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High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Infect Control Ctr, Div Infect Dis,Dept Internal Med, Kaohsiung 807, Taiwan;Kaohsiung Med Univ, Sepsis Res Ctr, Ctr Dengue Fever Control & Res, Sch Med,Grad Inst Med, Kaohsiung, Taiwan.ORCID iD: 0000-0001-5640-4969
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Infect Control Ctr, Div Infect Dis,Dept Internal Med, Kaohsiung 807, Taiwan;Kaohsiung Med Univ, Sepsis Res Ctr, Ctr Dengue Fever Control & Res, Sch Med,Grad Inst Med, Kaohsiung, Taiwan.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Tampere Univ Hosp, Dept Intens Care, Crit Care Med Res Grp, Tampere, Finland.
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 48, p. 425-441Article in journal (Refereed) Published
Abstract [en]

Background: A main pathological feature of severe dengue virus infection is endothelial hyper-permeability. The dengue virus nonstructural protein 1 (NS1) has been implicated in the vascular leakage that characterizes severe dengue virus infection, however, the molecular mechanisms involved are not known.

Methods: A cohort of 250 dengue patients has been followed from the onset of symptoms to the recovery phase. Set urn hyaluronan levels and several other clinical parameters were recorded. The effect of NS1 treatment of cultured fibroblasts and endothelial cells on the expressions of hyaluronan synthetic and catabolic enzymes and the hyaluronan receptor CD44, were determined, as have the effects on the formation of hyaluronan-rich matrices and endothelial permeability.

Findings: Elevated serum hyaluronan levels (70 ng/ml) during early infection was found to be an independent predictor for occurrence of warning signs, and thus severe dengue fever. High circulating levels of the viral protein NS1, indicative of disease severity, correlated with high concentrations of serum hyaluronan. NS1 exposure decreased the expression of CD44 in differentiating endothelial cells impairing the integrity of vessel-like structures, and promoted the synthesis of hyaluronan in dermal fibroblasts and endothelial cells in synergy with dengue-induced pro-inflammatory mediators. Deposited hyaluronan-rich matrices around cells cultured in vitro recruited CD44-expressing macrophage-like cells, suggesting a mechanism for enhancement of inflammation. In cultured endothelial cells, perturbed hyaluronan-CD44 interactions enhanced endothelial permeability through modulation of VE-cadherin and cytoskeleton re-organization, and exacerbated the NS1-induced disruption of endothelial integrity.

Interpretation: Pharmacological targeting of hyaluronan biosynthesis and/or its CD44-mediated signaling may limit the life-threatening vascular leakiness during moderate-to-severe dengue virus infection. 

Place, publisher, year, edition, pages
ELSEVIER , 2019. Vol. 48, p. 425-441
Keywords [en]
CD44, Dengue, Hyaluronan, Vascular leakage, VE-cadherin, Cytokines, HAS2, HYAL2, TGEbeta
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-397776DOI: 10.1016/j.ebiom.2019.09.014ISI: 000493830800045PubMedID: 31526718OAI: oai:DiVA.org:uu-397776DiVA, id: diva2:1374277
Funder
Swedish Cancer Society, 2018/337Swedish Cancer Society, 2016/445Swedish Research Council, 2015-02757Academy of FinlandAvailable from: 2019-11-29 Created: 2019-11-29 Last updated: 2019-11-29Bibliographically approved

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