Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

Petitdemange, Caroline; Maucourant, Christopher; Tarantino, Nadine; Rey, Juliana; Vieillard, Vincent

doi:10.1002/eji.201948284

Cited by 7 publications

(9 citation statements)

References 57 publications

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“…With respect to their activity in response to infection with other flaviviruses, we and others have observed that NK cells become activated and rapidly expand following infection of the host with DENV (10,14,23). Moreover, DENV type 2 was found to inhibit glycogen synthase kinase 3 activity and subsequently induce MIC-A expression in monocyte-derived DC (Mo-DCs), resulting in a specific increase in IFN-g and TNF-a production in the absence of cytotoxicity, by autologous NK cells (15). It has previously been shown that ZIKV inhibits NK cell cytotoxicity by upregulating the expression of MHC class I molecules in response to IFN-b (24), whereas a protective role of NK cells against ZIKV infection was reported in mice (25).…”

Section: Nk Cell Responses In Zika Virus Infection Are Biased Towards...mentioning

confidence: 97%

“…Monocytes were positively purified using CD14 1 beads (Miltenyi Biotec) from fresh PBMC isolated from buffy coat samples of healthy donors (Etablissement Franc ¸ais du Sang), and cultured for 6 d in the presence of 50 ng/ ml IL-4 and 100 ng/ml GM-CSF (BioTechne). Successful differentiation of Mo-DCs was verified by the presence of CD1a (HI149), DC-SIGN (DCN46), CD40 (5C3) (all from BD Pharmingen), and HLA-DR (Immu-357; BioLegend) expression and the absence of CD14 (61D3; eBioscience) expression, as previously described (15).…”

Section: Cell Isolation and Generation Of Mo-dcsmentioning

confidence: 99%

“…Isotype-matched Igs served as negative controls. The expression of ligands for NK cell receptors on Mo-DCs was assessed using specific mAbs: cells were first incubated with 1 mg/ml of fusion proteins (NKp30-Ig or NKp46-Ig, 1849-NK, and 1850-NK, respectively), antiULBP1-2-3 (170818, 165903, and 166510, respectively), or antiMIC-A/-B (159207) mAbs from R&D Systems, for 2 h at 4 C. Cells were washed in PBS-BSA 0.5% and then stained using anti-human IgG1-PE at 1/50 dilution (Jackson ImmunoResearch) for Ig-fusion proteins, and antimouse hu-IgG2a-PE (Beckman Coulter) for antiULBP1-2-3 and antiMIC-A/-B mAb or directly stained with allophycocyaninantiHLA-A,B,C (G46-2.6) mAbs for 1h at 4 C, as previously described (15,32). Cells were acquired on a Gallios Ccytometer (Beckman Coulter).…”

Section: Flow Cytometry Analyzes Of Mo-dcsmentioning

confidence: 99%

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NK Cell Responses in Zika Virus Infection Are Biased towards Cytokine-Mediated Effector Functions

Maucourant

Queiroz

Corneau

et al. 2021

The Journal of Immunology

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Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged as a global concern because of its impact on human health. ZIKV infection during pregnancy can cause microcephaly and other severe brain defects in the developing fetus and there have been reports of the occurrence of Guillain-Barré syndrome in areas affected by ZIKV. NK cells are activated during acute viral infections and their activity contributes to a first line of defense because of their ability to rapidly recognize and kill virus-infected cells. To provide insight into NK cell function during ZIKV infection, we have profiled, using mass cytometry, the NK cell receptor-ligand repertoire in a cohort of acute ZIKV-infected female patients. Freshly isolated NK cells from these patients contained distinct, activated, and terminally differentiated, subsets expressing higher levels of CD57, NKG2C, and KIR3DL1 as compared with those from healthy donors. Moreover, KIR3DL1+ NK cells from these patients produced high levels of IFN-γ and TNF-α, in the absence of direct cytotoxicity, in response to in vitro stimulation with autologous, ZIKV-infected, monocyte-derived dendritic cells. In ZIKV-infected patients, overproduction of IFN-γ correlated with STAT-5 activation (r = 0.6643; p = 0.0085) and was mediated following the recognition of MHC class 1–related chain A and chain B molecules expressed by ZIKV-infected monocyte-derived dendritic cells, in synergy with IL-12 production by the latter cells. Together, these findings suggest that NK cells contribute to the generation of an efficacious adaptive anti-ZIKV immune response that could potentially affect the outcome of the disease and/or the development of persistent symptoms.

