Key information
Research topics
Computational & Systems Biology Gene Expression Genetics & Genomics Immunology Infectious Disease Tumour Biology
A 2023 Crick PhD project with George Kassiotis
Project background and description
The ability of viruses to establish persistent infection of their host necessitates evasion of host immunity. One evolutionary strategy of immune evasion is mimicry, whereby virus components molecularly or functionally resemble the host. Accordingly, several virus families employ molecular mimicry to achieve persistence in the host, but none to the extreme form that endogenous retroviruses do. Owing to their ability to insert functional copies of their genome into the host germline DNA, retroviruses can integrate seamlessly into and, thus, become a part of the host. Indeed, our genome harbour hundreds of thousands of retrovirus integrations, acquired over successive waves of exogenous retrovirus infection and further amplification in the germline. Importantly, retrovirus endogenisation does not herald the end of the immunological conflict between the host and retrovirus. Instead, the now-endogenous virus enters a new phase in its relationship with its host; one that, over long evolutionary periods, will reach an equilibrium [1].
Despite perceived as a part of self, endogenous retroviruses, as well as other abundant types of retrotransposable elements, collectively known as endogenous retroelements – genomic parasites that also reverse-transcribe and integrate their genomes into ours – retain considerable immunogenicity. This is most evident in immunological disorders and disease that develops when epigenetic control of endogenous retroelements is compromised or when their nucleic acid replication intermediates accumulate. Indeed, immune responses to endogenous retroelements contribute to autoinflammatory and autoimmune disease, and to age-related inflammation [2]. However, recent evidence suggests that endogenous retroelements shape the evolution of the immune system, and that physiological immune reactivity to their products is essential for immune system development and function. For example, endogenous retroelements underpin cancer immunosurveillance [3], the homeostatic responses to the microbiota [4], and create novel immune molecules, such as the soluble form of PD-L1 with receptor antagonist function [5].
The project aims to examine specific points of interaction between endogenous retroelements and the host immune system. These include innate immune activation resulting from the action of endogenous reverse transcriptases encoded by endogenous retroviruses and long interspersed nuclear elements (LINE). They also include priming of T and B cells to antigens present in canonical retroviral proteins, as well as chimeric proteins produced through aberrant transcription and splicing of endogenous retroelements. The project will investigate the mechanisms underlying the immunogenicity of endogenous retroelement-derived products, as well as the consequences of ensuing innate and adaptive immune responses for host physiology and pathology. Immunogenicity studies will involve the use of primary immune cells and cell lines in ex vivo and in vitro experiments. However, given the complex interaction of the extensive network of cells that make up the immune system, the study will ultimately involve genetically-modified in vivo mouse models, currently being generated at the Crick.
Candidate background
This project would suit candidates with a background in immunology and an interest in genetics/genomics, computational analyses and animal models.
References
1. Kassiotis, G. and Stoye, J.P. (2016)
Immune responses to endogenous retroelements: taking the bad with the good.
Nature Reviews Immunology 16: 207-219. PubMed abstract
2. Gorbunova, V., Seluanov, A., Mita, P., McKerrow, W., Fenyö, D., Boeke, J.D., . . . Sedivy, J.M. (2021)
The role of retrotransposable elements in ageing and age-associated diseases.
Nature 596: 43-53. PubMed abstract
3. Attig, J., Young, G.R., Hosie, L., Perkins, D., Encheva-Yokoya, V., Stoye, J.P., . . . Kassiotis, G. (2019)
LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly.
Genome Research 29: 1578-1590. PubMed abstract
4. Lima-Junior, D.S., Krishnamurthy, S.R., Bouladoux, N., Collins, N., Han, S.J., Chen, E.Y., . . . Belkaid, Y. (2021)
Endogenous retroviruses promote homeostatic and inflammatory responses to the microbiota.
Cell 184: 3794-3811.e3719. PubMed abstract
5. Ng, K.W., Attig, J., Young, G.R., Ottina, E., Papamichos, S.I., Kotsianidis, I. and Kassiotis, G. (2019)
Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist.
eLife 8: e50256. PubMed abstract
