Protection against Dengue Virus Infection in Mice by Administration of Antibodies against Modified Nonstructural Protein 1

Wan, Shu; Lu, Yi; Huang, Chia Hui; Lin, Chiou Feng; Anderson, Robert; Liu, Hsiao Sheng; Yeh, Trai Ming; Yen, Yu Ting; Wu-Hsieh, Betty A.; Lin, Yee Shin

doi:10.1371/journal.pone.0092495

Cited by 63 publications

(79 citation statements)

References 56 publications

(70 reference statements)

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“…Abs against C-terminal residues of NS1 have been shown to cross-react with platelets and endothelial cells during dengue infection. Deletion of the C-terminal region 271-352 of NS1 abolished anti-NS1-mediated platelet dysfunction, endothelial damage, and bleeding tendency (37,38). Our results further demonstrated that Abs against C-terminal NS1 may also cause abnormal Plg activation.…”

Section: Discussionsupporting

confidence: 67%

Dengue Virus Nonstructural Protein 1–Induced Antibodies Cross-React with Human Plasminogen and Enhance Its Activation

Chuang

Lin

et al. 2016

The Journal of Immunology

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Dengue virus (DENV) infection is the most common mosquito-borne viral disease, and it can cause life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Abnormal activation of the coagulation and fibrinolysis system is one of the hallmarks of DHF/DSS. However, the mechanism underlying hemorrhage in DHF/DSS remains elusive. In previous studies, plasminogen (Plg) cross-reactive Abs, which can recognize DENV nonstructural protein (NS) 1, have been found in dengue patients. However, it is unclear whether these Abs are indeed induced by DENV NS1. Thus, we immunized mice with recombinant NS1 from both bacteria and drosophila to determine whether NS1 can induce Plg cross-reactive Abs. The results from the NS1-immunized mouse sera indicated that NS1 immunization induced Abs that could cross-react with Plg. To study the effects of these NS1-induced Plg cross-reactive Abs on fibrinolysis, we isolated several Plg cross-reactive anti-NS1 mAbs from these mice and found that some of them could enhance Plg activation. In addition, epitope mapping with a phage-displayed random peptide library revealed that one of these mAbs (2A5) could recognize NS1 C-terminal residues 305–311, which share sequence homology with Plg residues 590–597. A synthetic peptide of NS1 residues 305–311 could inhibit the binding of both 2A5 and its Fab to Plg and its enhanced activation. Thus, our results suggest that DENV NS1 can induce Plg cross-reactive Abs through molecular mimicry, which can enhance Plg activation and may contribute to the pathogenesis of DHF/DSS.

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Section: Discussionsupporting

confidence: 67%

Dengue Virus Nonstructural Protein 1–Induced Antibodies Cross-React with Human Plasminogen and Enhance Its Activation

Chuang

Lin

et al. 2016

The Journal of Immunology

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“…29 As increased bleeding time is an important indicator of DENV pathogenesis, we inoculated WT and Kit W-sh/W-sh mice with 1 9 10 9 PFU/mouse of DENV and determined the bleeding time on 2 and 3 days p.i. The results showed that DENV infection caused prolonged bleeding time, both in WT and Kit W-sh/W-sh mice.…”

Section: Bleeding Times Of Denv-infected Wt and Kitmentioning

confidence: 99%

Mast cell–macrophage dynamics in modulation of dengue virus infection in skin

et al. 2015

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SummaryDengue virus (DENV) infection causes dengue fever, dengue haemorrhagic fever, or dengue shock syndrome. Mast cells have been speculated to play a role in DENV disease although their precise roles are unclear. In this study, we used mast cell-deficient Kit W-sh/W-sh mice to investigate the involvement of mast cells after intradermal DENV infection. An approximately two-to three-fold higher level of DENV NS3 antigen was detected at the skin inoculation site in DENV-infected Kit W-sh/W-sh mice than in DENV-infected wild-type (WT) mice (using a dose of 1 3 10 9 plaqueforming units/mouse). Moreover, as an indicator of heightened pathogenesis, a more prolonged bleeding time was observed in DENV-infected Kit W-sh/W-sh mice than in WT mice. Monocytes/macrophages are considered to be important targets for DENV infection, so we investigated the susceptibility and chemokine response of DENV-infected peritoneal macrophages from Kit W-sh/W-sh and WT mice both ex vivo and in vivo. There was a tendency for higher DENV infection and higher secretion of CCL2 (MCP-1) from peritoneal macrophages isolated from Kit W-sh/W-sh mice than those from WT mice. In vivo studies using intradermal inoculation of DENV showed about twofold higher levels of infiltrating macrophages and CCL2 (MCP-1) at the inoculation site in both mock control and DENV-inoculated Kit W-sh/W-sh mice than in corresponding WT mice. In summary, compared with WT mice, Kit W-sh/W-sh mice show enhanced DENV infection and macrophage infiltration at the skin inoculation site as well as increased DENV-associated bleeding time. The results indicate an intriguing interplay between mast cells and tissue macrophages to restrict DENV replication in the skin.

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“…Now we could say that it is quite possible that development of PAIgM is contributing to the increasing vascular permeability. Krishnamurti et al demonstrated the platelets binding to the endothelial cells that were infected with dengue-virus [27,28] . As vascular permeability increases with DHF, so for this mechanism active platelets that are associated with denguevirus, anti-dengue virus IgM and endothelial cells that are infected with dengue-virus may be important [9,17,29] .…”

Section: Discussionmentioning

confidence: 99%

PAIgG and PAIgM levels in secondary dengue virus infections lead to thrombocytopenia in patients from KP, Pakistan

Alam

Hassan

Alam

et al. 2015

Asian Pacific Journal of Tropical Biomedicine

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Keywords:PAIgG PAIgM Secondary dengue virus Thrombocytopenia Dengue hemorrhagic fever A B S T R A C TObjective: To understand the impact of platelet associated immunoglobulin G (PAIgG)/ platelet associated immunoglobulin M (PAIgM) on severity of dengue virus infection leading to thrombocytopenia. Methods: In this study we examined a total of 52 patients who were having secondary infection of dengue in acute phase by using competitive ELISA. Results: A decrease in the platelet count was observed at the acute phase of infection while all along the recovery stage the count of platelet was significantly increased. A significant decrease was observed in PAIgG and PAIgM in these subjects. Inverse correlation was found between platelets count and PAIgG/PAIgM among the subjects studied. In the platelets elution from ten subjects, anti-dengue virus immunoglobulin G and immunoglobulin M were observed. PAIgG and PAIgM with inclined levels were higher in dengue hemorrhagic fever than the classical dengue fever. In the development of dengue hemorrhagic fever PAIgM inclined level was independently associated with high specificity, showing a possible indication of dengue hemorrhagic fever. Conclusions: This study suggests that in secondary dengue virus infection, the PAIgG and PAIgM levels, and the activity of anti-dengue virus play key roles, both in the development and severity of the disease.

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Protection against Dengue Virus Infection in Mice by Administration of Antibodies against Modified Nonstructural Protein 1

Cited by 63 publications

References 56 publications

Dengue Virus Nonstructural Protein 1–Induced Antibodies Cross-React with Human Plasminogen and Enhance Its Activation

Dengue Virus Nonstructural Protein 1–Induced Antibodies Cross-React with Human Plasminogen and Enhance Its Activation

Mast cell–macrophage dynamics in modulation of dengue virus infection in skin

PAIgG and PAIgM levels in secondary dengue virus infections lead to thrombocytopenia in patients from KP, Pakistan

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