Regulation of T lymphocyte apoptotic markers is associated to cell activation during the acute phase of dengue

Torrentes-Carvalho, Amanda; Marinho, Cíntia Ferreira; Oliveira-Pinto, Luzia Maria de; Oliveira, Débora Batista de; Damasco, Paulo Vieira; Cunha, Rivaldo Venâncio da; Souza, Luíz José de; Azeredo, Elzinandes Leal de; Kubelka, Claire Fernandes

doi:10.1016/j.imbio.2013.11.002

Cited by 14 publications

(15 citation statements)

References 60 publications

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“…On the other hand, the steroid hormone biosynthesis and heme degradation pathways were perturbed in dengue patients, but not in humice with DENV infection. DENV infects a multitude of cells and organs in humans (19, 20), and although significant levels of human monocytes/macrophages and hepatocytes are present in humice, many types of cells are still lacking. Thus, although many metabolic pathways were commonly perturbed in infected humice and dengue patients, some altered pathways in dengue patients could not be found in humice.…”

Section: Discussionmentioning

confidence: 99%

Serum Metabolomics Investigation of Humanized Mouse Model of Dengue Virus Infection

Liang

Hou

Fang

et al. 2017

J Virol

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Dengue is an acute febrile illness caused by dengue virus (DENV) and a major cause of morbidity and mortality in tropical and subtropical regions of the world. The lack of an appropriate small-animal model of dengue infection has greatly hindered the study of dengue pathogenesis and the development of therapeutics. In this study, we conducted mass spectrometry-based serum metabolic profiling from a model using humanized mice (humice) with DENV serotype 2 infection at 0, 3, 7, 14, and 28 days postinfection (dpi). Forty-eight differential metabolites were identified, including fatty acids, purines and pyrimidines, acylcarnitines, acylglycines, phospholipids, sphingolipids, amino acids and derivatives, free fatty acids, and bile acid. These metabolites showed a reversible-change trend—most were significantly perturbed at 3 or 7 dpi and returned to control levels at 14 or 28 dpi, indicating that the metabolites might serve as prognostic markers of the disease in humice. The major perturbed metabolic pathways included purine and pyrimidine metabolism, fatty acid β-oxidation, phospholipid catabolism, arachidonic acid and linoleic acid metabolism, sphingolipid metabolism, tryptophan metabolism, phenylalanine metabolism, lysine biosynthesis and degradation, and bile acid biosynthesis. Most of these disturbed pathways are similar to our previous metabolomics findings in a longitudinal cohort of adult human dengue patients across different infection stages. Our analyses revealed the commonalities of host responses to DENV infection between humice and humans and suggested that humice could be a useful small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics.IMPORTANCE Dengue virus is the most widespread arbovirus, causing an estimated 390 million dengue infections worldwide every year. There is currently no effective treatment for the disease, and the lack of an appropriate small-animal model of dengue infection has greatly increased the challenges in the study of dengue pathogenesis and the development of therapeutics. Metabolomics provides global views of small-molecule metabolites and is a useful tool for finding metabolic pathways related to disease processes. Here, we conducted a serum metabolomics study on a model using humanized mice with dengue infection that had significant levels of human platelets, monocytes/macrophages, and hepatocytes. Forty-eight differential metabolites were identified, and the underlying perturbed metabolic pathways are quite similar to the pathways found to be altered in dengue patients in previous metabolomics studies, indicating that humanized mice could be a highly relevant small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics.

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Section: Discussionmentioning

confidence: 99%

Serum Metabolomics Investigation of Humanized Mouse Model of Dengue Virus Infection

Liang

Hou

Fang

et al. 2017

J Virol

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“…The frequency of CD8 T-cells co-expressing both CD38 and HLA-DR was similar in ZIKV and in DENV patients 15 , but was lower than during EBOV infection 16, 18 , suggesting that a moderate activation may be associated to a protective activity and to a mild profile of the disease. In acute infection such as of DENV 19 or Ebola virus 16–18 , the activation of T-cells is associated to an increased expression of apoptotic markers. The role of apoptosis during ZIKV infection remains to be defined.…”

Section: Discussionmentioning

confidence: 99%

Human Zika infection induces a reduction of IFN-γ producing CD4 T-cells and a parallel expansion of effector Vδ2 T-cells

Cimini

Castilletti

Sacchi

et al. 2017

Sci Rep

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The definition of the immunological response to Zika (ZIKV) infection in humans represents a key issue to identify protective profile useful for vaccine development and for pathogenesis studies. No data are available on the cellular immune response in the acute phase of human ZIKV infection, and its role in the protection and/or pathogenesis needs to be clarified. We studied and compared the phenotype and functionality of T-cells in patients with acute ZIKV and Dengue viral (DENV) infections. A significant activation of T-cells was observed during both ZIKV and DENV infections. ZIKV infection was characterized by a CD4 T cell differentiation toward effector cells and by a lower frequency of IFN-γ producing CD4 T cells. Moreover, a substantial expansion of CD3+CD4−CD8− T-cell subset expressing Vδ2 TCR was specifically observed in ZIKV patients. Vδ2 T cells presented a terminally differentiated profile, expressed granzyme B and maintained their ability to produce IFN-γ. These findings provide new knowledge on the immune response profile during self-limited infection that may help in vaccine efficacy definition, and in identifying possible immuno-pathogenetic mechanisms of severe infection.

