenuated ASFV vaccine.
The major aims of this project are to further characterise the effect of African swine fever virus infection on the autophagy pathway, identify novel autophagy inhibitors in the African swine fever genome and generate recombinant viruses lacking these genes. The findings from these studies will contribute to the development of safe and effective, live attenuated ASFV vaccine candidates.
Autophagy is a highly conserved intracellular pathway that has evolved to breakdown and recycle damaged cytoplasmic components by delivering them to lysosomes. Autophagy can also be induced in response to physiological stress, most notably that of starvation (The word autophagy literally means self-eat in Greek). Many important responses to infection are dependent on the autophagy pathway and pathogens have evolved mechanisms to manipulate autophagy for their own benefit. Recent experiments have demonstrated that disrupting the ability of viruses to inhibit autophagy can enhance immune responses. We have shown that African swine fever virus can block part of the autophagy pathway, raising the possibility that deletion of viral proteins that inhibit autophagy may enhance the immunogenicity of a live attenuated ASFV vaccine.
The major aims of this project are to further characterise the effect of African swine fever virus infection on the autophagy pathway, identify novel autophagy inhibitors in the African swine fever genome and generate recombinant viruses lacking these genes. The findings from these studies will contribute to the development of safe and effective, live attenuated ASFV vaccine candidates.
Planned Impact
unavailable
Publications
Banjara S
(2019)
Crystal Structure of African Swine Fever Virus A179L with the Autophagy Regulator Beclin.
in Viruses
Goatley LC
(2020)
A Pool of Eight Virally Vectored African Swine Fever Antigens Protect Pigs Against Fatal Disease.
in Vaccines
Shimmon GL
(2022)
Purification of African Swine Fever Virus.
in Methods in molecular biology (Clifton, N.J.)
Shimmon GL
(2021)
Autophagy impairment by African swine fever virus.
in The Journal of general virology
| Description | Viruses manipulate the host cell to both facilitate their own replication and avoid intrinsic, innate and adaptive immune responses. Autophagy is a cellular recycling pathway that is involved in many important functions including directing the immune response against, as well as directly degrading invading pathogens. We have shown that African swine fever virus blocks a critical step in the autophagy pathway and hypothesised that viruses that were unable to block autophagy may induce enhanced immune responses and represent potential vaccine candidates. We screened 70 out of the 128 core viral genes for autophagy modulators and found only one that could inhibit autophagy, whereas several were capable of inducing the pathway. We were able to identify a specific domain within the African swine fever autophagy inhibitor that was responsible for the phenomenon. However, a mutant virus lacking the identified autophagy inhibitor was still able to inhibit the pathway suggesting this gene was not necessary to inhibit the cellular process alone. The identification of a number of viral autophagy inducing proteins may explain why ASFV encodes for redundancy in its ability to block the pathway and strongly suggests that inhibition of autophagy is important for the virus. We studied one of the genes that induced autophagy in greater detail and identified interacting partners my mass spectrometry, however no direct link with the pathway was observed. Detailed microscopy and biochemical analyses of the autophagy pathway suggested that the virus targets autophagy in at least two separate places which warrant further investigation. Remaining questions include, what mechanisms and genes does African swine fever virus use to manipulate the autophagy pathway and why? If we can identify these mechanisms can we manipulate them to improve African swine fever vaccine design? An early career researcher has been trained in a number of specialised techniques with high consequence pathogens in containment laboratories, so enhancing the UKs science base |
| Exploitation Route | The research increases our understanding of how viruses, and in particular African swine fever virus, manipulate their hosts. Newly identified interacting partners for individual viral proteins could be studied in greater detail to further our knowledge of virus-host interactions, likewise viral autophagy inducers may also contribute to how viruses interact with their host. |
| Sectors | Agriculture Food and Drink Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
| Title | Autophagy inducer interactors |
| Description | A mass spectrometry data set of cellular proteins that interact with an African swine fever protein the induces autophagy. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2018 |
| Provided To Others? | No |
| Impact | None as yet |
| Description | Membrane protein interactions |
| Organisation | University of Liverpool |
| Department | School of Veterinary Science Liverpool |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Samples from cells transduced with ASFV membrane proteins have been prepared. |
| Collaborator Contribution | Samples have been analysed for proteins interacting with ASFV membrane proteins by mass spectrometry. |
| Impact | Collaboration still in progress |
| Start Year | 2017 |
| Description | Structural analysis of ASFV-host protein interactions |
| Organisation | La Trobe University |
| Country | Australia |
| Sector | Academic/University |
| PI Contribution | Mutations were introduced into ASFV autophagy modulators and the effects of these were tested in cell based microscopy assays. |
| Collaborator Contribution | Structural analysis of virus-host interactions identified residues important for binding between virus and host proteins. These residues were the residues that chosen for mutation and subsequent analysis at Pirbright |
| Impact | One peer-reviewed paper (https://www.ncbi.nlm.nih.gov/pubmed/31461953) This is multi-disciplinary. Pirbright has expertise in virology and cell based assays. La Trobe have expertise in structural biology. |
| Start Year | 2017 |
| Description | Farnborough 6th Form College Careers Day |
| 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 | Visited careers day at local 6th Form College to discuss a career in research and the work carried out at our institution |
| Year(s) Of Engagement Activity | 2018 |
| Description | Pig and Poultry Fair 2019 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Industry/Business |
| Results and Impact | Discussed Institute research with pig and poultry farmers, related industry and the general public. Received requests for more information related to research, business and studentships. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://www.pigandpoultry.org.uk/ |
| Description | Surrey Skills Fair |
| 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 | Aimed at Year 9 students from Surrey Schools, promoting progression into further and higher education, training, employment and careers at a crucial time prior to choosing GCSE subject options. Aimed at Year 9s making their option choices, this skills and careers event is designed to help students understand the opportunities available to them post 16 and beyond. The 2014 event reached over 2000 students from 36 Surrey Schools, engaging with over 40 exhibitors. |
| Year(s) Of Engagement Activity | 2015 |
| Description | Talk as part of the University of Veterinary Medicine (Vienna) doctoral school "Infectious Diseases of Pig and Poultry" |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Policymakers/politicians |
| Results and Impact | Talked about the Pirbright Institute's work on African swine fever virus to researches in Veterinary Medicine (Virology and Immunology) in Vienna. |
| Year(s) Of Engagement Activity | 2018 |