Researchers have identified how a viral protein, which plays a major role in causing deadly Nipah and Hendra virus infections, targets a critical function in human cells to suppress immune responses and promote fatal disease.
The research team found the viral protein, called W protein, binds to two specific proteins in the host cell, importin α3 and importin α4, allowing it to move into the nucleus of cells. This allows the protein to disable defenses that protect cells from infection and promote growth of Nipah and Hendra viruses. The findings are published in the journal Nature Communications.
Nipah and Hendra viruses, closely related zoonotic pathogens that come from animal sources, are highly lethal in humans. Old World fruit bats are the source of both viruses in nature.
Forty percent of the people who became ill died. More recently, Nipah virus infections have been recognized in Bangladesh and India, with 70 to 75 percent fatality rates. This time, there seems to be a more direct transmission of the virus from bats to people.
"Right now, for humans, we lack any licensed vaccines or approved drugs to treat the infections," said Dr. Christopher Basler, senior author of the study. "We need vaccines, we need treatments, and we also need to better understand what makes the viruses so deadly.
Innate Immune Responses
"The protein we're studying is called the W protein. We've been studying this protein for several years because it suppresses innate immune responses. This means that it blocks the very early defenses that should protect us from virus infection."
Using facilities at University of Texas Medical Branch at Galveston, they engineered a Nipah virus that couldn't produce the W protein and then put this modified virus into animals. This changed the course of the disease and demonstrated that the function of the W protein is important for Nipah virus to cause disease.
In this study, a research team led by Dr. Jade K. Forwood of Charles Sturt University in Australia used structural biology approaches to investigate how the W protein travels from the cytoplasm to the nucleus of the cell through the interaction of W protein with importin α proteins, which allow the W protein to get into the nucleus.
W protein interaction
The Basler laboratory at Georgia State performed studies in living cells to investigate the W protein interaction with importin α proteins and define why this interaction is important for W protein function. In prior work, Basler has found the ability of the W protein to enter into the nucleus is important for its ability to block innate immune responses.
"One of the things that's interesting about the W protein being in the nucleus of the cell is that most of the other components of the virus remain in the cytoplasm of the cell throughout the replication cycle," Basler said. "We think that the W protein goes to the nucleus to do something, to somehow specifically target innate immune responses."
Human cells have seven different kinds of importin α proteins. In this study, the researchers found W protein is using two of them, importin α3 and importin α4, to get into the nucleus. They identified specific features on the W protein that allow it to recognize those two members of the importin α protein family and distinguish them from others.