This graphic depicts structures in the dengue virus that are critical for the infection process. Researchers have learned details about how the virus alters lipids in membranes surrounding structures called organelles, suggesting a potential new approach to control the aggressive mosquito-borne pathogen. Image: Purdue Department of Biological Sciences/Rushika Perera |
Researchers have identified enzymes and biochemical
compounds called lipids that are targeted and modified by the dengue virus
during infection, suggesting a potential new approach to control the aggressive
mosquito-borne pathogen.
Findings also suggest that medications used to treat high
cholesterol and other lipid-related conditions might also inhibit dengue’s
replication and could represent a potential new therapy. The researchers have
identified how infected mosquito cells undergo changes to certain lipids in
membranes and in biochemical sensors that alert cells of invading viruses.
“The virus reorganizes the internal architecture of the
cell to support its own needs,” said Purdue University
research scientist Rushika Perera. “Many details are unknown. This is our
first attempt to understand how the virus alters lipids as part of the
infection process. Part of what we looked at in this work was how the virus
changes the cell, and the next step will be to figure out why.”
The researchers uncovered new details of how the virus
alters lipids in membranes surrounding structures inside cells called
organelles, including the mitochondria, which provide energy critical for a
cell to function, and the endoplasmic reticulum, where proteins and lipids are
synthesized.
“Findings also show that important host enzymes are
used by the virus and may be targets for future antiviral drugs,” said Richard
J. Kuhn, a professor and head of Purdue’s Department of Biological Sciences and
director of the Bindley
Bioscience Center.
“It turns out, the pills you take to control your cholesterol might have
some capability to control dengue.”
The work was led by Perera in collaboration with researchers
at Purdue’s Bindley
Bioscience Center
and the Pacific Northwest National Laboratory. Findings are detailed in a
research paper to appear in PLoS
Pathogens.
The findings could apply to viruses similar to dengue,
including the West Nile virus, yellow fever,
and hepatitis C.
Dengue causes 50 million to 100 million infections per year
and is considered one of the most aggressive mosquito-borne human pathogens
worldwide. It is a leading cause of serious illness and death among children in
some Asian and Latin American countries.
“Identifying pathways of infection will help us
understand how these viruses work,” Kuhn said. “Many viruses,
including dengue, dramatically alter a host cell upon infection, and in this
paper we begin to dissect the precise changes that occur. Ultimately, we are
trying to understand how the virus subverts and exploits the host and uses it
for its own purpose, which is to replicate.”
The team learned specifically that an enzyme called fatty
acid synthase, which cells use to synthesize lipids, is affected by the virus.
Researchers showed that compounds inhibiting production of the enzyme also
inhibit virus replication, suggesting drugs already on the market to treat
diseases related to lipid synthesis and storage, including diabetes and cancer,
also might be used to treat dengue, Kuhn said.
The research paper was written by Perera; Kuhn; Bindley
researchers Catherine Riley, Amber S. Hopf-Jannasch, and Jiri Adamec; and PNNL
researchers Giorgis Isaac, Ronald J. Moore, Karl W. Weitz, Ljiljana Pasa-Tolic,
and Thomas O. Metz.
The researchers had previously studied a compound that
inhibits the production of fatty acid synthase in human cells. In the new
findings, the researchers showed that the virus commandeers some of the same
enzymes in both mosquito and human cells, meaning the same compound could work
to attack the virus in mosquito cells.
“This is important because it may be easier to control
the virus in mosquitoes than in humans,” Kuhn said.
Globally, dengue has grown dramatically in recent decades,
placing about half the world’s population at risk of infection. The infection
causes flulike illness and occasionally develops into a potentially lethal
complication called dengue hemorrhagic fever. Prompt medical care for this
severe form of dengue virus infection has been shown to decrease mortality
rates from more than 20% to less than 1%, according to the World Health
Organization.
The research hinges on recent advances in two areas:
high-resolution mass spectrometry and “informatics,” or using
computers to process volumes of information.
“You generate a large quantity of data that has to be
interpreted in terms of what molecules you are looking at,” Perera said.
“The mass spectrometer takes hundreds of lipids and breaks them apart, and
then a computer is needed to put it all back together and identify them. It’s
only in the past five years or so that we’ve had the capability to do this with
the required accuracy.”
The researchers also detail changes in the curvature of
membranes, using another technique called cryoelectron microscopy, and
pinpointed an isolated part of the cell where most of the virus replication
takes place, a complex of membranes modified by the infection. The virus is
thought to commandeer enzymes, relocating them to this region where virus replication
factories are situated.
Because the research tools enable scientists to see how
changes in membranes and signaling lipids alter how a cell functions, a
long-term benefit of the research is learning how to use a virus as a tool to
better understand cellular processes, Perera said.
The work is funded by the National Institutes of Health, and
the team recently received a new NIH grant to conduct research aimed at finding
commonalities in how dengue infects humans and mosquitoes. Linking the two
could lead to new ways of controlling the virus.
