Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity

Modhiran, Naphak, Watterson, Daniel, Muller, David A., Panetta, Adele K., Sester, David P., Liu, Lidong, Hume, David A., Stacey, Katryn J. and Young, Paul R. (2015) Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity. Science Translational Medicine, 7 304: 1-10. doi:10.1126/scitranslmed.aaa3863


Author Modhiran, Naphak
Watterson, Daniel
Muller, David A.
Panetta, Adele K.
Sester, David P.
Liu, Lidong
Hume, David A.
Stacey, Katryn J.
Young, Paul R.
Title Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity
Journal name Science Translational Medicine   Check publisher's open access policy
ISSN 1946-6242
1946-6234
Publication date 2015-09-09
Sub-type Article (original research)
DOI 10.1126/scitranslmed.aaa3863
Open Access Status Not Open Access
Volume 7
Issue 304
Start page 1
End page 10
Total pages 10
Place of publication Washington, DC, United States
Publisher American Association for the Advancement of Science (A A A S)
Collection year 2016
Language eng
Formatted abstract
Everyone knows how mosquitos can wreck an end-of-summer picnic. But in some climates, these pesky intruders persist and carry a variety of detrimental diseases—some with no preventative vaccines or targeted therapies. One such passenger is dengue virus (DENV), which infects up to 400 million people each year and comes in several serotypes (1 to 4) and disease presentations—from mild infection to severe disease and sometimes death. But to treat or prevent dengue requires that we have a more complete picture of the disease pathology. Now, Modhiran et al. and Beatty et al. describe the results of in vitro and in vivo experiments that point to circulating dengue virus non-structural protein 1 (NS1) and the innate immune Toll-like receptor 4 (TLR4) as a focus for basic scientists as well as vaccine and drug developers.

DENV infection protects a patient from future reinfection with the same DENV serotype as well as producing temporary immune protection from severe dengue disease caused by a different DENV serotype. But unlike diamonds, this immune protection doesn’t last forever, and when the protected period passes, the patient becomes at increased risk of enhanced infection and progression to severe disease if he or she is infected with a second DENV serotype. This severe form of dengue infection is believed to result from immunopathogenic processes that induce cytokine storm and cause vascular leakage that leads to shock. Until now, no dengue viral proteins have been linked to vascular endothelium permeability (that is, vascular leakage).

Beatty et al. show that inoculation of mice with DENV NS1 protein alone induces both vascular leak and secretion of inflammatory cytokines and that administration of NS1 with a sublethal dose of DENV2 leads to lethal vascular leak syndrome. In human endothelial cell monolayers in culture, NS1 from any of the four DENV serotypes triggered endothelial barrier permeability. NS1’s pathogenic effects were blocked by NS1-immune polyclonal mouse serum or monoclonal antibodies to NS1 (in vivo and in vitro), and immunization of mice with NS1 protected against lethal DENV2 challenge.

In an independent study, Mondrian et al. explore the underlying mechanism of NS1’s effects. They show that highly purified NS1 acts as a pathogen-associated molecular pattern (PAMP) that activates mouse macrophages and human peripheral blood mononuclear cells (PBMCs) in culture via TLR4, resulting in release of inflammatory cytokines—an effect that was blocked by either a TLR4 antagonist or an anti-TLR4 antibody. Then, in an in vitro model of vascular leak, the authors found that NS1 fractured the integrity of endothelial cell monolayers through a TLR4-dependent pathway, a finding that was supported by the observation that a TLR4 antagonist quelled capillary leak in a mouse model of dengue virus infection.

Together, these new findings highlight NS1 as an instigator of dengue-associated vascular leak and thus pinpoint a potential target for dengue drugs and component for dengue vaccines.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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