Dengue and Zika represent two of the major mosquito-borne flaviviruses that collectively have huge health implications worldwide. Dengue infects ~400 million people annually, often causing severe pathologies such as endothelial leakage. Zika too has emerged as a global threat with outbreaks linked to serious neuro-developmental complications in children and Guillain Barré syndrome in adults. Vaccines and therapeutic options for these viruses are currently unavailable, along with limited knowledge on the underlying mechanisms of pathogenesis and viral manipulation of host cell biology.
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Virus-triggered lipophagy and inhibition of ER-phagy during biogenesis of replication organelles.
Sec62-dependent ER-phagy in infected Ube2g2-/- cells.
Our current research investigates mechanisms of flavivirus biogenesis, using Zika and Dengue as models, and their strategies of evading host immune responses. Infection is accompanied by subversion of selective autophagy to hydrolyse lipid droplets on the one hand, while inhibiting ER-phagy on the other, followed by massive reorganisation of the host secretory pathway. In addition, innate and cellular immune responses such as MHC-I and II restricted antigen presentation are suppressed. We apply mass spectrometry with complementary approaches in biochemistry, cell biology, immunology and virology to investigate two major aspects of flavivirus pathogenesis: mechanisms underlying their assembly/secretion, and strategies they deploy to subvert host immunity.
Lipid droplets undergo dynamic changes in their composition upon immune stimulation versus flavivirus infection. We have identified specific lipid droplet components that are targeted by viral proteins to induce lipophagy, which are crucial for the formation of viral replication compartments. We apply CRISPR/Cas9 mediated genetic manipulation, combined with biochemical and cell biological methods in mammalian cells to characterise genes that drive ER reorganisation and virus assembly.
Despite increased autophagy, which in principle should enhance antigen presentation, surface expression of Major histocompatibility complex (MHC)-I and II is dramatically reduced upon infection. We investigate how viruses subvert antigen presentation in infected monocytes, to evade host immunity and drive pathogenesis. Monocytes and monocyte-derived cells prime virus-specific neutralising B- and T-cell responses, and are also major targets of Zika and Dengue replication. To determine viral interference with antigen presentation, we apply quantitative proteomics with immunology and biochemical techniques to deconstruct the multi-tiered process, and define the specific steps targeted by these viruses. We have identified several E3 ligases that are induced and copurify with MHC-I and II from Zika-infected cells. We will test whether they are co-opted by viruses to degrade, or mis-sort MHC molecules to evade host immunity.
2023
Viral subversion of selective autophagy is critical for biogenesis of virus replication organelles.
Lan, Y., van Leur, S.W, Fernando, J.A., Wong, H.H., Kampmann, M., Siu, L., Zhang, J., Li, M., Nicholls, J.M. and Sanyal, S.
Nature Communications – 14(1): 2698.
2021
Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection.
Munnur, D., Teo, Q.W., Eggermont, D., Lee, H., Thery, F., van Leur, S., Ho, J., Ng, W., Siu, L., Ploegh, H., Pinto-Fernandez, A., Damianou, A., Kessler, B., Impens, F., Mok, C. and Sanyal, S.
Nature Immunology – 22(11): 1416-1427.
2020
Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles.
Li, M.Y., Naik, T.S., Siu, L.Y.L., Acuto, O., Spooner, E., Wang, P., Yang, X., Lin, Y., Bruzzone, R., Ashour, J., Evans, M.J. and Sanyal, S.
Nature Communications – 11(1): 5189.
2019
OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1.
Jahan, A.S., Biquand, E., Muñoz-Moreno, R., Le Quang, A., Ka-Pun Mok, C., Wong, H.H., Teo, Q., Valkenburg, S.A., Chin, A.W.H., Poon, L.L,M., Te Velthuis, A., García-Sastre, A., Demeret, C. and Sanyal, S.
Cell Rep. – 30(5): 1570-1584.e6.
2019
Manipulation of autophagy by (+) RNA viruses.
Wong, H.H. and Sanyal, S.
Semin Cell Dev Biol. – 101: 3-11.
2018
Flaviviruses exploit the lipid droplet protein AUP1 to trigger lipophagy and drive virus production.
Zhang, J., Lan, Y., Li, M.Y., Lamers, M.M., Fusade-Boyer, M., Klemm, E., Thiele, C., Ashour, J. and Sanyal, S.
Cell Host Microbe – 23(6): 819-831.e5.
2016
Usp12 stabilizes the T-cell receptor at the cell surface during signaling.
Jahan, A.S., Lestra, M., Swee, L.K., Fan, Y., Lamers, M.M., Tafesse, F.G., Theile, C.S., Spooner, E., Bruzzone, R., Ploegh, H.L. and Sanyal, S.
Proc Natl Acad Sci USA. – 23(6): 819-831.e5.
Sumana Sanyal awarded title of Professor of Molecular Pathology
September 2023
Recognising her research on the cell biology of viral infection, as well as her teaching contributions, Sumana Sanyal has been awarded the title Professor of Molecular Pathology by the University of Oxford.
Prestigious Early Career Fellowship awarded to Viktoriya Stancheva
December 2022
Dr Viktoriya Stancheva from the Sanyal lab at the Dunn School was awarded a Wellcome Trust Early Career Fellowship.