Evidence map›Paper›PMID 41218088›Full record

ArticlePLoS pathogens2025

Dengue virus NS1 protein does not activate TLR4 and has a modest effect on endothelial monolayer integrity compared to TNF.

Parimala R Vajjhala, Jaehyeon Kim, Adriana Pliego Zamora, Helen Mostafavi, Larisa I Labzin, Katryn J Stacey

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PubMed Full text at PMC Publisher
In one paragraph

Article in PLoS pathogens, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Review
  3. Review
  4. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors.

Parimala R VajjhalaSchool of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.ORCID 0000-0002-3157-8417
Jaehyeon KimSchool of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
Adriana Pliego ZamoraSchool of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
Helen MostafaviInstitute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Larisa I LabzinInstitute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Katryn J StaceySchool of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.

Funding

Australian National Health and Medical Research Council
6 · The paper itself

Abstract

Severe dengue virus (DENV) infection is characterised by vascular leak and can lead to shock and death. The virus-derived non-structural protein 1 (NS1), which is released into the circulation as a lipoparticle, has been implicated in exacerbation of inflammation through activation of Toll-like receptor 4 (TLR4), and in disruption of endothelial monolayer integrity. We sought to identify the component of the NS1 lipoparticle that activates TLR4. Native and C-terminally His-tagged recombinant NS1 were produced in suspension HEK293 cells and formed hexamers indicating structural integrity. However, neither the recombinant NS1 nor NS1 secreted by DENV-infected Vero or K562 cells activated TLR4. Thus, the NS1 apoprotein itself does not activate TLR4, although it could potentially associate with inflammatory lipids as a lipoparticle. Notably, the lack of TLR4 stimulation by NS1 protein does not exclude a role for TLR4 in dengue disease as it may be activated by LPS influx from the gut or by putative endogenous stimulatory lipids. Furthermore, purified His-tagged NS1, at a biologically relevant concentration, only had a modest effect on endothelial monolayer integrity as assessed by changes in the electrical impedance of an endothelial monolayer. In contrast TNF, a cytokine with an established role in vascular leak, had a potent effect when used at a concentration seen in severe dengue disease. Medium from DENV-infected human macrophages also had a potent disruptive effect. This medium had low NS1, compared to that encountered in some patients, but high TNF concentration and its effect on endothelial monolayers was mostly ablated by an anti-TNF antibody. While multiple factors are likely to contribute to DENV-associated vascular leak in vivo, our data support a key role for TNF. Importantly, our data indicate that while NS1 has a modest effect on endothelial monolayer integrity there is no evidence for it activating TLR4.

Indexed as

DengueDengue VirusEndothelial CellsToll-Like Receptor 4Tumor Necrosis Factor-alphaViral Nonstructural ProteinsAnimalsChlorocebus aethiopsHEK293 CellsHumansVero CellsTLR4 protein, humanToll-Like Receptor 4Tumor Necrosis Factor-alphaViral Nonstructural Proteins

Identifiers

PMID41218088
PMCPMC12622831

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.