- by Alison

Could a protein be key to new dengue drug discoveries?

image, dengue virus

Each year, up to 396 million people are infected with the dengue virus (DENV), leading to an estimated 100 million dengue cases. Annually, hospitals around the globe admit around 500,000 victims (mainly children) with severe dengue. About 2.5% of those affected die, but in some regions, the fatality ratio can be as high as 20%. Severe dengue is a leading cause of hospitalization and death among children in Asia and Latin America, and with no dengue drug treatment available, the numbers are expected to rise.

These WHO estimates on the burden of dengue are shocking. With incidence growing dramatically in recent decades, the WHO set out objectives to ‘reduce mortality and morbidity from dengue by 2020 by at least 50% and 25% respectively’ in its Global Strategy for Dengue Prevention and Control 2012-2020.

The fight against severe dengue intensifies

One of the leading causes of death in patients with severe dengue is something called vascular leakage, in which fluids and small molecules flow out of blood vessels. In severe dengue, vascular leakage leads to the familiar symptoms of fluid accumulating in the lungs and other parts of the body, resulting in shock and circulatory failure. Otherwise healthy people can die in 24 to 48 hours.

A team of researchers at the School of Public Health at the University of California, Berkeley, are investigating how severe dengue causes vascular leakage. Led by Dr. Eva Harris, a professor of infectious diseases, their findings could open up new possibilities for saving the lives of people who are at risk of succumbing to severe dengue.

NS1 holds the key

Dr. Harris and her team have been studying dengue for many years, both at UC Berkeley and in Nicaragua through collaborative research projects. In the course of their research, they noticed a distinct protein that might play a fundamental role in bringing about vascular leakage in people with severe dengue – a non-structural DENV protein called NS1.

image, doctor collecting samples in Nicaragua for dengue.

Annual Collection of Serological Samples for the UC Berkeley/Nicaraguan Ministry of Health Pediatric Dengue Cohort Study in Managua, Nicaragua, monitored here by Eva Harris (right). Photo credit, Alejandro Belli.

Dengue virus is made up of just ten proteins, each with different characteristics and different roles to play in the life cycle of dengue infection, immune evasion, and disease.

In the first part of their research into NS1, the team found that vaccination with NS1 induced an immune response that protected mice from lethal DENV-induced vascular leakage and produced antibodies that could protect against the disease. “We had found NS1 on its own caused vascular leakage,” reveals Dr. Harris. “But we didn’t know how.”

In the second part of their research, studies focused on understanding how the NS1 protein caused permeability in human endothelial cells (cells that line blood vessels). The team has now identified two novel mechanisms by which NS1 causes endothelial leakage. “When this happens in the lung, for instance, lung tissue could become more permeable and result in the symptoms of severe dengue,” explains Dr. Harris.

Potential new types of vaccine and dengue drug treatments

The research could lead to new kinds of vaccines and new therapies for people at risk of contracting severe dengue. “We are already working on a research project that combines recombinant NS1 with new vaccine adjuvants,” comments Dr. Harris. “This could lead to a new vaccine or a new component that could be added to existing dengue vaccines.”

“This could lead to a new vaccine or a new component that could be added to existing dengue vaccines.”

It also opens the door for developing therapeutic treatments that could protect against vascular leakage for anyone who has contracted dengue and is at risk of severe dengue.

Watch Professor Harris explain her team’s findings below, and find out why she says that the NS1 protein should be considered part of the causal factors in severe dengue.

“Dengue is a very difficult disease that needs to be attacked on many different fronts.”

These new possibilities give real hope that there might one day be a cure for this potentially deadly infection.

Could this be the first step in stopping deaths of dengue?