Flaviviral manipulation of autophagy for biogenesis and evasion of host immune responses
This project will investigate mechanisms of flavivirus biogenesis, with particular emphasis on Zika and Dengue. Current understanding on how progeny virions are assembled and secreted is limited. However, infection is accompanied by upregulation of selective autophagy to hydrolyse lipid droplets, followed by massive reorganisation of the host secretory pathway, while suppressing MHC-I and II restricted antigen presentation.
We have identified specific lipid droplet (LD) components that are targeted by viral proteins to induce autophagy-mediated LD hydrolysis (lipophagy), and cholesterol-dependent degradation of several ER-proteins1-3. These processes are crucial for the formation of viral replication compartments. We will apply CRISPR/Cas9 technology to generate cells deleted in specific proteins that function in these pathways to investigate how they affect virus assembly. Functional assays will be combined with biochemical and cell biological methods to address how autophagy drives membrane reorganization and virus biogenesis.
Despite upregulation of autophagy, which typically increases antigen presentation and subsequent host immune responses, infection by Dengue and Zika results in dramatic loss of Major histocompatibility complex (MHC)-I and II from the cell surface, when compared to UV-inactivated or viral dsRNA-treated cells. We will address how these 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. They are also major targets of virus replication. MHC-I and II restricted antigen presentation are multi-tiered pathways. We aim to deconstruct them into biosynthesis, assembly, transport and turnover to 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 during infection to ubiquitylate and degrade, or mis-sort MHC molecules to evade host immunity. We will apply quantitative mass spectrometry with complementary approaches in biochemistry, cell biology, immunology and virology to investigate the interplay of autophagy with virus biogenesis and their mode of host immune evasion.
4 Year DPhil Prize Studentships cover University fees, a tax free stipend of ~£17,009 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See https://www.path.ox.ac.uk/content/prospective-graduate-students for full details and to apply.
1. Zhang, J. et al. Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigger Lipophagy and Drive Virus Production. Cell Host & Microbe 23, 819–831.e5 (2018).
2. Zhang, J., Lan, Y. & Sanyal, S. Modulation of Lipid Droplet Metabolism-A Potential Target for Therapeutic Intervention in Flaviviridae Infections. Front Microbiol 8, 2286 (2017).
3. Pombo, J. P. & Sanyal, S. Perturbation of Intracellular Cholesterol and Fatty Acid Homeostasis During Flavivirus Infections. Front Immunol 9, 1276 (2018).
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