Investigation of Glycerophospholipid Metabolism and Long-Chain Fatty Acid Function in Orthoflavivirus Infection
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Philipps-Universität Marburg
Abstract
Viruses of the genus orthoflavivirus within the family of Flaviviridae are arthropod-borne
emerging pathogens due to rising global temperature and increasing human population.
Among these viruses are the human pathogenic dengue virus (DENV), Zika virus (ZIKV),
yellow fever virus (YFV), West Nile virus (WNV), and tick-borne encephalitis virus
(TBEV). The rapid spread of the vector and the lack of direct antiviral treatment highlight
the relevance of comprehensive understanding of the viral replication cycle. A number
of studies have already established a connection between orthoflavivirus infection and
host lipid metabolism.
In this context, we used a semi-targeted shotgun lipidomic approach to analyze changes
in lipid abundance and species in cell culture models infected with DENV, ZIKV, YFV,
WNV, and TBEV. We observed that orthoflavivirus infection caused a large increase in
ceramide levels for viruses causing cytopathic effects and a decrease in triglycerides for
all viruses analyzed, resulting in fewer lipid droplets. Overall, fatty acid desaturation and
glycerophospholipid metabolism also changed significantly. Using inhibitors and a
shRNA-based knockdown approach of phosphatidylinositol biosynthesis, ceramide
synthesis, and phosphatidylserine metabolism, we detected reduced orthoflavivirus titers
and decreased cytopathic effect.
In the second project, the impact of fatty acid elongases and desaturases in
orthoflavivirus infection was investigated using RNAi in order to characterize their
potential role as an antiviral target. Interestingly, only DENV viral titers were drastically
affected by depletion of different elongases and desaturases. In line with this, additional
analysis of our lipidomics dataset revealed an increased abundance of long-chain fatty
acids with a higher desaturation grade in DENV-infected cells. Depletion of the
desaturase FADS2 and the elongase ELOVL4 resulted in the most significant reduction
in DENV viral titers. In follow-up experiments, we showed that ELOVL4 is required for
DENV replication, whereas FADS2 is important for the assembly of infectious viral
particles.
These findings highlight that orthoflaviviruses strongly remodel host cell lipid metabolism
for efficient replication. We identified distinct changes as well as commonly shared
patterns, pointing towards lipid metabolizing enzymes as potential antiviral targets.
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