– Mosquito-borne outbreaks of Rift Valley fever
virus cause economic devastation across Africa and the Arabian Peninsula with alarming frequency. And mosquitoes capable of transmitting the virus can be found all over the world, necessitating a need for better understanding and control.
“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,” said co-senior author Amy Hartman, Ph.D.
, an associate professor of infectious diseases & microbiology at Pitt. “This discovery opens new opportunities to study virus-host interactions at the cellular and organismal level and enriches our understanding of the basic biology of mosquito-transmitted viruses.”
The World Health Organization
lists Rift Valley fever as a prioritized disease likely to cause epidemics in the near future. Mosquitos spread the virus among domesticated animals, who then pass it on to people.
To find out how the virus invades cells, the researchers grew the virus on mouse cells. By systematically disrupting normal mouse genes, the researchers found that the virus failed to infect cells that lacked the gene for LDL receptor-related protein 1, or LRP1. Further experiments showed that the virus needs LRP1 to infect hamster, cow, monkey and human cells, indicating that it 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. Using a naturally occurring protein that blocks LRP1, the researchers showed that animals whose LRP1 was inactivated were more likely to survive the infection, suggesting that targeting LRP1 may lead to therapeutics for Rift Valley fever.
“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, Ph.D.
, 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 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 Hartman, Amarasinghe and their collaborators already have several projects underway to explore these connections.
Additional authors of the paper include Madeline Schwarz, B.S., Cynthia McMillen, Ph.D., Joseph Albe, M.P.H., Devin Boyles, M.S., Zachary Koenig, M.S., Michael Kujawa, B.S., Matthew Demers, B.S., Ryan Hoehl, B.S., Anita McElroy, M.D., Ph.D., all of Pitt; Safder Ganaie, Ph.D., David Price, Ph.D., Annie Feng, B.S., Wenjie Wang, Ph.D., Anthony Orvedahl, M.D., Ph.D., Aidan Cole, B.S., Monica Sentmanat, Ph.D., Nawneet Mishra, Ph.D., Austin Moyle, B.S., Nicole Wagner, Ph.D., Michael Gross, M.D., Sean Whelan, Ph.D., Xiaoxia Cui, Ph.D., Tom Brett, Ph.D., Herbert Virgin, M.D., Ph.D., Takeshi Egawa, M.D., Ph.D., Daisy Leung, Ph.D., all of Washington University in St. Louis; Shane Miersch, Ph.D., Lia Cardarelli, Ph.D., Joan Teyra, Ph.D., Sachdev Sidhu, Ph.D., of the University of Toronto
, Canada; Sarah Stubbs, Ph.D., of Harvard University
; and John Doench, Ph.D., of Broad Institute of MIT and Harvard
This research was supported by the National Institutes of Health
(NIH) grant numbers R01NS101100, R01AI161765, R21AI163603, P01AI120943, R01AI123926, R01AI107056, U19AI142784, U19AI10972505, R01AI130152, T32AI060525, T32AI106688 and 1K08AI144033; the Burroughs Wellcome Fund
, award number 1013362.02; the Pediatric Infectious Diseases Society
; St. Jude Children’s Research Hospital
; Society for Pediatric Research
; Alzheimer’s Association
, grant number AARG-16-441560; and The Leukemia and Lymphoma Society
PHOTO INFO: (click image for high-res version)
CAPTION: Amy Hartman, Ph.D.