In a groundbreaking discovery, scientists at the University of Pittsburgh Center for Vaccine Research have pinpointed a critical protein responsible for causing lethal liver disease in mice infected with the deadly Rift Valley fever virus (RVFV). The findings, published in Science Advances, pave the way for future vaccine development and represent a significant step forward in understanding how RVFV replicates within the body.

Known for its ability to transmit via mosquitoes and infect a wide array of animals, insects, and humans, RVFV poses a severe threat to public health, especially in Africa. While RVFV generally causes milder symptoms in humans, it can lead to severe complications like vision loss, liver disease, and encephalitis. With no approved vaccines or treatments available, understanding the virus's mechanisms is crucial in mitigating potential outbreaks.

Amy Hartman, Ph.D., Associate Professor of Infectious Diseases and Microbiology at Pitt's School of Public Health, highlighted the urgent need for vaccine development, stating, "The way in which viruses like RVFV can infect wide ranges of species is not well-understood. If RVFV were to emerge in the U.S., it would be highly concerning due to how fast it can spread. Our ultimate goal is to use this research to create a vaccine for protection."

Understanding the disease

The liver plays a significant role in the replication of viruses like RVFV. In previous research, Dr. Hartman and her team identified a cholesterol receptor called low-density lipoprotein receptor-related protein 1 (Lrp1) responsible for initiating RVFV infection in animal cells. However, the specific role of Lrp1 in hepatic disease and how the virus spreads and infects specific groups of cells within an organism remained unknown—until now.

To unravel this crucial interaction, the researchers at Washington University in St. Louis engineered mice lacking the Lrp1 receptor in their livers. The results were astonishing. The liver-specific knockout mice showed significantly reduced viral replication of RVFV in the liver and lived twice as long as mice with intact Lrp1 levels. Although the Lrp1-knockout mice didn't contract lethal RVFV hepatic disease, they did develop a neurological disease mediated through Lrp1 in their brains.

Results

Dr. Hartman commented on the significance of their findings, stating, "Our results are important because they showed that Lrp1 is responsible for lethal RVFV liver disease in a mouse model. We can translate these results—as the liver is also responsible for viral replication in humans—and we now have the capability in future research to dissect how the virus spreads throughout the body."

This groundbreaking research provides a critical step towards understanding RVFV and devising strategies for vaccine development, potentially safeguarding human and animal populations from the ravages of this lethal virus.

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