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Dengue Fever Protein Spurs Severe Form of the Disease

Two research teams have identified a viral protein’s role in driving blood vessel leakage in severe dengue. The findings open potential avenues for developing vaccines and repurposing existing drugs for dengue, the most common and often fatal viral infection spread by mosquito in humans.

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The Aedes aegypti mosquito is a major carrier of the dengue virus in tropical regions. | James Gathany - PHIL, CDC

The studies, published in the 9 September issue of Science Translational Medicine, pinpoint the dengue virus nonstructural protein 1 (NS1) as a leading culprit behind severe infection.

"We show that there is a completely new player in causation of vascular leak that has not been taken into account," said Eva Harris from the University of California, Berkeley, senior author of one of the studies. "We're not saying that NS1 is the entire story behind disease pathogenesis, but the role of the protein itself has definitely been overlooked in the paradigm of what causes severe dengue."

Harris and her team showed that NS1 vaccination can protect mice against lethal dengue infection, building a case for including the protein in future vaccines.

In a separate study, Paul Young and colleagues from University of Queensland, Australia uncovered parallels between dengue infection and bacterial infection in the life-threatening condition known as sepsis. This finding raises the possibility of repurposing sepsis drug candidates for the virus.

"After 30 years in the dengue field, I have never been more excited than I am about the prospects for this therapeutic approach," said Young. "We should be able to test these [sepsis] drugs within one to two years if our next pre-clinical studies prove successful."

There are no effective dengue vaccines or treatments. The dengue virus infects nearly 400 million people worldwide, particularly in tropical areas, and causes illness in about a quarter of them each year. Most patients develop only mild fever, but some progress to severe disease resulting in massive blood vessel leak, shock, and even death. How dengue infection advances to this life-threatening stage remains poorly understood.

The researchers zeroed in on NS1, which is secreted by infected cells and circulates in the blood of dengue patients. The protein is known to help the virus replicate and evade a person’s immune system.

"NS1 has several functions, but no one had shown that the protein itself has pathogenic effects in dengue," said Harris.

The two research teams showed in cells and in mice that the viral protein alone damages the tight layer of cells lining the inner walls of blood vessels, causing them to leak fluid.

"After 30 years in the dengue field, I have never been more excited than I am about the prospects for this therapeutic approach. We should be able to test these [sepsis] drugs within one to two years if our next pre-clinical studies prove successful."

Paul Young

Young's group found that NS1 activated a protein on the surface of immune cells known as toll-like receptor 4 (TLR4), driving inflammation. By blocking the action of this receptor in dengue-infected mice, the researchers were able to markedly reduce vascular leak.

The results indicate that NS1 acts as a viral toxin similar to certain bacterial toxins that activate TLR4 and trigger sepsis, suggesting that sepsis drugs might also work against dengue, said Young.

The results could also help develop new dengue vaccines, said Naphak Modhiran from University of Queensland. "Our finding that NS1 engages TLR4 will allow a more rational approach to vaccine design. We could design a new vaccine which could elicit antibodies to block this interaction and prevent the disease development directly," said Modhiran.

One of the biggest challenges in developing a dengue vaccine stems from the fact that there are four distinct but closely related virus groups, called serotypes, of the virus, requiring a vaccine that is effective against them all. Antibodies against one serotype can protect against reinfection by the same serotype, but can prime patients for more severe disease when they are infected by a different serotype.

Harris' group examined potential strategies for harnessing NS1 as a dengue vaccine. Immunizing mice with the protein from each serotype staved off lethal dengue infection. NS1 from one serotype provided complete protection against that serotype, and NS1 from the three other serotypes each offered between 60 and 75% protection.

Clinical trials of various dengue vaccines containing NS1 are currently underway. It remains to be seen whether a vaccine containing NS1 from all four serotypes may offer a viable strategy for preventing dengue, the researchers say.