The role of lipid droplets in Zika virus-host interactions

Thesis

Zika virus (ZIKV) and other flaviviruses extensively remodel the endoplasmic reticulum (ER) membrane to facilitate replication organelle (RO) biogenesis and virion morphogenesis. While growing evidence highlights the importance of lipids in ER remodelling, the contribution of lipid droplets (LDs) to this process remains poorly defined, and it is unclear whether specific LDs with distinct lipid and protein compositions are exploited by flaviviruses. Conversely, LDs also accumulate antiviral proteins, suggesting that LDs may function in host defence. This thesis investigates these dual roles of LDs during ZIKV infection.

LDs store cholesteryl esters and triacylglycerols, which are synthesised by sterol O-acyltransferase 1 and 2 (SOAT1 and SOAT2) and diacylglycerol O-acyltransferase 1 and 2 (DGAT1 and DGAT2), respectively. Using pharmacological inhibition and genetic deletion approaches, I identified SOAT1 and SOAT2, but not DGAT1 and DGAT2, as critical host factors for ZIKV infection. Transmission electron microscopy revealed that SOAT1 and SOAT2 deficiency resulted in an absence of virions, as well as defective ROs that were fewer, smaller, and devoid of viral RNA. SOAT1 and SOAT2 upregulation during ZIKV infection coincided with an increased abundance of cholesteryl-ester enriched LDs (CE-LDs). These SOAT1/2-induced CE-LDs displayed an altered proteome that supported lipid mobilisation and ER remodelling, and their breakdown was also critical for ZIKV infection, releasing cholesterol to interact with ZIKV proteins prM, capsid, and NS1. Together, these findings reveal that ZIKV induces and exploits specialised SOAT1/2-dependent CE-LDs to support RO biogenesis and virion morphogenesis.

In parallel, I also confirmed that LDs were induced during an IFN-I-mediated antiviral response and accumulated the antiviral protein RNF213, which stabilised these LDs. Using RNF213 knockout cells, I found that ZIKV exploited RNF213, suggesting that antiviral LDs can be hijacked to support viral infection.

Together, this thesis advances our understanding of LDs in ZIKV infection and reveals new insights into how flaviviruses exploit host lipid metabolism.

Authors: Banducci-Karp, A

• DOI: 10.5287/ora-ao7d05xkj
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: lipid droplets; Zika virus; lipid metabolism; virus-host interactions