scholarly journals Vascular Leakage in Severe Dengue Virus Infections: A Potential Role for the Nonstructural Viral Protein NS1 and Complement

2006 ◽  
Vol 193 (8) ◽  
pp. 1078-1088 ◽  
Author(s):  
Panisadee Avirutnan ◽  
Nuntaya Punyadee ◽  
Sansanee Noisakran ◽  
Chulaluk Komoltri ◽  
Somchai Thiemmeca ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Viral Protein ◽  
Potential Role ◽  
Vascular Leakage ◽  
Severe Dengue ◽  
Virus Infections

Elevated plasma levels of the long pentraxin, pentraxin 3, in severe dengue virus infections

2005 ◽  
Vol 76 (4) ◽  
pp. 547-552 ◽  
Author(s):  
Albert T.A. Mairuhu ◽  
Giuseppe Peri ◽  
Tatty E. Setiati ◽  
C. Erik Hack ◽  
Penelopie Koraka ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Plasma Levels ◽  
Severe Dengue ◽  
Pentraxin 3 ◽  
Virus Infections ◽  
Elevated Plasma

scholarly journals Mitochondrial Import of Dengue Virus NS3 Protease and Cleavage of GrpEL1, a Cochaperone of Mitochondrial Hsp70

2020 ◽  
Vol 94 (17) ◽  
Author(s):  
Chaitanya Gandikota ◽  
Fareed Mohammed ◽  
Lekha Gandhi ◽  
Deepti Maisnam ◽  
Ushodaya Mattam ◽  
...  
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Severe Dengue ◽  
Clinical Samples ◽  
Mitochondrial Matrix ◽  
Virus Infections ◽  
Mitochondrial Import ◽  
Mitochondrial Transport ◽  
Infected Cells ◽  
Mitochondrial Hsp70

ABSTRACT Dengue virus infections, which have been reported in nearly 140 countries, pose a significant threat to human health. The genome of dengue virus encodes three structural and seven nonstructural (NS) proteins along with two untranslated regions, one each on both ends. Among them, dengue protease (NS3) plays a pivotal role in polyprotein processing and virus multiplication. NS3 is also known to regulate several host proteins to induce and maintain pathogenesis. Certain viral proteins are known to interact with mitochondrial membrane proteins and interfere with their functions, but the association of a virus-coded protein with the mitochondrial matrix is not known. In this report, by using in silico analysis, we show that NS3pro alone is capable of mitochondrial import; however, this is dependent on its innate mitochondrial transport signal (MTS). Transient-transfection and protein import studies confirm the import of NS3pro to the mitochondrial matrix. Similarly, NS3pro-helicase (amino acids 1 to 464 of NS3) also targets the mitochondria. Intriguingly, reduced levels of matrix-localized GrpE protein homolog 1 (GrpEL1), a cochaperone of mitochondrial Hsp70 (mtHsp70), were noticed in NS3pro-expressing, NS3pro-helicase-expressing, and virus-infected cells. Upon the use of purified components, GrpEL1 undergoes cleavage, and the cleavage sites have been mapped to KR81A and QR92S. Importantly, GrpEL1 levels are seriously compromised in severe dengue virus-infected clinical samples. Our studies provide novel insights into the import of NS3 into host mitochondria and identify a hitherto unknown factor, GrpEL1, as a cleavage target, thereby providing new avenues for dengue virus research and the design of potential therapeutics. IMPORTANCE Approximately 40% of the world’s population is at risk of dengue virus infection. There is currently no specific drug or potential vaccine for these infections. Lack of complete understanding of the pathogenesis of the virus is one of the hurdles that must be overcome in developing antivirals for this virus infection. In the present study, we observed that the dengue virus-coded protease imports to the mitochondrial matrix, and our report is the first ever of a virus-coded protein, either animal or human, importing to the mitochondrial matrix. Our analysis indicates that the observed mitochondrial import is due to an inherited mitochondrial transport signal. We also show that matrix-localized GrpE protein homolog 1 (GrpEL1), a cochaperone of mitochondrial Hsp70 (mtHsp70), is also the substrate of dengue virus protease, as observed in vitro and ex vivo in virus-infected cells and dengue virus-infected clinical samples. Hence, our studies reveal an essential aspect of the pathogenesis of dengue virus infections, which may aid in developing antidengue therapeutics.

