PhD project

Supervisor: Sumana Sanyal

This project focuses on how (+)RNA viruses, particularly Dengue and Zika viruses assemble, spread, and evade host immune responses. Current understanding on how small (+)RNA viruses assemble and spread from cell to cell while evading innate and cellular immune responses is limited. This research aims to uncover the complex interplay between virus-induced cellular changes and host defence mechanisms. We are particularly interested in how these viruses trigger selective autophagy of lipid droplets, reorganise host secretory pathways, while downregulating immune receptors, MHC-I/II antigen presentation and interferon production.

We have identified host factors (e.g. ubiquitylation enzymes, GTPases) that are targeted by these pathogens to impair ER-phagy while inducing lipophagy and unconventional secretory processes^1-3. We will apply 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, while subverting innate and cellular immune responses to drive pathogenesis^4-6.

The project will employ a range of cutting-edge methodologies, including CRISPR/Cas9 gene editing, biochemical and cell biological techniques, functional assays, and quantitative mass spectrometry. These will be complemented by approaches from immunology and virology. Through this multidisciplinary approach, we aim to elucidate the intricate relationships between host cellular pathways and viral biogenesis, as well as the mechanisms of immune evasion that drive pathogenesis.

Keywords:

• Cell Biology, Virology, Molecular Biology, Immunology

Publications:

• Lan Y, van Leur SW et al and Sanyal S. Viral subversion of ER-phagy is critical to membrane remodelling for biogenesis of (+)RNA virus replication organelles (2023) Nature Communications 14(1): 2698
• 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
• 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
• Munnur D et al and Sanyal S  Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection (2021) Nature Immunology 22(11): 1416-1427
• Teo QW et al and Sanyal S. Usp25-Erlin1/2 limits cholesterol flux to restrict a broad range of viruses. (2023) Developmental Cell 58 (22): 2495-2509
• 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