Dengue virus infection mediates HMGB1 release from monocytes involving PCAF acetylase complex and induces vascular leakage in endothelial cells

• Published in: PloS one 2012-07, Vol.7 (7), p.e41932-e41932
• Main Authors: Ong, Siew Pei, Lee, Ling Min, Leong, Yew Fai Ivan, Ng, Mah Lee, Chu, Justin Jang Hann
• Format: Article
• Language: English
• Subjects: Acetylation; Antibodies; Biology; Blood & organ donations; Blotting, Western; Cancer research; Capsid; Capsid protein; Cell culture; Chromosomal proteins; Cytokines; Cytoplasm; Dengue - physiopathology; Dengue fever; Dengue hemorrhagic fever; Dengue virus; Electrophoresis, Polyacrylamide Gel; Endothelial cells; Endothelium; Endothelium, Vascular - physiopathology; Event-related potentials; Fever; Flavivirus; Fluorescent Antibody Technique, Indirect; Gene expression; Health aspects; Hemorrhagic fevers; High mobility group proteins; HMGB1 protein; HMGB1 Protein - secretion; Hostages; Humans; Immunoglobulins; Infection; Infections; Inflammation; K562 Cells; Kinases; Laboratories; Leukemia; Leukocyte migration; Lymphocytes; Medicine; Monocytes; Monocytes - metabolism; Multiplicity of infection; Myeloid leukemia; Nuclear transport; Nuclei (cytology); p300-CBP Transcription Factors - metabolism; Pathogenesis; Peripheral blood; Permeability; Phosphorylation; Product introduction; Proteins; Pyruvic acid; Structural integrity; Translocation; Vector-borne diseases; Viral diseases; Viral infections; Viral proteins; Virology; Viruses; West Nile virus
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0041932

High mobility group box 1 (HMGB1) protein is released from cells as a pro-inflammatory cytokine in response to an injury or infection. During dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS), a number of pro-inflammatory cytokines are released, contributing to disease pathogenesis. In this study, the release of HMGB1 from human myelogenous leukemia cell line K562 and primary peripheral blood monocytes (PBM) cells was examined during dengue virus (DV)-infection. HMGB1 was shown to translocate from cell nuclei to the cytoplasm in both K562- and PBM-infected cells. The translocation of HMGB1 from the nucleus to the cytoplasm was shown to be mediated by the host cell p300/CBP-associated factor (PCAF) acetylase complex in K562 cells. In addition, DV capsid protein was observed to be the putative viral protein in actuating HMGB1 migration from the nucleus to cytoplasm through the involvement of PCAF acetylase. HMGB1 was released from DV-infected K562 cells into the extracellular milieu in a multiplicity of infection (M.O.I.)-independent manner and its release can be inhibited by the addition of 1-5 mM of ethyl pyruvate (EP) in a dose-dependent manner. Application of DV-infected K562 cell culture supernatants to primary endothelial cells induced vascular permeability. In contrast, supernatants from DV-infected K562 cells treated with EP or HMGB1 neutralizing antibody were observed to maintain the structural integrity of the vascular barrier.