Human T Cell Response to Dengue Virus Infection.
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ABSTRACT:
SUBMITTER: Tian Y
PROVIDER: S-EPMC6737489 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
Human T Cell Response to Dengue Virus Infection.
Tian Yuan Y Grifoni Alba A Sette Alessandro A Weiskopf Daniela D
Frontiers in immunology 20190904
DENV is a major public health problem worldwide, thus underlining the overall significance of the proposed Program. The four dengue virus (DENV) serotypes (1-4) cause the most common mosquito-borne viral disease of humans, with 3 billion people at risk for infection and up to 100 million cases each year, most often affecting children. The protective role of T cells during viral infection is well-established. Generally, CD8 T cells can control viral infection through several mechanisms, including ...[more]
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Project description:BackgroundDengue viral infection is a global health threat without vaccine or specific treatment. The clinical outcome varies from asymptomatic, mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF). While adaptive immune responses were found to be detrimental in the dengue pathogenesis, the roles of earlier innate events remain largely uninvestigated. Invariant natural killer T (iNKT) cells represent innate-like T cells that could dictate subsequent adaptive response but their role in human dengue virus infection is not known. We hypothesized that iNKT cells play a role in human dengue infection.MethodsBlood samples from a well-characterized cohort of children with DF, DHF, in comparison to non-dengue febrile illness (OFI) and healthy controls at various time points were studied. iNKT cells activation were analyzed by the expression of CD69 by flow cytometry. Their cytokine production was then analyzed after α-GalCer stimulation. Further, the CD1d expression on monocytes, and CD69 expression on conventional T cells were measured.ResultsiNKT cells were activated during acute dengue infection. The level of iNKT cell activation associates with the disease severity. Furthermore, these iNKT cells had altered functional response to subsequent ex vivo stimulation with α-GalCer. Moreover, during acute dengue infection, monocytic CD1d expression was also upregulated and conventional T cells also became activated.ConclusioniNKT cells might play an early and critical role in the pathogenesis of severe dengue viral infection in human. Targeting iNKT cells and CD1d serve as a potential therapeutic strategy for severe dengue infection in the future.
| S-EPMC4063705 | biostudies-literature
Project description:Dengue virus (DENV) is the most prevalent mosquito-borne virus in the world and a major cause of morbidity in the tropics and subtropics. Upregulation of HLA class I molecules has long been considered a feature of DENV infection, yet this has not been evaluated in the setting of natural infection. Natural killer (NK) cells, an innate immune cell subset critical for mounting an early response to viral infection, are inhibited by self HLA class I, suggesting that upregulation of HLA class I during DENV infection could dampen the NK cell response. Here we addressed whether upregulation of HLA class I molecules occurs during in vivo DENV infection and, if so, whether this suppresses the NK cell response. We found that HLA class I expression was indeed upregulated during acute DENV infection across multiple cell lineages in vivo. To better understand the role of HLA class I upregulation, we infected primary human monocytes, a major target of DENV infection, in vitro. Upregulation of total HLA class I is dependent on active viral replication and is mediated in part by cytokines and other soluble factors induced by infection, while upregulation of HLA-E occurs in the presence of replication-incompetent virus. Importantly, blocking DENV-infected monocytes with a pan-HLA class I Fab nearly doubles the frequency of degranulating NK cells, while blocking HLA-E does not significantly improve the NK cell response. These findings demonstrate that upregulation of HLA class I during DENV infection suppresses the NK cell response, potentially contributing to disease pathogenesis.
