An effective vaccine against dengue has remained elusive for quite a while. While we are still a long way from finding an effective solution, there is some good news in our fight against dengue. Researchers at the University of California, Berkeley, have identified the thing responsible for the fluid loss and resulting shock that are the hallmark of severe and potentially fatal dengue virus infections.
Eva Harris, a molecular virologist and a UC Berkeley professor in the Division of Infectious Diseases and Vaccinology lead the team of researchers who found that the culprit is a protein secreted by cells infected with mosquito-borne dengue virus. This protein is called nonstructural protein 1 (NS1) and it is the only one of the 10 viral proteins secreted by infected cells to circulate freely in the bloodstream. Through their experiment on human lung endothelial cells and in mice, the researchers discovered that NS1 cause permeability of the endothelium, which lines the walls of blood and lymph vessels making it leak fluid. Another remarkable discovery made by the researchers is that by blocking this protein in mice, the lethal effects of the dengue virus infection on the mice could be prevented.
The results of the study were published recently in the journal Science Translational Medicine.
Harris, senior author of the study said that this was the missing part in the pathogenesis of dengue. Till now, the role of NS1 itself was overlooked in severe forms of dengue disease, but since it is known now that has an important role to play, it is a prime target for drugs, and vaccine development.
As per statistics every year 390 million people are infected with this virus and because of lack of vaccine or treatment, reducing mosquito breeding sites and supportive care, such as fluid replacement, for patients with severe dengue has been the focus for treating the disease. The most severe symptoms of dengue range from fever, joint and muscle pain, dengue hemorrhagic fever and dengue shock syndrome caused by the loss of fluids from blood vessels. Dengue hemorrhagic fever and dengue shock syndrome can be fatal and result in the death of 22,000 people annually.
Harris said that if fluid loss begins in a patient infected with dengue, it can get fatal in just a day or two. Dengue is caused by 4 serotypes of the virus, so people who have had prior infection are more prone to get a more severe dengue infection the second time. An initial infection can impart long-term immunity for that one of the four virus type, but only temporary immunity against the rest. The dominant hypothesis to explain this has been that the antibodies from the first infection react with the new serotype in a way that worsens the damage.
P. Robert Beatty, an assistant research scientist at UC Berkeley’s School of Public Health and study's lead author said that the interaction with the antibodies might be happening, but it never fully explained all cases of dengue hemorrhagic fever. The toxicity of NS1 makes more sense than just having an over-reactive immune response.
NS1 is produced by all serotypes of dengue virus. The researchers zeroed in on this viral protein after they observed that the pathogenic effects of dengue virus infection were blocked in mice that had generated antibodies to NS1. In fact, the team found that when they injected the mice with NS1 alone, without the virus present, it developed symptoms of dengue disease. When the researchers added a sublethal dose of dengue virus type 2, the resulting infection was fatal. It was also found that immunization of mice with recombinant NS1 from each of the four serotypes protected mice against vascular leak and the lethal effects of dengue virus. These finding can surely pave the way for the nipping the disease at an early stage.