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Viral manipulation of host cell biology for assembly, secretion and immune evasion


   Sir William Dunn School of Pathology

  Dr S Sanyal  Friday, December 09, 2022  Competition Funded PhD Project (Students Worldwide)

About the Project

This project will investigate mechanisms of assembly, secretion and immune subversion adopted by (+)RNA viruses, with a particular emphasis on Dengue/Zika from the flavivirus and SARS-CoV-2 from the coronavirus families. Current understanding on how small (+)RNA viruses assemble and spread from cell to cell while evading innate and cellular immune responses is limited. Virus-infected cells induce selective autophagy of lipid droplets, which is accompanied by massive reorganisation of the host secretory pathway, but downregulate MHC-I and II restricted antigen presentation and interferon production.  

We have identified host factors that are targeted by viral proteins to induce autophagy-mediated LD hydrolysis (lipophagy) and unconventional secretory processes2,4. Collectively they are crucial for formation of viral replication compartments, assembly and cell-to-cell spread of virus progenies. We are applying CRISPR/Cas9 gene editing technology combined with biochemical and cell biological methods and functional assays to investigate how specific genes affect virus assembly and secretion. Replication of these (+)RNA viruses occurs in the cytoplasm, facilitated by suppressing host innate immune responses and MHC-I and II restricted antigen presentation in monocytes and monocyte-derived cells. We are addressing how these viruses subvert innate and cellular immune responses to drive pathogenesis1,3. We aim to delineate biosynthesis, maturation and turnover of immune effectors, e.g. MHC-I and signalling components to define the specific steps targeted by these viruses. We will test host E3 ligase candidates and viral factors that copurify with these immune components from infected cells, that may degrade or mis-sort such molecules to suppress host immunity. We will combine quantitative mass spectrometry with complementary approaches in biochemistry, cell biology, immunology and virology to investigate the interplay of host cellular pathways such as autophagy, with that of virus biogenesis, and their mode of host immune evasion. 


Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£20,168 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

1. Munnur D, Teo QW, Eggermont D, Lee H, Ho J, Ng W, Siu L, Ploegh H, Pinto-Fernandez A, Damianou A, Kessler B, Impens F, Mok C and Sanyal S Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection (2021) Nature Immunology 22(11): 1416-1427
2. Li MY, Naik TS, Siu LYL, Acuto O, Spooner E, Wang P, Yang X, Lin Y, Ashour J, Evans MJ and Sanyal S. Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles (2020) Nature Communications 11: 5189
3. Jahan AS, Teo Q, Biquand E, Demeret C, Spooner E, Poon LLM, Munoz R, García-Sastre A and Sanyal S. OTUB1 activates RIG-I dependent immune signaling and is targeted for proteasomal degradation by NS1 (2020) Cell Reports 30(5): 1570-1584.e6
4. Zhang J, Lan Y, Li MY, Lamers MM, Fusade-Boyer M, Klemm E, Thiele C, Ashour J and Sanyal S. Flaviviruses exploit the lipid droplet protein AUP1 to trigger lipophagy and drive virus production (2018) Cell Host Microbe. 23 (6): 819-831

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