| S-EPMC6663972 | biostudies-literature
Project description:IntroductionZika virus (ZIKV) and dengue virus (DENV) co-circulated during latest outbreaks in Brazil, hence, it is important to evaluate the host cross-reactive immune responses to these viruses. So far, little is known about human T cell responses to ZIKV and no reports detail adaptive immune responses during DENV/ZIKV coinfection.MethodsHere, we studied T cells responses in well-characterized groups of DENV, ZIKV, or DENV/ZIKV infected patients and DENV-exposed healthy donors. We evaluated chemokine receptors expression and single/multifunctional frequencies of IFN?, TNF, and IL2-producing T cells during these infections. Even without antigenic stimulation, it was possible to detect chemokine receptors and IFN?, TNF, and IL2-producing T cells from all individuals by flow cytometry. Additionally, PBMCs' IFN? response to DENV NS1 protein and to polyclonal stimuli was evaluated by ELISPOT.ResultsDENV and ZIKV infections and DENV/ZIKV coinfections similarly induced expression of CCR5, CX3CR1, and CXCR3 on CD4 and CD8 T cells. DENV/ZIKV coinfection decreased the ability of CD4+ T cells to produce IFN?+ , TNF+ , TNF?+? IFN?+ , and TNF?+ ?IL2+ , compared to DENV and ZIKV infections. A higher magnitude of IFN? response to DENV NS1 was found in donors with a history of dengue infection, however, a hyporesponsiveness was found in acute DENV, ZIKV, or DENV/ZIKV infected patients, even previously infected with DENV.ConclusionTherefore, we emphasize the potential impact of coinfection on the immune response from human hosts, mainly in areas where DENV and ZIKV cocirculate.
| S-EPMC5946158 | biostudies-literature
Project description:Half of the world's population is exposed to the risk of dengue virus infection. Although a vaccine for dengue virus is now available in a few countries, its reported overall efficacy of about 60% is not ideal. Protective immune correlates following natural dengue virus infection remain undefined, which makes it difficult to predict the efficacy of new vaccines. In this study, we address the protective capacity of dengue virus-specific antibodies that are produced by plasmablasts a few days after natural secondary infection. Among a panel of 18 dengue virus-reactive human monoclonal antibodies, four groups of antibodies were identified based on their binding properties. While antibodies targeting the fusion loop of the glycoprotein of dengue virus dominated the antibody response, two smaller groups of antibodies bound to previously undescribed epitopes in domain II of the E protein. The latter, largely serotype-cross-reactive antibodies, demonstrated increased stability of binding at pH 5. These antibodies possessed weak to moderate neutralization capacity in vitro but were the most efficacious in promoting the survival of infected mice. Our data suggest that the cross-reactive anamnestic antibody response has a protective capacity despite moderate neutralization in vitro and a moderate decrease of viremia in vivo IMPORTANCE: Antibodies can protect from symptomatic dengue virus infection. However, it is not easy to assess which classes of antibodies provide protection because in vitro assays are not always predictive of in vivo protection. During a repeat infection, dengue virus-specific immune memory cells are reactivated and large amounts of antibodies are produced. By studying antibodies cloned from patients with heterologous secondary infection, we tested the protective value of the serotype-cross-reactive "recall" or "anamnestic" response. We found that results from in vitro neutralization assays did not always correlate with the ability of the antibodies to reduce viremia in a mouse model. In addition, a decrease of viremia in mice did not necessarily improve survival. The most protective antibodies were stable at pH 5, suggesting that antibody binding in the endosomes, after the antibody-virus complex is internalized, might be important to block virus spread in the organism.
| S-EPMC5126370 | biostudies-literature
Project description:Human blood monocytes play a central role in dengue infections and form the majority of virus infected cells in the blood. Human blood monocytes are heterogeneous and divided into CD16(-) and CD16(+) subsets. Monocyte subsets play distinct roles during disease, but it is not currently known if monocyte subsets differentially contribute to dengue protection and pathogenesis. Here, we compared the susceptibility and response of the human CD16(-) and CD16(+) blood monocyte subsets to primary dengue virus in vitro. We found that both monocyte subsets were equally susceptible to dengue virus (DENV2 NGC), and capable of supporting the initial production of new infective virus particles. Both monocyte subsets produced anti-viral factors, including IFN-α, CXCL10 and TRAIL. However, CD16(+) monocytes were the major producers of inflammatory cytokines and chemokines in response to dengue virus, including IL-1β, TNF-α, IL-6, CCL2, 3 and 4. The susceptibility of both monocyte subsets to infection was increased after IL-4 treatment, but this increase was more profound for the CD16(+) monocyte subset, particularly at early time points after virus exposure. These findings reveal the differential role that monocyte subsets might play during dengue disease.