scholarly journals A Critical Role for Perivascular Cells in Amplifying Vascular Leakage Induced by Dengue Virus Nonstructural Protein 1

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Yin P. Cheung ◽  
Valeria Mastrullo ◽  
Davide Maselli ◽  
Teemapron Butsabong ◽  
Paolo Madeddu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Dengue Virus ◽  
Nonstructural Protein ◽  
Critical Role ◽  
Vascular Leakage ◽  
World Health ◽  
Severe Dengue ◽  
Perivascular Cells ◽  
Nonstructural Protein 1

ABSTRACT Dengue is the most prevalent arthropod-borne viral disease affecting humans, with severe dengue typified by potentially fatal microvascular leakage and hypovolemic shock. Blood vessels of the microvasculature are composed of a tubular structure of endothelial cells ensheathed by perivascular cells (pericytes). Pericytes support endothelial cell barrier formation and maintenance through paracrine and contact-mediated signaling and are critical to microvascular integrity. Pericyte dysfunction has been linked to vascular leakage in noncommunicable pathologies such as diabetic retinopathy but has never been linked to infection-related vascular leakage. Dengue vascular leakage has been shown to result in part from the direct action of the secreted dengue virus (DENV) nonstructural protein NS1 on endothelial cells. Using primary human vascular cells, we show here that NS1 also causes pericyte dysfunction and that NS1-induced endothelial hyperpermeability is more pronounced in the presence of pericytes. Notably, NS1 specifically disrupted the ability of pericytes to support endothelial cell function in a three-dimensional (3D) microvascular assay, with no effect on pericyte viability or physiology. These effects are mediated at least in part through contact-independent paracrine signals involved in endothelial barrier maintenance by pericytes. We therefore identify a role for pericytes in amplifying NS1-induced microvascular hyperpermeability in severe dengue and thus show that pericytes can play a critical role in the etiology of an infectious vascular leakage syndrome. These findings open new avenues of research for the development of drugs and diagnostic assays for combating infection-induced vascular leakage, such as severe dengue. IMPORTANCE The World Health Organization considers dengue one of the top 10 global public health problems. There is no specific antiviral therapy to treat dengue virus and no way of predicting which patients will develop potentially fatal severe dengue, typified by vascular leakage and circulatory shock. We show here that perivascular cells (pericytes) amplify the vascular leakage-inducing effects of the dengue viral protein NS1 through contact-independent signaling to endothelial cells. While pericytes are known to contribute to noncommunicable vascular leakage, this is the first time these cells have been implicated in the vascular effects of an infectious disease. Our findings could pave the way for new therapies and diagnostics to combat dengue and potentially other infectious vascular leakage syndromes.

High plasma mid-regional pro-adrenomedullin levels in children with severe dengue virus infections

2011 ◽  
Vol 50 (1) ◽  
pp. 8-12 ◽  
Author(s):  
Meta Michels ◽  
Kis Djamiatun ◽  
Sultana M.H. Faradz ◽  
Mieke M.J.F. Koenders ◽  
Quirijn de Mast ◽  
...  
Keyword(s):  
Dengue Virus ◽  
High Plasma ◽  
Severe Dengue ◽  
Virus Infections

A T164S mutation in the dengue virus NS1 protein is associated with greater disease severity in mice

2019 ◽  
Vol 11 (498) ◽  
pp. eaat7726 ◽  
Author(s):  
Kitti Wing Ki Chan ◽  
Satoru Watanabe ◽  
Jocelyn Y. Jin ◽  
Julien Pompon ◽  
Don Teng ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Mutant Virus ◽  
Vascular Leakage ◽  
Wild Type Virus ◽  
Severe Dengue ◽  
Mosquito Vector ◽  
Type Virus ◽  
Wild Type ◽  
Dengue Disease ◽  
Nonstructural Protein 1

