DENV NS1 protein could cause vascular leakage in severe dengue

Highlights

• DENV (dengue virus) NS1, a protein secreted by infected dengue cells is the likelier cause of vascular leakage, the hallmark of severe dengue disease
• Infection with the mosquito-borne dengue virus can be mild, but sometimes it can also lead to shock or death due to excessive leakage of fluids from the blood vessels
• DENV (dengue virus) NS1 protein has exhibited disruptive properties against the endothelial glycocalyx-like layer, a protective barrier that lines blood vessels

A protein called dengue virus (DENV) NS1 secreted by infected dengue virus cells can cause harmful leakage of fluid from blood vessels found a new study published in PLOS Pathogen journal. This leakage of fluids from blood vessels is considered be one of the important signs of severe dengue disease. Blood vessel fluid leakage caused by dengue virus NS1 protein
Infection with the mosquito-borne dengue virus can be mild, but it sometimes results in shock or death due to leaky blood vessels. Prior research has shown that the DENV NS1, which is secreted by infected human cells, is a likely culprit behind such leaks. However, the details of its mechanism have been unclear.

In previous research, Dustin Glasner and his colleagues at the University of California, Berkeley, used human cell lines to show that DENV NS1 can disrupt the endothelial glycocalyx-like layer, a protective barrier that lines blood vessels.

Other recent evidence suggests that DENV NS1 can also trigger release of proteins called inflammatory cytokines from immune cells, which could contribute to blood vessel leakage.

To determine the relative impact of these two mechanisms, Glasner and colleagues performed several experiments. They exposed uninfected human cells derived from blood vessels in the skin to DENV NS1 and found evidence suggesting that the cells did not produce inflammatory cytokines in response.

In another experiment, blocking the activity of inflammatory cytokines in the presence of DENV NS1 did not prevent disruption of human cell layers similar to those found in the lining of blood vessels.

The researchers also showed that DENV NS1 caused similar levels of blood vessel leak in normal mice as in mice bred to have inhibited cytokine activity, suggesting that cytokines were not necessary for this effect.

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However, in a final experiment, inhibiting molecules involved in the disruption of glycocalyx components prevented blood vessel leakage in both mice and human cells exposed to DENV NS1.

These results suggest that response to inflammatory cytokines by endothelial cells is not required for NS1 to cause blood vessel leakage. Instead, the underlying mechanism appears to be disruption of glycocalyx components lining blood vessels.

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With further research, inhibiting molecules involved in this disruption could serve as the foundation of new potential treatments for severe dengue disease.

"Following the exciting discovery that dengue virus NS1 protein can directly cause vascular leak, the hallmark of severe dengue disease, we have now succeeded in disentangling the mechanisms responsible, suggesting new drug targets for inhibiting severe dengue", says Dr. Eva Harris, the senior investigator.

Reference

1. Dustin R. Glasner, Kalani Ratnasiri, Henry Puerta-Guardo, Diego A. Espinosa,P. Robert Beatty, Eva Harris Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components, PLOS Pathogens (2017).https://doi.org/10.1371/journal.ppat.1006673

Source-Eurekalert