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DENV NS1 and MMP-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction

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 permeabilit...

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Autores principales: Pan, Pan, Li, Geng, Shen, Miaomiao, Yu, Zhenyang, Ge, Weiwei, Lao, Zizhao, Fan, Yaohua, Chen, Keli, Ding, Zhihao, Wang, Wenbiao, Wan, Pin, Shereen, Muhammad Adnan, Luo, Zhen, Chen, Xulin, Zhang, Qiwei, Lin, Luping, Wu, Jianguo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341711/
https://www.ncbi.nlm.nih.gov/pubmed/34310658
http://dx.doi.org/10.1371/journal.ppat.1008603
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author Pan, Pan
Li, Geng
Shen, Miaomiao
Yu, Zhenyang
Ge, Weiwei
Lao, Zizhao
Fan, Yaohua
Chen, Keli
Ding, Zhihao
Wang, Wenbiao
Wan, Pin
Shereen, Muhammad Adnan
Luo, Zhen
Chen, Xulin
Zhang, Qiwei
Lin, Luping
Wu, Jianguo
author_facet Pan, Pan
Li, Geng
Shen, Miaomiao
Yu, Zhenyang
Ge, Weiwei
Lao, Zizhao
Fan, Yaohua
Chen, Keli
Ding, Zhihao
Wang, Wenbiao
Wan, Pin
Shereen, Muhammad Adnan
Luo, Zhen
Chen, Xulin
Zhang, Qiwei
Lin, Luping
Wu, Jianguo
author_sort Pan, Pan
collection PubMed
description 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.
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spelling pubmed-83417112021-08-06 DENV NS1 and MMP-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction Pan, Pan Li, Geng Shen, Miaomiao Yu, Zhenyang Ge, Weiwei Lao, Zizhao Fan, Yaohua Chen, Keli Ding, Zhihao Wang, Wenbiao Wan, Pin Shereen, Muhammad Adnan Luo, Zhen Chen, Xulin Zhang, Qiwei Lin, Luping Wu, Jianguo PLoS Pathog Research Article 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. Public Library of Science 2021-07-26 /pmc/articles/PMC8341711/ /pubmed/34310658 http://dx.doi.org/10.1371/journal.ppat.1008603 Text en © 2021 Pan et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Pan, Pan
Li, Geng
Shen, Miaomiao
Yu, Zhenyang
Ge, Weiwei
Lao, Zizhao
Fan, Yaohua
Chen, Keli
Ding, Zhihao
Wang, Wenbiao
Wan, Pin
Shereen, Muhammad Adnan
Luo, Zhen
Chen, Xulin
Zhang, Qiwei
Lin, Luping
Wu, Jianguo
DENV NS1 and MMP-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction
title DENV NS1 and MMP-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction
title_full DENV NS1 and MMP-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction
title_fullStr DENV NS1 and MMP-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction
title_full_unstemmed DENV NS1 and MMP-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction
title_short DENV NS1 and MMP-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction
title_sort denv ns1 and mmp-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341711/
https://www.ncbi.nlm.nih.gov/pubmed/34310658
http://dx.doi.org/10.1371/journal.ppat.1008603
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