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High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Tampere Univ Hosp, Dept Intens Care, Crit Care Med Res Grp, Tampere, Finland.
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2019 (engelsk)Inngår i: EBioMedicine, E-ISSN 2352-3964, Vol. 48, s. 425-441Artikkel i tidsskrift (Fagfellevurdert) 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. 

sted, utgiver, år, opplag, sider
ELSEVIER , 2019. Vol. 48, s. 425-441
Emneord [en]
CD44, Dengue, Hyaluronan, Vascular leakage, VE-cadherin, Cytokines, HAS2, HYAL2, TGEbeta
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-397776DOI: 10.1016/j.ebiom.2019.09.014ISI: 000493830800045PubMedID: 31526718OAI: oai:DiVA.org:uu-397776DiVA, id: diva2:1374277
Forskningsfinansiär
Swedish Cancer Society, 2018/337Swedish Cancer Society, 2016/445Swedish Research Council, 2015-02757Academy of FinlandTilgjengelig fra: 2019-11-29 Laget: 2019-11-29 Sist oppdatert: 2019-11-29bibliografisk kontrollert

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