In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2021-7-26), p. e1008603-
Abstract:
Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients and highly associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure, and disseminated intravascular coagulation as the disease progresses of DHF/DSS patients, which can lead to the death of patients. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patients’ sera, peripheral blood mononuclear cells (PBMCs), and macrophages. This study further reveals that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor κB (NF-κB) signaling pathway. Additionally, NS1 facilitates the MMP-9 enzymatic activity, which alters the adhesion and tight junction and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with β-catenin and Zona occludens protein-1/2 (ZO-1 and ZO-2) and to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1008603
DOI:
10.1371/journal.ppat.1008603.g001
DOI:
10.1371/journal.ppat.1008603.g002
DOI:
10.1371/journal.ppat.1008603.g003
DOI:
10.1371/journal.ppat.1008603.g004
DOI:
10.1371/journal.ppat.1008603.g005
DOI:
10.1371/journal.ppat.1008603.g006
DOI:
10.1371/journal.ppat.1008603.g007
DOI:
10.1371/journal.ppat.1008603.g008
DOI:
10.1371/journal.ppat.1008603.g009
DOI:
10.1371/journal.ppat.1008603.s001
DOI:
10.1371/journal.ppat.1008603.s002
DOI:
10.1371/journal.ppat.1008603.s003
DOI:
10.1371/journal.ppat.1008603.s004
DOI:
10.1371/journal.ppat.1008603.s005
DOI:
10.1371/journal.ppat.1008603.s006
DOI:
10.1371/journal.ppat.1008603.s007
DOI:
10.1371/journal.ppat.1008603.s008
DOI:
10.1371/journal.ppat.1008603.s009
DOI:
10.1371/journal.ppat.1008603.s010
DOI:
10.1371/journal.ppat.1008603.s011
DOI:
10.1371/journal.ppat.1008603.s012
DOI:
10.1371/journal.ppat.1008603.s013
DOI:
10.1371/journal.ppat.1008603.s014
DOI:
10.1371/journal.ppat.1008603.s015
DOI:
10.1371/journal.ppat.1008603.s016
DOI:
10.1371/journal.ppat.1008603.r001
DOI:
10.1371/journal.ppat.1008603.r002
DOI:
10.1371/journal.ppat.1008603.r003
DOI:
10.1371/journal.ppat.1008603.r004
DOI:
10.1371/journal.ppat.1008603.r005
DOI:
10.1371/journal.ppat.1008603.r006
DOI:
10.1371/journal.ppat.1008603.r007
DOI:
10.1371/journal.ppat.1008603.r008
DOI:
10.1371/journal.ppat.1008603.r009
DOI:
10.1371/journal.ppat.1008603.r010
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2205412-1
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