High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrityResearch in context

Chun-Yu Lin; Constantinos Kolliopoulos; Chung-Hao Huang; Jyrki Tenhunen; Carl-Henrik Heldin; Yen-Hsu Chen; Paraskevi Heldin

EBioMedicine (Oct 2019)

High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrityResearch in context

Chun-Yu Lin,
Constantinos Kolliopoulos,
Chung-Hao Huang,
Jyrki Tenhunen,
Carl-Henrik Heldin,
Yen-Hsu Chen,
Paraskevi Heldin

Affiliations

Chun-Yu Lin: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden; Division of Infectious Diseases, Department of Internal Medicine, Infection Control Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center of Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgical Sciences, Uppsala University, Akademiska Hospital, 751 85 Uppsala, Sweden
Constantinos Kolliopoulos: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden
Chung-Hao Huang: Division of Infectious Diseases, Department of Internal Medicine, Infection Control Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center of Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan
Jyrki Tenhunen: Department of Surgical Sciences, Uppsala University, Akademiska Hospital, 751 85 Uppsala, Sweden; Critical Care Medicine Research Group, Department of Intensive Care, Tampere University Hospital, Tampere, Finland
Carl-Henrik Heldin: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden
Yen-Hsu Chen: School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center of Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Deparent of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan; Correspondence to: Y-H Chen, Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, No.68, Jhonghua 3rd Rd, Kaohsiung City 80145, Taiwan.
Paraskevi Heldin: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden; Correspondence to: P. Heldin, Uppsala University, Department of Medical Biochemistry and Microbiology, Biomedical Center, Box 582, SE-751 23 Uppsala, Sweden.

Journal volume & issue: Vol. 48
pp. 425 – 441

Abstract

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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. Serum 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. Fund: This work was supported in part by grants from the Swedish Cancer Society (2018/337; 2016/445), the Swedish Research Council (2015-02757), the Ludwig Institute for Cancer Research, Uppsala University, the Ministry of Science and Technology, Taiwan (106–2314-B-037-088- and 106–2915-I-037-501-), Kaohsiung Medical University Hospital (KMUH103-3 T05) and Academy of Finland. The funders played no role in the design, interpretation or writing of the manuscript. Keywords: CD44, Dengue, Hyaluronan, Vascular leakage, VE-cadherin, Cytokines, HAS2, HYAL2, TGFbeta

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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