| S-EPMC3344872 | biostudies-literature
Project description:Activated microglial cells are present in dengue virus (DENV)-infected brains; however, the possible effects of DENV on microglia remain unclear. Here, we demonstrated DENV caused infection, including viral entry, RNA replication, viral protein expression, and virus release, in the murine microglial cell line BV2. DENV infection caused an increase in the formation of the multipolar phenotype in vitro and in vivo without affecting cell growth and cytotoxicity. DENV infection considerably increased cell motility and disrupting either actin filaments or clathrin retarded such effect. Increase in cell migration was only occurred by DENV infection following a clathrin-regulated endocytosis of DENV entry. Ultraviolet-inactivated DENV did not affect cell migration, and pharmacologically blocking toll-like receptor (TLR) 3 and TLR3-related signaling pathways reduced the DENV-induced increase in cell migration. These results demonstrate an advanced effect of DENV infection on microglial migration via a mechanism involving viral entry, RNA release, and TLR3 signal activation.
| S-EPMC5427823 | biostudies-literature
Project description:The four serotypes of dengue virus (DENV) cause dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Severe disease has been associated with heterotypic secondary DENV infection, mediated by cross-reactive antibodies (Abs) and/or cross-reactive T cells. The role of cross-reactive immunity in mediating enhanced disease versus cross-protection against secondary heterotypic DENV infection is not well defined. A better understanding of the cross-reactive immune response in natural infections is critical for development of safe and effective tetravalent vaccines. We studied the B cell phenotype of circulating B cells in the blood of pediatric patients suspected of dengue during the 2010-2011 dengue season in Managua, Nicaragua (n = 216), which was dominated by the DENV-3 serotype. We found a markedly larger percentage of plasmablast/plasma cells (PB/PCs) circulating in DENV-positive patients as compared to patients with Other Febrile Illnesses (OFIs). The percentage of DENV-specific PB/PCs against DENV-3 represented 10% of the circulating antibody-producing cells (ASCs) in secondary DENV-3 infections. Importantly, the cross-reactive DENV-specific B cell response was higher against a heterotypic serotype, with 46% of circulating PB/PCs specific to DENV-2 and 10% specific to DENV-3 during acute infection. We also observed a higher cross-reactive DENV-specific IgG serum avidity directed against DENV-2 as compared to DENV-3 during acute infection. The neutralization capacity of the serum was broadly cross-reactive against the four DENV serotypes both during the acute phase and at 3 months post-onset of symptoms. Overall, the cross-reactive B cell immune response dominates during secondary DENV infections in humans. These results reflect our recent findings in a mouse model of DENV cross-protection. In addition, this study enabled the development of increased technical and research capacity of Nicaraguan scientists and the implementation of several new immunological assays in the field.
| S-EPMC3308930 | biostudies-literature
Project description:Dengue virus (DENV) infection is a worldwide public health threat. To date, the knowledge about the pathogenesis and progression of DENV infection is still limited. Combining global profiling based on proteomic analysis together with functional verification analysis is a powerful strategy to investigate the interplay between the virus and host cells. In the present study, quantitative proteomics has been applied to evaluate host responses (as indicated by altered proteins and modifications) in human cells (using K562 cell line) upon DENV-2 infection, as DENV-2 spreads most widely among all DENV serotypes. Comparative analysis was performed to define differentially expressed proteins in the infected cells compared to the mock-control, and it revealed critical pathogen-induced changes covering a broad spectrum of host cellular compartments and processes. We also discovered more dramatic changes (> 20%, 160 regulated phosphoproteins) in protein phosphorylation compared to protein expression (14%, 321 regulated proteins). Most of these proteins/phosphoproteins were involved in transcription regulation, RNA splicing and processing, immune system, cellular response to stimulus, and macromolecule biosynthesis. Western blot analysis was also performed to confirm the proteomic data. Potential roles of these altered proteins were discussed. The present study provides valuable large-scale protein-related information for elucidating the functional emphasis of host cell proteins and their post-translational modifications in virus infection, and also provides insight and protein evidence for understanding the general pathogenesis and pathology of DENV.