Dengue viruses cause severe and sudden human epidemics worldwide. The secreted form of the nonstructural protein 1 (sNS1) of dengue virus causes vascular leakage, a hallmark of severe dengue disease. Here, we reverse engineered the T164S mutation of NS1, associated with the severity of dengue epidemics in the Americas, into a dengue virus serotype 2 mildly infectious strain. The T164S mutant virus decreased infectious virus production and increased sNS1 production in mammalian cell lines and human peripheral blood mononuclear cells (PBMCs) without affecting viral RNA replication. Gene expression profiling of 268 inflammation-associated human genes revealed up-regulation of genes induced in response to vascular leakage. Infection of the mosquito vectorAedes aegyptiwith the T164S mutant virus resulted in increased viral load in the mosquito midgut and higher sNS1 production compared to wild-type virus infection. Infection of type 1 and 2 interferon receptor–deficient AG129 mice with the T164S mutant virus resulted in severe disease coupled with increased complement activation, tissue inflammation, and more rapid mortality compared to AG129 mice infected with wild-type virus. Molecular dynamics simulations predicted that mutant sNS1 formed stable dimers similar to the wild-type protein, whereas the hexameric mutant sNS1 was predicted to be unstable. Immunoaffinity-purified sNS1 from T164S mutant virus–infected mammalian cells was associated with different lipid classes compared to wild-type sNS1. Treatment of human PBMCs with sNS1 purified from T164S mutant virus resulted in a twofold higher production of proinflammatory cytokines, suggesting a mechanism for how mutant sNS1 may cause more severe dengue disease.

scholarly journals Adapting Rapid Diagnostic Tests to Detect Historical Dengue Virus Infections

2021 ◽  
Vol 12 ◽  
Author(s):  
Fernando Echegaray ◽  
Peter Laing ◽  
Samantha Hernandez ◽  
Sully Marquez ◽  
Amanda Harris ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Diagnostic Tests ◽  
High Specificity ◽  
Denv Infection ◽  
Cross Reactivity ◽  
Rapid Diagnostic Tests ◽  
World Health ◽  
Severe Dengue ◽  
Virus Infections ◽  
Health Organization

The only licensed dengue vaccine, Dengvaxia®, increases risk of severe dengue when given to individuals without prior dengue virus (DENV) infection but is protective against future disease in those with prior DENV immunity. The World Health Organization has recommended using rapid diagnostic tests (RDT) to determine history of prior DENV infection and suitability for vaccination. Dengue experts recommend that these assays be highly specific (≥98%) to avoid erroneously vaccinating individuals without prior DENV infection, as well as be sensitive enough (≥95%) to detect individuals with a single prior DENV infection. We evaluated one existing and two newly developed anti-flavivirus RDTs using samples collected >6 months post-infection from individuals in non-endemic and DENV and ZIKV endemic areas. We first evaluated the IgG component of the SD BIOLINE Dengue IgG/IgM RDT, which was developed to assist in confirming acute/recent DENV infections (n=93 samples). When evaluated following the manufacturer’s instructions, the SD BIOLINE Dengue RDT had 100% specificity for both non-endemic and endemic samples but low sensitivity for detecting DENV seropositivity (0% non-endemic, 41% endemic). Sensitivity increased (53% non-endemic, 98% endemic) when tests were allowed to run beyond manufacturer recommendations (0.5 up to 3 hours), but specificity decreased in endemic samples (36%). When tests were evaluated using a quantitative reader, optimal specificity could be achieved (≥98%) while still retaining sensitivity at earlier timepoints in non-endemic (44-88%) and endemic samples (31-55%). We next evaluated novel dengue and Zika RDTs developed by Excivion to detect prior DENV or ZIKV infections and reduce cross-flavivirus reactivity (n=207 samples). When evaluated visually, the Excivion Dengue RDT had sensitivity and specificity values of 79%, but when evaluated with a quantitative reader, optimal specificity could be achieved (≥98%) while still maintaining moderate sensitivity (48-75%). The Excivion Zika RDT had high specificity (>98%) and sensitivity (>93%) when evaluated quantitatively, suggesting it may be used alongside dengue RDTs to minimize misclassification due to cross-reactivity. Our findings demonstrate the potential of RDTs to be used for dengue pre-vaccination screening to reduce vaccine-induced priming for severe dengue and show how assay design adaptations as well quantitative evaluation can further improve RDTs for this purpose.

scholarly journals Differential Gene Expression Changes in Children with Severe Dengue Virus Infections

2008 ◽  
Vol 2 (4) ◽  
pp. e215 ◽  
Author(s):  
Martijn D. de Kruif ◽  
Tatty E. Setiati ◽  
Albertus T. A. Mairuhu ◽  
Penelopie Koraka ◽  
Hella A. Aberson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dengue Virus ◽  
Differential Gene Expression ◽  
Severe Dengue ◽  
Virus Infections ◽  
Differential Gene

scholarly journals A Critical Role for Perivascular Cells in Amplifying Viral Haemorrhage Induced by Dengue Virus Non-Structural Protein 1

