Vascular leakage in severe dengue virus infections

This virus—cell interaction may be associated with the receptor complex specific for DV infection of endothelial cells Wei et al. Dewi et al. Anderson et al. The findings of Talavera et al. The physiological basis of endothelial integrity lies in the presence of intercellular junctions known as tight junctions complexes TJCs that allow vectorial transport of solutes and other biological macromolecules Blum et al.

The TJCs also regulate the overall permeability of endothelial barrier functions. The cellular basis of this has been studied extensively and has been attributed to dynamic rearrangements of the cytoskeleton and its association with TJCs primarily through actin. Alterations in the sealing capacity of the junctions through modifications of the TJ can lead to enhanced permeability Cereijido et al.

All three protein families are integral to normal functioning of the TJC in maintaining endothelial permeability. Lee et al. Recently, Meertens et al. Jose et al. Sera from the day of defervescence had the strongest activating potential in relation to later stages of disease and correlated with the risk for DHF. Although DV can infect different cell types, cells of the monocytic lineage such as Langerhans cells and interstitial DCs are thought to be the primary targets of DV.

An injury causes transendothelial migration of the DCs and expression of matrix metalloproteinases that can have deleterious effects of endothelial cell integrity Asahi et al. Luplertlop et al. Jiang et al. Zhang et al. Schematic representation of the possible interaction between DVs, cytokines and host factors leading to endothelial cell pathology.

Its synthesis is highly regulated by the cell because an alteration in NO production is associated with a variety of pathological effects, such as vasodilatation, inflammation, thrombosis, immune response and neurotransmission. Generation of NO may result in either initiation or suppression of apoptosis.

The involvement of NO in apoptosis induction has been reported in different cell systems, although the mechanisms are not fully understood. Macrophage lineage cells are professional NO producers. NO produced by them downregulates replication of DV.

CF2 also induces production of superoxide anion O 2 — and hydrogen peroxide H 2 O 2 by the spleen cells of mice in vitro and in vivo and the killing Fig. Lin et al. Cytochrome c release is also observed. Complement activation was proposed to be responsible for DHF, but the cause of complement activation was not known.

Avirutnan et al. Endothelial cells produce a number of factors that maintain their physiological activity. The findings summarized in Table 4 show that dysfunction of these factors during DV infections increases permeability. Thrombin, cytokines, reactive oxygen species, etc. Effects of DV infection on vascular permeability through factors secreted by the endothelial cells.

Schematic representation of possible molecular events leading to altered permeability changes in endothelial cells. Presence of DV has been detected in endothelial cells but it does not cause morphological damage, and the vascular leakage is mediated indirectly by various host factor cascades induced by the virus. Absence of tissue inflammation suggests a transient change in factors that regulate vascular permeability.

In spite of a large number of mechanisms proposed from time to time, as discussed above, the precise mechanism of the pathogenesis is not clearly understood.

As the ultimate target is the endothelial cells, a large body of data has accumulated from the in vitro studies on pathophysiology of endothelial cell monolayers during DV infection. As in mice, the endothelial cell monolayers are not the true model of the human disease, and only point to various possibilities that may operate in vivo. Efforts have been made to develop animal models but success has been limited. More intense studies are required to translate the knowledge obtained from animal models and in vitro experiments to human pathology.

National Center for Biotechnology Information , U. Published online Jun 3. Atanu Basu 1 and Umesh C.

Chaturvedi 2. Umesh C. Chaturvedi 2 Department of Microbiology, K. Author information Article notes Copyright and License information Disclaimer. Medical College, Lucknow, India. Correspondence: Umesh C. Published by Blackwell Publishing Ltd. All rights reserved. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

This article has been cited by other articles in PMC. Keywords: dengue virus, dengue haemorrhagic fever, vascular endothelium, vascular permeability, cytokines, pathogenesis. Open in a separate window. Increased capillary permeability Chaturvedi et al. Increased capillary permeability Jiang et al. Leitmeyer et al. Cologna et al. Infection of endothelial cells with DV in patients with DHF and in mice Electron microscopic studies of capillaries in skin biopsies from patients with DHF show marked distortion, but severely damaged vessels are not observed, and most of the endothelial junctions are intact, although swelling of stray endothelial cells is noted Sahaphong et al.