| S-EPMC6814695 | biostudies-literature
Project description:Retinopathy is a recently recognized complication of dengue, affecting up to 10% of hospitalized patients. Research on the pathogenesis has focused largely on effects of dengue virus (DENV) at the blood-retinal barrier. Involvement of retinal Müller glial cells has received little attention, although this cell population contributes to the pathology of other intraocular infections. The goal of our work was to establish the susceptibility of Müller cells to infection with DENV and to identify characteristics of the cellular antiviral, inflammatory, and immunomodulatory responses to DENV infection in vitro. Primary human Müller cell isolates and the MIO-M1 human Müller cell line were infected with the laboratory-adapted Mon601 strain and DENV serotype 1 and 2 field isolates, and cell-DENV interactions were investigated by immunolabelling and quantitative real-time polymerase chain reaction. Müller cells were susceptible to DENV infection, but experiments involving primary cell isolates indicated inter-individual variation. Viral infection induced an inflammatory response (including tumour necrosis factor-α, interleukin [IL]-1β, and IL-6) and an immunomodulatory response (including programmed death-ligand [PD-L]1 and PD-L2). The type I interferon response was muted in the Müller cell line compared to primary cell isolates. The highest infectivity and cell responses were observed in the laboratory-adapted strain, and overall, infectivity and cell responses were stronger in DENV2 strains. This work demonstrates that Müller cells mount an antiviral and immune response to DENV infection, and that this response varies across cell isolates and DENV strain. The research provides a direction for future efforts to understand the role of human retinal Müller glial cells in dengue retinopathy.
| S-EPMC10385653 | biostudies-literature
Project description:Ab-dependent enhancement (ADE) of dengue virus (DENV) infection is mediated through the interaction of viral immune complexes with FcγRs, with notable efficiency of FcγRII. Most human dengue target cells coexpress activating (FcγRIIa) and inhibitory (FcγRIIb) isoforms, but their relative roles in ADE are not well understood. We studied the effects of FcγRIIa and FcγRIIb by transfecting cells to express each individual receptor isoform or through coexpression of both isoforms. We showed that although both isoforms similarly bind dengue-immune complexes, FcγRIIa efficiently internalized virus leading to productive cellular infection, unlike FcγRIIb. We next focused on the main discriminating feature of these isoforms: their distinct intracytoplasmic tails (FcγRIIa with an immunoreceptor tyrosine-based activation motif [ITAM] and FcγRIIb with an immunoreceptor tyrosine-based inhibitory motif [ITIM]). We engineered cells to express "swapped" versions of their FcγRII by switching the cytoplasmic tails containing the ITAM/ITIM motifs, leaving the remainder of the receptor intact. Our data show that both FcγRIIa and FcγRIIb comparably bind dengue immune complexes. However, wild type FcγRIIa facilitates DENV entry by virtue of the ITAM motif, whereas the swapped version FcγRIIa-ITIM significantly inhibited ADE. Similarly, replacing the inhibitory motif in FcγRIIb with an ITAM (FcγRIIb-ITAM) reconstituted ADE capacity to levels of the wild type activating counterpart, FcγRIIa. Our data suggest that FcγRIIa and FcγRIIb isoforms, as the most abundantly distributed class II Fcγ receptors, differentially influence Ab-mediated DENV infection under ADE conditions both at the level of cellular infection and viral production.
| S-EPMC3659957 | biostudies-other