Deadly virus's pathway to infect cells identified
Mosquito-borne Rift Valley fever virus slips into cells via protein
linked to cholesterol metabolism

Date:
September 23, 2021
Source:
Washington University School of Medicine
Summary:
Researchers have discovered how Rift Valley fever virus enters
cells, pointing the way to new therapies to treat deadly Rift
Valley fever.



FULL STORY ==========================================================================
Rift Valley fever virus causes economically devastating outbreaks of hemorrhagic fever in livestock such as sheep, goats and cattle. These
mosquito- borne outbreaks lead to infection in people working with dead
or dying animals, sometimes causing hundreds of human cases and dozens
of deaths.


==========================================================================
Rift Valley fever, for which there is no specific treatment, has been
limited to Africa and the Arabian Peninsula. But mosquitoes capable of transmitting the virus can be found all over the world, necessitating
a need to understand and control the virus.

Researchers at Washington University School of Medicine in St. Louis
and the University of Pittsburgh Center for Vaccine Research and School
of Public Health have discovered that the virus gets inside cells by
taking advantage of a protein normally involved in taking up low-density lipoproteins (LDL, the carriers of so-called bad cholesterol) from the
blood. The discovery, published Sept. 23 in the journal Cell, could
lead to therapies that prevent Rift Valley fever or reduce its impact
by interfering with the ability of the virus to get into cells.

"For people in areas where Rift Valley fever is endemic, an outbreak
threatens not only their livelihood but their health," said co-senior
author Gaya K.

Amarasinghe, PhD, a professor of pathology & immunology and of
biochemistry & molecular biophysics at Washington University. "People
have a 1% to 2% chance of death if they get infected with this virus,
which doesn't sound like much, but it's about the same as COVID-19. The
disease is much more severe in domesticated animals, especially young
animals, which get very ill and die in large numbers. This virus has been flying under the radar, but given that it's transmitted by mosquitoes
that are found everywhere, it could spread into other parts of the world
and become a serious issue." The World Health Organization has listed
Rift Valley fever as a prioritized disease likely to cause epidemics in
the near future. The virus spreads easily among domesticated animals
via mosquito bite. People also can be infected by mosquito bite, but
most people who become infected are workers exposed to infected animal
body fluids as they care for sick animals or dispose of their remains.

To find out how the virus invades cells, first author Safder Ganaie, PhD,
a postdoctoral researcher who works with Amarasinghe, grew the virus on
mouse cells in a dish. By systematically disrupting normal mouse genes,
Ganaie and colleagues found that the virus failed to infect mouse cells
that lacked certain genes, notably the gene for LDL receptor-related
protein 1 (Lrp1).

Further experiments showed that the virus needs LRP1 to infect mouse,
hamster, cow, monkey and human cells, indicating that the virus uses
the same protein across distantly related species.

The finding constitutes an opportunity. If the virus needs LRP1
to infect cells, then temporarily taking LRP1 out of commission may
limit its ability to spread in the body, thereby reducing disease. The researchers used a protein that effectively does this. Called RAP, the
protein attaches to LRP1 and fends off anything else that tries to attach.

The researchers infected a group of mice with the virus and simultaneously treated them with RAP. A second group of mice also was infected but
was left untreated for comparison. Most of the treated mice survived,
while all of the untreated mice died. Further, the treated mice had
lower levels of virus throughout their bodies on the third day after
infection compared with the untreated mice.

RAP itself is not a good prospect for drug development, since it's a
normal mammalian protein that plays a role in many important biological processes. But the results suggest that targeting LRP1 may lead to
therapeutics for Rift Valley fever.

"This finding is the key to understanding how Rift Valley fever virus
spreads not only throughout the human body but also how it is able to
infect mosquitoes and different species of mammals. Knowing how the
virus spreads will help us develop targeted therapies, which currently
do not exist for Rift Valley fever," said co-senior author Amy Hartman,
PhD, an associate professor of infectious diseases & microbiology at the University of Pittsburgh. "This discovery opens up new opportunities to
study virus-host interactions at the cellular and organismal level and
enriches our understanding of the basic biology of mosquito-transmitted emerging viruses." The discovery that Rift Valley fever virus uses LRP1
to get inside cells is interesting because the protein is better known
for its role in cholesterol metabolism. It also is thought to play a
role in Alzheimer's disease and possibly in infections by the intestinal bacterium C. difficile. It's not clear why these disparate biological
processes are linked, but Amarasinghe, Hartman and their collaborators
already have several projects underway to explore these connections.

========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Tamara
Bhandari. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Safder S. Ganaie, Madeline M. Schwarz, Cynthia M. McMillen, David A.

Price, Annie X. Feng, Joseph R. Albe, Wenjie Wang, Shane Miersch,
Anthony Orvedahl, Aidan R. Cole, Monica F. Sentmanat, Nawneet
Mishra, Devin A.

Boyles, Zachary T. Koenig, Michael R. Kujawa, Matthew A. Demers,
Ryan M.

Hoehl, Austin B. Moyle, Nicole D. Wagner, Sarah H. Stubbs, Lia
Cardarelli, Joan Teyra, Anita McElroy, Michael L. Gross, Sean P.J.

Whelan, John Doench, Xiaoxia Cui, Tom J. Brett, Sachdev
S. Sidhu, Herbert W. Virgin, Takeshi Egawa, Daisy W. Leung, Gaya
K. Amarasinghe, Amy L.

Hartman. Lrp1 is a host entry factor for Rift Valley fever
virus. Cell, 2021; DOI: 10.1016/j.cell.2021.09.001 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210923115604.htm

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