Figure 1. Vascular endothelium The vascular endothelial cells lining the inner lumen of blood vessels and capillaries constitute the primary anatomical blood—tissue barrier. In vitro alterations in endothelial cell biology by dengue viruses Endothelial cells are permissive to DV infection in vitro.

Effects of DV infection on tight junction complex of endothelium The physiological basis of endothelial integrity lies in the presence of intercellular junctions known as tight junctions complexes TJCs that allow vectorial transport of solutes and other biological macromolecules Blum et al. Dengue viruses and changes in endothelium permeability Dewi et al. Figure 2. Role of endothelin in endothelium permeability Endothelial cells produce a number of factors that maintain their physiological activity.

Figure 3. Statement U. Notes Editor: Willem van Leeuwen. Corresponding author. Received Jun 18; Accepted Nov 4. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

This article has been cited by other articles in PMC. Abstract The pathogenesis of dengue virus infection is attributed to complex interplay between virus, host genes and host immune response.

Introduction Dengue infection is a major public health problem and has been reported from the Americas, Africa, Southeast Asia, Europe, Western Pacific, and Eastern Mediterranean regions. Open in a separate window. Complex interplay of viral and host factors in pathogenesis of dengue virus infection. Role of T Cells Various studies have implied that cross-reactive T cells, which are active during secondary heterotypic infections, play a role in mediating the pathogenesis of DHF [ 16 ].

Table 1 Summary of various factors implicated in pathogenesis of dengue virus infection. Fox A et al. Moon SL et al. Brown MG et al. Role of Host Genetic Factors Apart from various viral factors implicated in the pathogenesis of DENV infection, host genetic factors also play an important role. Recent Insights into Dengue Pathogenesis and Biomarkers Identification of markers for disease severity or increase risk of progression to more severe forms of the disease is a major interest in dengue research.

Conclusion The exact mechanisms responsible for severe manifestations of dengue virus disease are not yet fully elucidated and are likely to be multifactorial. Acknowledgements None. Compliance with Ethical Standards Conflict of interest None to declare. Contributor Information Puneet Bhatt, Email: moc. References 1. Dengue burden in India: recent trends and importance of climatic parameters. Emerg Microbes Infect. The global distribution and burden of dengue.

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Vet Microbiol. Innate immunity to dengue virus infection and subversion of antiviral responses. J Mol Biol. Ang-1 is a ligand for the endothelial specific receptor, tyrosine kinase with Ig-like loops and epidermal growth factor homology domains-2 Tie2 [ 16 ] and is essential for embryonic vascular development [ 27 ].

In addition, Thurston et al. Binding of Ang-1 to Tie2 receptor activates Tie2, and angiopoietin-2 Ang-2 is an antagonist of Ang It has been believed that Ang-2 is thought to inactivate Tie2 and destabilize vessels by dissociating endothelial cells into endothelial cells and endothelial cells into mural cells [ 28 ]. Ang-1 mediated protection against vascular leakage caused by several diseases has been reported. Vessels in Ang-1 overexpressing mice are resistant to leakage caused by inflammatory agents [ 29 ].

Moreover, Witzenbichler et al. A more detailed study is needed to clarify whether the improvement in mouse survival brought about by administration of Ang-1 is due to its indirect blocking effect against a yet unidentified factor that induces vascular leakage or its protective role in the blood vessel restoration step. This work was supported by: 1. National Center for Biotechnology Information , U. PLoS One. Published online Feb 4. Xia Jin, Editor.

Author information Article notes Copyright and License information Disclaimer. Competing Interests: The authors have declared that no competing interests exist. Received Sep 7; Accepted Jan This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

This article has been cited by other articles in PMC. Abstract Severe dengue is caused by host responses to viral infection, but the pathogenesis remains unknown. Focus-forming assays Virus infectivity was measured in focus-forming assays and expressed as focus-forming units FFU.

Quantitation of vascular permeability Vascular leakage was examined by intravascular administration of Evans blue Sigma-Aldrich as previously described [ 9 ]. Open in a separate window. Fig 1. Fig 2. Fig 3. Fig 4. Fig 5. Fig 6. Fig 7. Fig 8. Fig 9. Funding Statement This work was supported by: 1.

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Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Angiopoietin-1 protects the adult vasculature against plasma leakage.