2020 ◽  
Author(s):  
Yin P. Cheung ◽  
Valeria Mastrullo ◽  
Davide Maselli ◽  
Teemapron Butsabong ◽  
Paolo Madeddu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Dengue Virus ◽  
Critical Role ◽  
Vascular Leakage ◽  
World Health ◽  
Severe Dengue ◽  
Structural Protein ◽  
Perivascular Cells ◽  
Endothelial Cell Function

ABSTRACTDengue is the most prevalent arthropod-borne viral disease affecting humans, with severe dengue typified by potentially fatal microvascular leakage and hypovolaemic shock. Blood vessels of the microvasculature are composed of a tubular structure of endothelial cells ensheathed by perivascular cells (pericytes). Pericytes support endothelial cell barrier formation and maintenance through paracrine and contact-mediated signalling, and are critical to microvascular integrity. Pericyte dysfunction has been linked to vascular leakage in noncommunicable pathologies such as diabetic retinopathy, but has never been linked to infection-related vascular leakage. Dengue vascular leakage has been shown to result in part from the direct action of the secreted dengue virus (DENV) non-structural protein NS1 on endothelial cells. Using primary human vascular cells, we show here that NS1 also causes pericyte dysfunction, and that NS1-induced endothelial hyperpermeability is more pronounced in the presence of pericytes. Notably, NS1 specifically disrupted the ability of pericytes to support endothelial cell function in a 3D microvascular assay, with no effect on pericyte viability or physiology. These effects are mediated at least in part through contact-independent paracrine signals involved in endothelial barrier maintenance by pericytes. We therefore identify a role for pericytes in amplifying NS1-induced microvascular hyperpermeability in severe dengue, and thus show that pericytes can play a critical role in the aetiology of an infectious vascular leakage syndrome. These findings open new avenues of research for the development of drugs and diagnostic assays for combating infection-induced vascular leakage, such as severe dengue.SIGNIFICANCE STATEMENTThe World Health Organisation considers dengue one of the top ten global public health problems. There is no specific antiviral therapy to treat dengue virus and no way of predicting which patients will develop potentially fatal severe dengue, typified by vascular leakage and circulatory shock. We show here that perivascular cells (pericytes) amplify the vascular leakage-inducing effects of the dengue viral protein NS1 through contact-independent signalling to endothelial cells. While pericytes are known to contribute to noncommunicable vascular leakage, this is the first time these cells have been implicated in the vascular effects of an infectious disease. Our findings could pave the way for new therapies and diagnostics to combat dengue, and potentially other infectious vascular leakage syndromes.

scholarly journals Co-circulation and co-infections of all dengue virus serotypes in Hyderabad, India 2014

2017 ◽  
Vol 145 (12) ◽  
pp. 2563-2574 ◽  
Author(s):  
K. VADDADI ◽  
C. GANDIKOTA ◽  
P. K. JAIN ◽  
V. S. V. PRASAD ◽  
M. VENKATARAMANA
Keyword(s):  
Dengue Virus ◽  
Severe Dengue ◽  
Nucleotide Sequencing ◽  
Virus Infections ◽  
Disease Epidemiology ◽  
Igm Elisa ◽  
Dengue Virus Serotypes ◽  
First Time ◽  
Close Relatedness

SUMMARYThe burden of dengue virus infections increased globally during recent years. Though India is considered as dengue hyper-endemic country, limited data are available on disease epidemiology. The present study includes molecular characterization of dengue virus strains occurred in Hyderabad, India, during the year 2014. A total of 120 febrile cases were recruited for this study, which includes only children and 41 were serologically confirmed for dengue positive infections using non-structural (NS1) and/or IgG/IgM ELISA tests. RT-PCR, nucleotide sequencing and evolutionary analyses were carried out to identify the circulating serotypes/genotypes. The data indicated a high percent of severe dengue (63%) in primary infections. Simultaneous circulation of all four serotypes and co-infections were observed for the first time in Hyderabad, India. In total, 15 patients were co-infected with more than one dengue serotype and 12 (80%) of them had severe dengue. One of the striking findings of the present study is the identification of serotype Den-1 as the first report from this region and this strain showed close relatedness to the Thailand 1980 strains but not to any of the strains reported from India until now. Phylogenetically, all four strains of the present study showed close relatedness to the strains, which are reported to be high virulent.

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