Dengue virus–elicited tryptase induces endothelial permeability and shock

Rathore, Abhay P. S.; Mantri, Chinmay K.; Aman, Siti A B; Syenina, Ayesa; Ooi, Justin S. G.; Jagaraj, Cyril J.; Goh, Chi Ching; Tissera, Hasitha; Wilder‐Smith, Annelies; Ng, Lai Guan; Gubler, Duane J.; John, Ashley L. St.

doi:10.1172/jci128426

Cited by 70 publications

(87 citation statements)

References 80 publications

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“…Clinical studies will prove necessary in order to evaluate the safety and efficacy of these medications [65,73,85,86]. Preclinical in vitro and in vivo studies and clinical studies will emergently cultivate an appreciation of the influence of pharmacological agonists, inverse agonists, antagonists of β adrenergic receptor modulated signaling, and fenoterol derivative bitopics upon the biomolecular mechanistic underpinnings of β adrenergic receptor modulated signaling upon molecular behavior of glioma cells and dynamic patterns of glioma growth, invasion, angiogenesis, and metastasis, and effects on survival metrics [65,73,85,86,151] (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Nafamostat mesylate was shown to prevent 'S'-mediated membrane fusion according to a Renilla luciferase assay and prevent MERS-CoV infection in vitro in a preparation of Calu3 cells [149]. Nafamostat mesylate interferes with the proteolytic cleavage of Ebola virus envelope proteins necessary for virus-host cell fusion by reducing the proteolytic release of CatB from rat pancreas [150] and microvascular leakage in patients with Dengue hemorrhage fever and shock through tryptase inhibition, blocking vascular leakage in vivo [151].…”

Section: Drug Developmentmentioning

confidence: 99%

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RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

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Neoplastically transformed astrocytes express functionally active cell surface β adrenergic receptors (βARs). Treatment of glioma models in vitro and in vivo with β adrenergic agonists variably amplifies or attenuates cellular proliferation. In the majority of in vivo models, β adrenergic agonists generally reduce cellular proliferation. However, treatment with β adrenergic agonists consistently reduces tumor cell invasive potential, angiogenesis, and metastasis. β adrenergic agonists induced decreases of invasive potential are chiefly mediated through reductions in the expression of matrix metalloproteinases types 2 and 9. Treatment with β adrenergic agonists also clearly reduce tumoral neoangiogenesis, which may represent a putatively useful mechanism to adjuvantly amplify the effects of bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor. We may accordingly designate βagonists to represent an enhancer of bevacizumab. The antiangiogenic effects of β adrenergic agonists may thus effectively render an otherwise borderline effective therapy to generate significant enhancement in clinical outcomes. β adrenergic agonists upregulate expression of the major histocompatibility class II DR alpha gene, effectively potentiating the immunogenicity of tumor cells to tumor surveillance mechanisms. Authors have also demonstrated crossmodal modulation of signaling events downstream from the β adrenergic cell surface receptor and microtubular polymerization and depolymerization. Complex effects and desensitization mechanisms of the β adrenergic signaling may putatively represent promising therapeutic targets. Constant stimulation of the β adrenergic receptor induces its phosphorylation by β adrenergic receptor kinase (βARK), rendering it a suitable substrate for alternate binding by β arrestins 1 or 2. The binding of a β arrestin to βARK phosphorylated βAR promotes receptor mediated internalization and downregulation of cell surface receptor and contemporaneously generates a cell surface scaffold at the βAR. The scaffold mediated activation of extracellular regulated kinase 1/2, compared with protein kinase A mediated activation, preferentially favors cytosolic retention of ERK1/2 and blunting of nuclear translocation and ensuant pro-transcriptional activity. Thus, βAR desensitization and consequent scaffold assembly effectively retains the cytosolic homeostatic functions of ERK1/2 while inhibiting its pro-proliferative effects. We suggest these mechanisms specifically will prove quite promising in developing primary and adjuvant therapies mitigating glioma growth, angiogenesis, invasive potential, and angiogenesis. We suggest generating compounds and targeted mutations of the β adrenergic receptor favoring β arrestin binding and scaffold facilitated activation of ERK1/2 may hold potential promise and therapeutic benefit in adjuvantly treating most or all cancers. We hope our discussion will generate fruitful research endeavors seeking to exploit these mechanisms.

