Viral protein discovery offers hope for first dengue treatment

Scientists have identified a viral protein's role in driving blood vessel leak in severe dengue infection, opening up a potential avenue for developing the first treatment for the world's most common mosquito-borne disease.

The culprit, called nonstructural protein 1 (NS1), one of the 10 viral proteins secreted by cells infected with the dengue virus, is responsible for the fluid loss and resulting shock that are the hallmark of severe -- and potentially fatal -- infections, according to a pair of studies published Wednesday in the U.S. journal Science Translational Medicine.

In one study conducted on human lung endothelial cells and in mice, researchers from the University of California (UC) Berkeley showed that NS1 directly activated a surface receptor known as toll-like receptor 4 (TLR4), triggering the cells to release proinflammatory molecules.

Then, NS1-induced inflammation damaged layers of human endothelial cells, which line the inner walls of blood vessels, causing the cells' tight barrier to become leaky. Treating dengue-infected mice with a compound that blocks TLR4, however, markedly reduced vascular leak.

"Our findings show that NS1 could be a prime target for drugs, and that it should be considered in vaccine development," said Eva Harris, a UC Berkeley professor and senior author of the study.

In a separate study, researchers from the University of Queensland (UQ) showed that NS1 from all four types of the dengue virus damaged human endothelial cells and that vaccination with the protein can protect mice against severe dengue.

The results suggested that NS1 behaves as a viral toxin in much the same way as certain bacterial toxins activate TLR4 and trigger body-wide inflammation in sepsis, said Paul Young, UQ's School of Chemistry and Molecular Biosciences Head Professor and senior author of the study.

The parallels between septic shock and dengue shock syndrome lend support to repurposing sepsis drug candidates, which are expected to advance to clinical trials in dengue patients within the next two years, Young added.

Dengue, estimated to infect up to 400 million people globally each year, typically causes a debilitating fever but can progress to potentially fatal dengue hemorrhagic fever and dengue shock syndrome. Up to 500,000 cases of dengue hemorrhagic fever are diagnosed each year, with as many as 25,000 deaths.

Because there is no treatment or vaccine for dengue, the main method of controlling the disease has focused on reducing mosquito breeding sites and supportive care, such as fluid replacement, for patients with severe dengue. Endit