Defence and Counter-defence: The interplay between Zika virus and the immune system

Supervisor: Associate Prof Jan Rehwinkel

Project Overview
Virus infection triggers a multitude of immune responses. Detection of virus presence by the innate immune system is a crucial event mediated by germ-line encoded receptors inside cells. These sensors of virus presence signal for the induction of innate immune response genes, such as those encoding type I interferons. Many of these receptors sense viral nucleic acids. For example, RIG-I recognizes the RNA genomes of viruses such as influenza A virus (Rehwinkel et al., Cell 2010). Viruses in turn have developed strategies to counteract and evade detection by innate immune receptors. As such, cells and viruses are in a dynamic arms race in which host defence mechanisms and viral counter-measures rapidly co-evolve. One of our aims is to understand the molecular basis of host pathogen interactions.
This project will address these questions in the context of Zika virus, which is a major public health concern in the Americas where ZIKV infection has been linked with neurological conditions, including microcephaly and Guillain-Barré syndrome. Little is known about innate immune responses to ZIKV. Our unpublished observations suggest that ZIKV infection induces a type I interferon response via RIG-I-like receptors. Furthermore, we found that ZIKV interferes with this response by multiple mechanisms, including blockade of RIG-I activation and inhibition of signalling downstream of the type I interferon receptor.

The successful candidate will extend these studies by investigating the molecular mechanisms underlying these observations. In particular, we will (i) identify the types of RNAs that activate RIG-I-like receptors in Zika virus infected cells, (ii) investigate which Zika virus proteins block RIG-I signalling and (iii) analyse how these host-virus interactions shape the outcome of infection using mutant viruses and in vivo models. The project has basic and translational research components. Taken together, this exciting project builds on strong preliminary results and may lead to a better understanding of the immune response to Zika virus.

Training Opportunities
Based in the MRC Human Immunology Unit at the Weatherall Institute of Molecular Medicine, with access to state-of-the-art facilities, this project provides an opportunity for training in a broad range of different techniques, including cell culture, molecular biology, immunology, virology and mouse models. This project will additionally benefit from close collaboration with many scientists. The successful candidate will be supervised by Jan Rehwinkel and additional day-to-day supervision will be provided by an experienced member of the Rehwinkel lab.

Molecular Biology

For further information, please contact: Prof Jan Rehwinkel