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“…In the dengue group, frequencies of dead cells were comparable in children with or without antigenemia (positive detection of plasma NS1) (data not shown), suggesting that other mechanisms in addition to the cell viral infection are responsible for the higher death levels found in dengue PBMCs. Activation-induced apoptosis (activation-induced cell death [AICD]) would be a critical mechanism for PBMC death, as high expression levels of members of the TNF receptor superfamily classically associated with cell death, such as CD95 (FAS) and sTRAIL, in PBMCs and the plasma of patients with the infection have been shown (33)(34)(35)(36). This mechanism modulates immune cell activation against the virus, ensuring homeostasis (37).…”

Section: Discussionmentioning

confidence: 99%

Viability and Functionality of Cryopreserved Peripheral Blood Mononuclear Cells in Pediatric Dengue

Perdomo‐Celis

Salgado

Castañeda

et al. 2016

Clin Vaccine Immunol

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bCryopreserved peripheral blood mononuclear cells (PBMCs) are widely used in studies of dengue. In this disease, elevated frequency of apoptotic PBMCs has been described, and molecules such as soluble tumor necrosis factor (TNF)-related apoptosisinducing ligands (sTRAIL) are involved. This effect of dengue may affect the efficiency of PBMC cryopreservation. Here, we evaluate the viability (trypan blue dye exclusion and amine-reactive dye staining) and functionality (frequency of gamma interferon [IFN-␥]-producing T cells after polyclonal stimulation) of fresh and cryopreserved PBMCs from children with dengue (in acute and convalescence phases), children with other febrile illnesses, and healthy children as controls. Plasma sTRAIL levels were also evaluated. The frequencies of nonviable PBMCs detected by the two viability assays were positively correlated (r ‫؍‬ 0.74; P < 0.0001). Cryopreservation particularly affected the PBMCs of children with dengue, who had a higher frequency of nonviable cells than healthy children and children with other febrile illnesses (P < 0.02), and PBMC viability levels were restored in the convalescent phase. In the acute phase, an increased frequency of CD3 ؉ CD8 ؉ amine-positive cells was found before cryopreservation (P ‫؍‬ 0.01). Except for B cells in the acute phase, cryopreservation usually did not affect the relative frequencies of viable PBMC subpopulations. Dengue infection reduced the frequency of IFN-␥-producing CD3؉ cells after stimulation compared with healthy controls and convalescent-phase patients (P < 0.003), and plasma sTRAIL correlated with this decreased frequency in dengue (rho ‫؍‬ ؊0.56; P ‫؍‬ 0.01). Natural dengue infection in children can affect the viability and functionality of cryopreserved PBMCs. Cryopreservation is the maintenance of cells and biological tissues at low temperatures and is based on the use of various media or solutions that form hydrogen bonds with water molecules, preventing cellular damage. The low temperatures allow the cells to enter a quiescent state in which cellular functions are suspended without affecting their intrinsic characteristics (1). Peripheral blood mononuclear cells (PBMCs) are frequently cryopreserved for use in transplants or immunological studies (2, 3). However, the cryopreservation process may affect viability, phenotype, and cellular functionality due to factors such as inadequate temperatures, the freezing protocol used, the expertise of the personnel, and freezing time (4, 5). The disease of the individual from whom the PBMCs come also affects cryopreservation. For example, PBMCs from subjects infected with human immunodeficiency virus (HIV) presented reduced viability after cryopreservation, possibly due to the increased numbers of apoptotic cells circulating during the course of the disease (6). Similar findings have been found in the acute phases of diseases, such as visceral leishmaniasis (7). Particularly for HIV, great efforts have been undertaken to optimize the evaluation and comparability of immune tests...

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Regulation of T lymphocyte apoptotic markers is associated to cell activation during the acute phase of dengue

Cited by 14 publications

References 60 publications

Serum Metabolomics Investigation of Humanized Mouse Model of Dengue Virus Infection

Serum Metabolomics Investigation of Humanized Mouse Model of Dengue Virus Infection

Human Zika infection induces a reduction of IFN-γ producing CD4 T-cells and a parallel expansion of effector Vδ2 T-cells

Viability and Functionality of Cryopreserved Peripheral Blood Mononuclear Cells in Pediatric Dengue

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