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

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.