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Mosquito-borne Rift Valley fever virus sneaks into cells via proteins linked to cholesterol metabolism
Goats shelter inside a pen during an investigation into an outbreak of Rift Valley fever in Saudi Arabia in 2000. Researchers at the Washington University School of Medicine in St. Louis and the The University of Pittsburgh discovered how the Rift Valley fever virus enters cells, leading the way for new therapies to treat this deadly disease.
The Rift Valley fever virus causes economically devastating epidemics of hemorrhagic fever in livestock such as sheep, goats and cattle. These mosquito-borne outbreaks cause 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, was limited to Africa and the Arabian Peninsula. But mosquitoes capable of transmitting the virus can be found all over the world, which requires understanding and controlling the virus.
Researchers at the Washington University School of Medicine in St. Louis and the University of Pittsburgh Center for Vaccine Research and School of Public Health have found that the virus enters cells by taking advantage of a protein normally involved in absorption of low density lipoproteins (LDL, carriers of the 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 virus’s ability to enter cells.
“For people living in areas where Rift Valley fever is endemic, an epidemic threatens not only their livelihoods but their health,” said lead author Gaya K. Amarasinghe, PhD, professor of pathology and of Immunology and Biochemistry and Molecular Biophysics in Washington. University. “People have a 1% to 2% chance of dying if they get infected with this virus, which doesn’t sound like much, but it’s pretty much the same as COVID-19. The disease is much more severe in domestic animals, especially young animals, which get very sick and die in large numbers. This virus has gone unnoticed, but given that it is transmitted by mosquitoes that can be found everywhere, it could spread to other parts of the world and become a serious problem. “
The World Health Organization has classified Rift Valley fever as a priority disease with the potential to cause epidemics in the near future. The virus is easily spread among pets by mosquito bite. People can also get infected from a mosquito bite, but most infected people are workers exposed to bodily fluids from infected animals when treating sick animals or disposing 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 box. By systematically disrupting normal genes in mice, Ganaie and his colleagues found that the virus failed to infect mouse cells lacking certain genes, including the protein 1 gene linked to the LDL receptor (Lrp1). Further experiments have shown that the virus needs LRP1 to infect cells in mice, hamsters, cows, monkeys and humans, indicating that the virus uses the same protein in distant species.
The observation constitutes an opportunity. If the virus needs LRP1 to infect cells, temporarily turning off LRP1 may limit its ability to spread throughout the body, thereby reducing disease. The researchers used a protein that does this effectively. Called RAP, the protein attaches to LRP1 and repels anything 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 were also infected but were not treated for comparison. Most of the treated mice survived, while all of the untreated mice died. In addition, the treated mice had lower levels of virus throughout their body on the third day after infection compared to untreated mice.
RAP itself is not a good prospect for drug development, as it is a normal mammalian protein that plays a role in many important biological processes. But the results suggest that targeting LRP1 may lead to treatments for Rift Valley fever.
“This discovery is the key to understanding how the 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-lead author Amy Hartman, PhD, associate professor of infectious diseases and microbiology at the University of Pittsburgh. “This discovery opens up new opportunities to study virus-host interactions at the cellular and organism level and enriches our understanding of the fundamental biology of emerging viruses transmitted by mosquitoes. “
The finding that the Rift Valley fever virus uses LRP1 to get inside cells is interesting because the protein is best known for its role in cholesterol metabolism. It is also believed to play a role in Alzheimer’s disease and possibly infections with intestinal bacteria. It’s hard. It is not known why these disparate biological processes are linked, but Amarasinghe, Hartman and their collaborators already have several projects underway to explore these connections.
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