A team of scientists at the University of Michigan (UoM) and Purdue University have discovered how the viruses of dengue and West Nile fever replicate in the cells of their host and how they manipulate the immune system. The mosquito-borne diseases affect millions of people worldwide each year, but there is no vaccine against either. In a study that was published recently in the journal Science, the team led by Janet Smith of the UoM Sciences Institute talks about how the structure of a protein that helps the viruses replicate and spread infection for the very first time.
“We were inspired by the scientific challenge and the potential impact on human health. So much is still unknown about this virus family and from a research point of view, there was a lot we could learn. But of course, these viruses make millions of people sick and can be fatal, so we were motivated by the possibility that our discoveries could someday help to prevent or treat these diseases,” Janet Smith, faculty member at the life Sciences Institute, says, adding that the design of this key protein provides a target for a potential vaccine or even a therapeutic drug.
The protein, NS1 (a test for dengue), is produced inside infected cells, where it plays a key role in replication of the virus. NS1 is also released into the bloodstream, where it may help disguise the infection from the patient’s immune system and may play a role in the hemorrhage that is seen in severe dengue virus infection.
Smith and her colleagues created images of the protein using X-ray crystallography, a technique that uses X-ray beams to map the positions of atoms in a crystal. Isolating the protein in its natural form was a challenge. “Scientifically, we’re very excited about finally seeing the protein in atomic detail, and working out how we might target antiviral drugs to it or develop it as a vaccine,” Smith tells you.
Researchers have pursued this protein for years because both its role in replication and its unique release into the bloodstream mark it as a target for treatment of infection. The researchers discovered that NS1 has a 3-D structure with two distinct sides, one facing the replication system of the virus inside cells it infects and the other facing the immune system outside infected cells.
Developing a clearer picture of how the NS1 protein interacts with the immune system and influences disease may pave the way for researchers to develop a vaccine that protects people — without inadvertently increasing their risk. “If a vaccine comes of this work, the public health implications would be tremendous, given the number of people around the world who are infected every year by flaviviruses, especially dengue,” Smith says.
The research required the different expertise of a range of scientists, Smith explains. First, researchers in the lab crystallised the protein at lSI’s Center for Structural Biology. Then they put the crystals in an X-ray beam at the advanced photon source at Argonne National laboratory in Illinois to create a map of the protein. They then used the map to build a 3-D structure in atomic detail.
However, she is quick to point out that there’s no telling how much time is needed to develop a vaccine. “The immediate benefits are for the structures to inform basic research into the currently mysterious ways that the virus uses this protein to sneak around and hide from virus killers in the immune system,” Smith says.