Research

Immune evasion strategies of (+)RNA viruses

Lipid droplets accumulate in cells to serve as storage organelles. However, upon infection various immune complexes involved in innate immune responses are enriched on the lipid droplets. In particular, substrates that are modified by interferon stimulated gene 15 (ISG15) - a post translational modifier closely related to ubiquitin - are dramatically increased on lipid droplets when macrophages are either infected or treated with type I interferon. Many viruses encode for de-ISGylase enzymatic activities (e.g coronaviruses) or utilise a host de-ISGylase to hydrolyse ISGylated proteins and utilise lipid droplets for replication/assembly of viral progenies. This project will investigate whether lipid droplets have a direct role in cellular immune responses during virus infections via two specific questions:

1) Whether lipid droplets serve as innate immune signalling platforms during virus infections. We will use a combination of mass spectrometry and biochemical/cell biological assays to characterise the proteome of lipid droplets when cells are stimulated with interferon-I or infected with wild-type or mutant flavi/coronaviruses and measure their impact on specific immune signalling cascades.

2) Understand the mechanism by which viral proteases (or other viral factors) are able to subvert these responses, such as by hydrolysis of ISG15 modifications from LD-associated proteins to evade innate immune responses.

To address both the questions we will use epithelial cells and monocyte-derived macrophages that serve as targets of both flavivirus and coronavirus infections. Infection will be performed with specific strains of viruses (e.g. the African and Asian lineages of Zika virus), which display distinct abilities to suppress host innate immune responses and hydrolyse lipid droplets, to characterise differences underlying this phenomenon.

Cell Biology of Virus infections

We are interested in understanding interactions of enveloped (+)RNA viruses (e.g. flaviviruses, coronaviruses) with the host cell, at different stages in their lifecycle. Our goal is to identify and characterise host factors that are exploited by these viruses in order to trigger membrane reorganisation and form sites of replication and assembly. We have identified lipid droplets as key organelles targeted by flaviviruses, not only for energy resources but also for generating replication organelles. The mechanisms employed by viruses to replicate, assemble, and traffic within host cells are of fundamental interest, both for improved understanding of infection and pathogenesis, but also for mechanistic insights into how cells work.

Funding:

Our research is generously funded by the Wellcome Trust and the UKRI.