Deadly virus’s pathway to infect cells identified – Washington University School of Medicine in St. Louis

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The mosquito-borne Rift Valley fever virus hatches into cells through proteins linked to cholesterol metabolism

Goats seek shelter in an enclosure during an investigation into a Rift Valley fever outbreak in Saudi Arabia in 2000. Researchers at Washington University School of Medicine in St. Louis and the University of Pittsburgh have discovered how the Rift Valley fever virus enters cells and paves the way for new therapies to treat the deadly disease.

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The Rift Valley Fever Virus is causing economically devastating outbreaks of hemorrhagic fever in farm animals such as sheep, goats, and cattle. These mosquito-borne outbreaks lead to infections in people who work 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, is restricted to Africa and the Arabian Peninsula. But mosquitoes that can transmit 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 found that the virus entered cells using a protein that is normally involved in the uptake of low-density lipoproteins (LDL.) Is involved, the carrier of the so-called bad cholesterol) from the blood. The discovery, published in Cell magazine on Sept. 23, could lead to therapies that prevent Rift Valley fever or reduce its effects by interfering with the virus’ ability to enter cells.

“For people in areas where Rift Valley fever is endemic, an outbreak threatens not only their livelihoods but also their health,” said co-senior author Gaya K. Amarasinghe, PhD, professor of pathology and immunology as well Biochemistry and Molecular Biophysics at Washington University. “People have a 1% to 2% chance of death contracting this virus, which doesn’t sound like much, but it’s kind of like COVID-19. The disease is much more severe in domesticated animals, especially young animals, which become very sick and die in large numbers. This virus has flown under the radar, but since 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 that is likely to cause epidemics in the near future. The virus spreads easily among domesticated animals through mosquito bites. People can also become infected from mosquito bites, but most people who become infected are workers who are exposed to infected animal body fluids in the process of caring for sick animals or disposing of their remains.

To find out how the virus penetrates cells, first author Safder Ganaie, PhD, a postdoctoral fellow working at Amarasinghe, grew the virus on mouse cells in a dish. By systematically destroying normal mouse genes, Ganaie and colleagues found that the virus could not infect mouse cells that lacked certain genes, particularly the gene for the LDL receptor-related protein 1 (Lrp1). Further experiments showed that the virus requires LRP1 to infect mouse, hamster, cow, monkey, and human cells, suggesting that the virus uses the same protein in distantly related species.

The finding represents an opportunity. If the virus requires LRP1 to infect cells, temporarily putting LRP1 out of operation can limit its ability to spread in the body and thereby reduce disease. The researchers used a protein that does this effectively. The protein called RAP binds to LRP1 and wards off anything else that tries to attach.

The researchers infected a group of mice with the virus and treated them with RAP at the same time. A second group of mice was also infected, but remained untreated 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 in the whole body compared to the untreated mice on the third day after infection.

RAP itself is not a good prospect for drug development because it is a normal mammalian protein that plays a role in many important biological processes. However, the results suggest that targeted treatment for LRP1 may lead to therapeutics for Rift Valley fever.

“This finding is key to understanding how the Rift Valley fever virus not only spreads in the human body, but also how it can infect mosquitoes and various mammalian species. Knowing how the virus is spreading will help us develop targeted therapies that are currently not available for Rift Valley fever, ”said co-senior author Amy Hartman, PhD, Associate Professor of Infectious Diseases and Microbiology at the University of Pittsburgh. “This discovery opens up new possibilities for studying virus-host interactions at the cellular and organismic level and enriches our understanding of the basic biology of mosquito-borne emerging viruses.”

The discovery that the Rift Valley fever virus uses LRP1 to enter cells is interesting as the protein is better known for its role in cholesterol metabolism. It is also thought to play a role in Alzheimer’s disease and possibly infections caused by the intestinal bacterium C. difficile. It’s not clear why these different biological processes are linked, but Amarasinghe, Hartman, and their co-workers already have several projects underway to explore these links.

Ganaie SS, Schwarz MM, McMillen CM, Preis DA, Feng A, Albe JR, Wang W, Miersch S Orvedahl A, Cole AR, Sentmanat MF, Mishra N, Boyles DA, Koenig ZT, Kujawa MR, Demers MA, Hoehl RM, Moyle A, Wagner N, Stubbs SH, Cardarelli L, Teyra J, McElroy AK, Gross ML, Whelan SJP, Doench JG, Cui X, BrettT, Sidhu SS, Virgin HW, Egawa T, Leung DW, Amarasinghe GK, Hartman AL. Lrp1 is a host entry factor for the Rift Valley Fever Virus. Cell. 23.09.2021. DOI: 10.1016 / j.cell.2021.09.001

This research was supported by the National Institutes of Health (NIH) Grant Numbers R01NS101100, P01AI120943, R01AI123926, R01AI107056, U19AI142784, U19AI10972505, R01AI130152, T32AI060525, T32AI12338688, 114K06688; the Burroughs Wellcome Fund, property number 1013362.02; the Society for Pediatric Infectious Diseases; St. Jude Children’s Research Hospital; Society for Pediatric Research; Alzheimer’s Association, Grant Number AARG-16-441560; and The Leukemia and Lymphoma Society.

The 1,700 faculty physicians at Washington University School of Medicine are also the medical staff for the Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care and consistently ranks among the top medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its affiliation with Barnes-Jewish and St. Louis Children’s Hospital.