Deciphering the role of lipid droplets in Hepatitis C virus replication
Final Report Abstract
During the funding period we successfully used unbiased and targeted approaches to further define HCV particle assembly, maturation, and release, to elucidate the biological function of LDs and lipids in HCV infection, and to investigate L1 retroelements in HCV infection. We additionally performed lipidomic analysis of HCV-infected cells and subcellular compartments including LDs, a project that was not directly funded by this grant, but greatly benefited from methods and tools that were developed and established through this grant. These results led to a DFG funded project that has been granted for funding in 2018: “Elucidating the role of lipids in positive-sense RNA virus infection”. While we continue to work on HCV, we recently also established infection models for Dengue, Zika, West Nile, yellow fever and tick-borne encephalitis virus. We will now use the methods and tools that we established for HCV to study the functional role of lipid metabolic pathways and LDs in flaviviral infection. We hypothesize that flaviviruses depend on select lipid metabolic pathways for their replication. Preliminary experiments revealed that capsid proteins from different flaviviruses localize to lipid droplets (unpublished data) and that some of them rely on lipophagy of LDs for infection. However, the precise lipid metabolic requirements of the different viruses that likely also depend on the specific host cells are currently unknown. With this new angle of research, I was appointed to a professorship funded through the LOEWE-Center DRUID (Novel Drug Targets against Poverty-related and Neglected Tropical Infectious Diseases) where we seek to identify common and diverse metabolic pathways required for viral replication and pathogenesis in the Flaviviridae family that can be used to develop broadly acting antivirals.
Publications
- (2016). Quantitative Lipid Droplet Proteome Analysis Identifies Annexin A3 as a Cofactor for HCV Particle Production. Cell Rep 16, 3219
Rosch K, Kwiatkowski M, Hofmann S, Schobel A, Gruttner C, Wurlitzer M, Schluter H, Herker E
(See online at https://doi.org/10.1016/j.celrep.2016.08.052) - (2017). Lipid Droplet Isolation for Quantitative Mass Spectrometry Analysis. J Vis Exp 10.3791/55585
Rosch K, Kwiatkowski M, Schluter H, Herker E
(See online at https://doi.org/10.3791/55585) - (2018). Complex lipid metabolic remodeling is required for efficient hepatitis C virus replication. Biochim Biophys Acta Mol Cell Biol Lipids 1863, 1041
Hofmann S, Krajewski M, Scherer C, Scholz V, Mordhorst V, Truschow P, Schobel A, Reimer R, Schwudke D, Herker E
(See online at https://doi.org/10.1016/j.bbalip.2018.06.002) - (2019). Perilipin-2 is critical for efficient lipoprotein and hepatitis C virus particle production. J Cell Sci 132
Lassen S, Gruttner C, Nguyen-Dinh V, Herker E
(See online at https://doi.org/10.1242/jcs.217042)
