Rewiring the organellar contact sites during flavivirus infection

Flaviviruses are globally distributed pathogens without currently available effective control measures. Flaviviruses trigger extensive membrane rearrangements of the host's endoplasmic reticulum, which generate replication organelles (ROs). I will address the longstanding question of how flaviviruses reorganize cellular resources and signaling platforms to avoid immune detection and reproduce within the RO. RO formation depends on host organelles including the endoplasmic reticulum, mitochondria and lipid droplets. These are connected through contact sites, which regulate organelle homeostasis and immune signalling, and are altered during infection. The molecular mechanism of contact site remodelling and its significance in flavivirus infection and associated immune response, however, has been understudied. I will combine biochemical, imaging and genetics-based techniques to map the flavivirus- induced contact site changes (Aim 1); analyse their requirement for virus propagation (Aim 2); and involvement in immune signalling subversion (Aim 3). This will generate a comprehensive mechanistic understanding of the importance of organellar interactions during flavivirus infection and associated innate immune responses. Being universal for (+)RNA virus propagation, insights into RO formation will highlight important differences between viruses and inform of potential therapeutic targets. Ultimately, this project will increase the understanding of flavivirus infection and the biology of the underlying organellar networks that support it.