Increase of Plasminogen Activator Inhibitor-1 and Decrease of Transforming Growth Factor-B1 in Children with Dengue Haemorrhagic Fever in Indonesia

Djamiatun, Kis; Faradz, Sultana Mh; Setiati, Tatty E.; Netea, Mihai G.; Ven, A.J.A.M. van der; Dolmans, W.M.V.

doi:10.1093/tropej/fmq122

Cited by 17 publications

(12 citation statements)

References 30 publications

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“…Interestingly, none of them found a correlation between elevated levels of PAI-1 and disease severity. However, both elevated PAI-1 levels and disease severity did correlate with poor clinical outcome and platelet count (43)(44)(45). Additionally, it has been demonstrated that the EIII domain of the DENV2 E protein induces PAI-1 gene expression (46).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

Conde

Silva

Allonso

et al. 2016

J Virol

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Dengue virus (DENV) infects millions of people worldwide and is a major public health problem. DENV nonstructural protein 1 (NS1) is a conserved glycoprotein that associates with membranes and is also secreted into the plasma in DENV-infected patients. The present study describes a novel mechanism by which NS1 inhibits the terminal complement pathway. We first identified the terminal complement regulator vitronectin (VN) as a novel DENV2 NS1 binding partner by using a yeast two-hybrid system. This interaction was further assessed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) assay. The NS1-VN complex was also detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the DENV2 NS1 protein, either by itself or by interacting with VN, hinders the formation of the membrane attack complex (MAC) and C9 polymerization. Finally, we showed that DENV2, West Nile virus (WNV), and Zika virus (ZIKV) NS1 proteins produced in mammalian cells inhibited C9 polymerization. Taken together, our results points to a role for NS1 as a terminal pathway inhibitor of the complement system. IMPORTANCE Dengue is the most important arthropod-borne viral disease nowadays and is caused by dengue virus (DENV).The flavivirus NS1 glycoprotein has been characterized functionally as a complement evasion protein that can attenuate the activation of the classical, lectin, and alternative pathways. The present study describes a novel mechanism by which DENV NS1 inhibits the terminal complement pathway. We identified the terminal complement regulator vitronectin (VN) as a novel DENV NS1 binding partner, and the NS1-VN complex was detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the NS1-VN complex inhibited membrane attack complex (MAC) formation, thus interfering with the complement terminal pathway. Interestingly, NS1 itself also inhibited MAC activity, suggesting a direct role of this protein in the inhibition process. Our findings imply a role for NS1 as a terminal pathway inhibitor of the complement system. D engue constitutes a major public health problem in tropical and subtropical countries. According to current estimates, at least 390 million cases of dengue occur annually, of which approximately 100 million are symptomatic (1). The infection is caused by dengue virus (DENV), a member of the Flaviviridae family that cocirculates in nature as four distinct antigenic serotypes (DENV1 to -4). DENV infection in humans is generally asymptomatic, but symptomatic cases can vary from a mild and self-limited fever to a potentially fatal hemorrhagic syndrome (2). The DENV genome is composed of a single positive-sense RNA that encodes a single viral polyprotein that is further processed by viral and host proteases into three structural proteins (C, prM/M, and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (3).NS1 ...

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

Conde

Silva

Allonso

et al. 2016

J Virol

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“…PAI-1 values correlated well with platelet counts, plasma leakage, serum albumin on admission and the degree of pleural effusion. There was no correlation between mildly elevated liver function tests and PAI-1 levels [12].…”

Section: Plasminogen Activator Inhibitormentioning

confidence: 73%

“…The existing laboratory tests to monitor abnormal host response [10][11][12] are complex, costly and require sophisticated laboratory infrastructure and trained personnel. Researchers should standardize 1-2 step in vitro assays which can be carried out in non-academic, non-research health centres.…”

Section: Point-of-care Assays Of Abnormal Host Factors In Denv Infectmentioning

confidence: 99%

Pathogenesis of Dengue Thrombocytopenia: Prospective Challenges for Researchers

Agarwal¹

2013

J Immunol Tech Infect Dis

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“…Elevated PAI-1 concentration in children suffering from dengue hemorrhagic fever was also reported [3,31,32]. In addition, a recent study on Ebola virus infection showed that PAI-1 levels were elevated in pediatric patients, and were strongly elevated in patients who died and in those with hemorrhagic manifestations [33].…”

Section: Discussionmentioning

confidence: 86%

A microfluidic cell culture system for monitoring of sequential changes in endothelial cells after heat stress

Tazawa¹,

Sato²,

Tsutiya³

et al. 2015

Thrombosis Research

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Endothelial damage induced by a highly elevated body temperature is crucial in some diseases including viral hemorrhagic fevers. Here, we report the heat-induced sequential changes of endothelial cells under shear stress, which were determined with a microfluidic culture system. Although live cell imaging showed only minor changes in the appearance of heat-treated cells, Hsp70 mRNA expression analysis demonstrated that the endothelial cells in channels of the system responded well to heat treatment. F-actin staining also revealed clear changes in the bundles of actin filaments after heat treatment. Well-organized bundles of actin filaments in control cells disappeared in heat-treated cells cultured in the channel. Furthermore, the system enabled detection of sequential changes in plasminogen activator inhibitor-1 (PAI-1) secretion from endothelial cells. PAI-1 concentration in the effluent solution was significantly elevated for the first 15min after initiation of heat treatment, and then decreased subsequently. This study provides fundamental information on heat-induced endothelial changes under shear stress and introduces a potent tool for analyzing endothelial secretions.

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Increase of Plasminogen Activator Inhibitor-1 and Decrease of Transforming Growth Factor-B1 in Children with Dengue Haemorrhagic Fever in Indonesia

Cited by 17 publications

References 30 publications

Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

Pathogenesis of Dengue Thrombocytopenia: Prospective Challenges for Researchers

A microfluidic cell culture system for monitoring of sequential changes in endothelial cells after heat stress

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