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Section: Resultsmentioning

confidence: 99%

Section: Drug Developmentmentioning

confidence: 99%

RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

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“…Although certain mediators such as PAF and VEGF can also be produced by other cells types such as macrophages, monocytes and endothelial cells (Walterscheid et al, 2002), chymases and tryptases are only produced by mast cells (Krystel-Whittemore et al, 2015). Both chymase and tryptase have been shown to be high in patients with acute dengue during early illness and shown to be an important predictor of progression to severe dengue, suggesting that mast cells indeed do have an important role in disease pathogenesis (Tissera et al, 2017;Rathore et al, 2019). Chymase levels were shown to be higher in those who progressed to develop DHF after day 3 of illness (Rathore et al, 2020).…”

Section: Mast Cells In Denguementioning

confidence: 99%

“…However, it is not yet clear whether the differences between those with primary and secondary dengue associate with increased mast cell activation. Serum tryptase has been shown to be higher in patients with DHF and this rise was especially seen during day early illness (Jeewandara et al, 2017;Rathore et al, 2019). Tryptase has been shown to induce vascular leak by acting on endothelial gap junctions and was shown to induce plasma leakage and shock in animal models, suggesting that it indeed is likely to have an important role in inducing vascular leak in dengue (Rathore et al, 2019).…”

Section: Mast Cells In Denguementioning

confidence: 99%

“…Serum tryptase has been shown to be higher in patients with DHF and this rise was especially seen during day early illness (Jeewandara et al, 2017;Rathore et al, 2019). Tryptase has been shown to induce vascular leak by acting on endothelial gap junctions and was shown to induce plasma leakage and shock in animal models, suggesting that it indeed is likely to have an important role in inducing vascular leak in dengue (Rathore et al, 2019). In acute dengue, no differences were observed in tryptase levels in those with primary and secondary dengue (Jeewandara et al, 2017), suggesting that the role of DENVspecific antibodies activating mast cells through their FcγRs should be further investigated.…”

Section: Mast Cells In Denguementioning

confidence: 99%

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Dysfunctional Innate Immune Responses and Severe Dengue

Malavige

Jeewandara

Ogg

2020

Front. Cell. Infect. Microbiol.

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Although infection with the dengue virus (DENV) causes severe dengue, it causes a mild self-limiting illness in the majority of individuals. There is emerging evidence that an aberrant immune response in the initial stages of infection lead to severe disease. Many inflammatory cytokines, chemokines, and lipid mediators are significantly higher in patients with severe dengue compared to those who develop mild infection, during febrile phase of illness. Monocytes, mast cells, and many other cells of the immune system, when infected with the DENV, especially in the presence of poorly neutralizing antibodies, leads to production of pro-inflammatory cytokines and inhibition of interferon signaling pathways. In addition, production of immunosuppressive cytokines such as IL-10 further leads to inhibition of cellular antiviral responses. This dysregulated and aberrant immune response leads to reduced clearance of the virus, and severe dengue by inducing a vascular leak and excessive inflammation due to high levels of inflammatory cytokines. Individuals with comorbid illnesses could be prone to more severe dengue due to low grade endotoxemia, gut microbial dysbiosis and an altered phenotype of innate immune cells. The immunosuppressive and inflammatory lipid mediators and altered phenotype of monocytes are likely to further act on T cells and B cells leading to an impaired adaptive immune response to the virus. Therefore, in order to identify therapeutic targets for treatment of dengue, it would be important to further characterize these mechanisms in order for early intervention. In this review, we discuss the differences in the innate immune responses in those who progress to develop severe dengue, compared to those with milder disease in order to understand the mechanisms that lead to severe dengue.

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A murine model of dengue virus infection in suckling C57BL/6 and BALB/c mice

Byrne

García

Brahamian

et al. 2020

Anim Models and Exp Med

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Dengue is a significant public health concern across tropical and subtropical regions worldwide, principally causing disease in children. Very young children are at increased risk of severe manifestations of dengue infection. The mechanism of dengue disease in this population is not fully understood. In this study, we present a murine model of dengue virus primary infection in suckling C57BL/6 and BALB/c mice in order to investigate disease pathogenesis. Three‐day‐old C57BL/6 mice intraperitoneally infected with DENV‐2 NGC were more susceptible to infection than BALB/c mice, showing increased liver enzymes, extended viremia, dissemination to organs and histological alterations in liver and small intestine. Furthermore, the immune response in DENV‐infected C57BL/6 mice exhibited a marked Th1 bias compared to BALB/c mice. These findings highlight the possibility of establishing an immunocompetent mouse model of DENV‐2 infection in suckling mice that reproduces certain signs of disease observed in humans and that could be used to further study age‐related mechanisms of dengue pathogenesis.

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Dengue virus–elicited tryptase induces endothelial permeability and shock

Cited by 70 publications

References 80 publications

Dysfunctional Innate Immune Responses and Severe Dengue

A murine model of dengue virus infection in suckling C57BL/6 and BALB/c mice

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