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Now published in The Lancet

High Levels of Serum Hyaluronan Predicts Severe Dengue Infection and Perturbs Vascular Integrity

39 Pages Posted: 15 May 2019

See all articles by Chun-Yu Lin

Chun-Yu Lin

Uppsala University - Department of Medical Biochemistry and Microbiology; Kaohsiung Medical University - Kaohsiung Medical University Hospital; Kaohsiung Medical University - Center of Dengue Fever Control and Research; Uppsala University - Uppsala University Hospital

Constantinos Kolliopoulos

Uppsala University - Department of Medical Biochemistry and Microbiology

Chung-Hao Huang

Kaohsiung Medical University - Kaohsiung Medical University Hospital; Kaohsiung Medical University - Center of Dengue Fever Control and Research

Jyrki Tenhunen

Uppsala University - Uppsala University Hospital; Tampere University - Tampere University Hospital

Carl-Henrik Heldin

Uppsala University - Department of Medical Biochemistry and Microbiology

Yen-Hsu Chen

Kaohsiung Medical University - Center of Dengue Fever Control and Research; Kaohsiung Municipal Ta-Tung Hospital - Department of Internal Medicine; National Chiao Tung University - Department of Biological Science and Technology

Paraskevi Heldin

Uppsala University - Department of Medical Biochemistry and Microbiology

More...

Abstract

A main pathological feature of severe dengue virus infection is endothelial hyperpermeability. We demonstrate that elevated serum hyaluronan levels (≥70 ng/ml)during early infection is 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, correlate with high concentration 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 recruited CD44-expressing macrophages, thus perpetuating inflammation. Perturbed hyaluronan-CD44 interactions enhanced endothelial permeability through modulation of VEcadherin and cytoskeleton re-organization, and exacerbated the NS1 induced disruption of endothelial integrity. Thus, pharmacological targeting of hyaluronan biosynthesis and/or its CD44-mediated signaling may limit the life-threatening vascular leakiness during severe dengue virus infection.

Funding Statement: This work was supported in part by grants from the Swedish Cancer Society (2015- 0778), 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 (KMUH103-3T05) and Academy of Finland.

Declaration of Interests: The authors have declared that no conflict of interest exists.

Ethics Approval Statement: The human study protocol was approved by the Institutional Review Board (IRB) of Kaohsiung Medical University Hospital (IRB Number: KMUH-IRB-20110451). Informed consent was obtained from all subjects.

Keywords: CD44, dengue, hyaluronan, vascular leakage, VE-cadherin, cytokines, HAS2, HYAL2, TGFbeta

Suggested Citation

Lin, Chun-Yu and Kolliopoulos, Constantinos and Huang, Chung-Hao and Tenhunen, Jyrki and Heldin, Carl-Henrik and Chen, Yen-Hsu and Heldin, Paraskevi, High Levels of Serum Hyaluronan Predicts Severe Dengue Infection and Perturbs Vascular Integrity (October 5, 2019). Available at SSRN: https://ssrn.com/abstract=3387505 or http://dx.doi.org/10.2139/ssrn.3387505

Chun-Yu Lin

Uppsala University - Department of Medical Biochemistry and Microbiology

Sweden

Kaohsiung Medical University - Kaohsiung Medical University Hospital

Kaohsiung
Taiwan

Kaohsiung Medical University - Center of Dengue Fever Control and Research

Taiwan

Uppsala University - Uppsala University Hospital

Sweden

Constantinos Kolliopoulos

Uppsala University - Department of Medical Biochemistry and Microbiology

Sweden

Chung-Hao Huang

Kaohsiung Medical University - Kaohsiung Medical University Hospital

Kaohsiung
Taiwan

Kaohsiung Medical University - Center of Dengue Fever Control and Research

Taiwan

Jyrki Tenhunen

Uppsala University - Uppsala University Hospital

Sweden

Tampere University - Tampere University Hospital

Tampere
Finland

Carl-Henrik Heldin

Uppsala University - Department of Medical Biochemistry and Microbiology

Sweden

Yen-Hsu Chen

Kaohsiung Medical University - Center of Dengue Fever Control and Research ( email )

Taiwan

Kaohsiung Municipal Ta-Tung Hospital - Department of Internal Medicine ( email )

Taiwan

National Chiao Tung University - Department of Biological Science and Technology ( email )

Taiwan

Paraskevi Heldin (Contact Author)

Uppsala University - Department of Medical Biochemistry and Microbiology ( email )

Sweden