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Section: Nk Cell Responses In Zika Virus Infection Are Biased Towards...mentioning

confidence: 97%

Section: Cell Isolation and Generation Of Mo-dcsmentioning

confidence: 99%

Section: Flow Cytometry Analyzes Of Mo-dcsmentioning

confidence: 99%

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NK Cell Responses in Zika Virus Infection Are Biased towards Cytokine-Mediated Effector Functions

Maucourant

Queiroz

Corneau

et al. 2021

The Journal of Immunology

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“…In addition to CD8+ T cells, NK cells appear as a cell type of particular interest to harness for curative strategies. NK cells play an important role in the recognition and elimination of abnormal cells, including stressed or infected cells, and they have raised growing interest in the field of oncology [ 148 , 149 , 150 , 151 ] and infectious diseases [ 152 , 153 , 154 ]. NK cells clearly impact viremia levels [ 155 ].…”

Section: Evaluation Of Hiv Cure Strategies With the Help Of Nhp Modelsmentioning

confidence: 99%

Interests of the Non-Human Primate Models for HIV Cure Research

et al. 2021

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Non-human primate (NHP) models are important for vaccine development and also contribute to HIV cure research. Although none of the animal models are perfect, NHPs enable the exploration of important questions about tissue viral reservoirs and the development of intervention strategies. In this review, we describe recent advances in the use of these models for HIV cure research and highlight the progress that has been made as well as limitations using these models. The main NHP models used are (i) the macaque, in which simian immunodeficiency virus (SIVmac) infection displays similar replication profiles as to HIV in humans, and (ii) the macaque infected by a recombinant virus (SHIV) consisting of SIVmac expressing the HIV envelope gene serving for studies analyzing the impact of anti-HIV Env broadly neutralizing antibodies. Lessons for HIV cure that can be learned from studying the natural host of SIV are also presented here. An overview of the most promising and less well explored HIV cure strategies tested in NHP models will be given.

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“…(9) DENV-2 inhibits GSK-3 activity to induce expression of MHC Class-1-related chain (MIC) A and MIC-B, and IL-12 production in monocyte-derived dendritic cells (Mo-DCs). (10) Considering that PI3K/Akt kinase pathway is involved in the infection of epithelial cells, Huh-7 and Vero, by DENV-2 (11) and that GSK3β is downstream of this cascade, it is intriguing to evaluate the role of GSK3β in the infective process of DENV-2. Current reports on the participation of GSK3β activity in DENV-2 infection process has been contrasting.…”

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confidence: 99%

Glycogen synthase kinase 3ß participates in late stages of Dengue virus-2 infection

Cuartas-López

Gallego-Gómez

2020

Mem. Inst. Oswaldo Cruz

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BACKGROUND Viruses can modulate intracellular signalling pathways to complete their infectious cycle. Among these, the PI3K/Akt pathway allows prolonged survival of infected cells that favours viral replication. GSK3β, a protein kinase downstream of PI3K/Akt, gets inactivated upon activation of the PI3K/Akt pathway, and its association with viral infections has been recently established. In this study, the role of GSK3β during Dengue virus-2 (DENV-2) infection was investigated. METHODS GSK3β participation in the DENV-2 replication process was evaluated with pharmacological and genetic inhibition during early [0-12 h post-infection (hpi)], late (12-24 hpi), and 24 hpi in Huh7 and Vero cells. We assessed the viral and cellular processes by calculating the viral titre in the supernatants, In-Cell Western, western blotting and fluorescence microscopy. RESULTS Phosphorylation of GSK3β-Ser9 was observed at the early stages of infection; neither did treatment with small molecule inhibitors nor pre-treatment prior to viral infection of GSK3β reduce viral titres of the supernatant at these time points. However, a decrease in viral titres was observed in cells infected and treated with the inhibitors much later during viral infection. Consistently, the infected cells at this stage displayed plasma membrane damage. Nonetheless, these effects were not elicited with the use of genetic inhibitors of GSK3β. CONCLUSIONS The results suggest that GSK3β participates at the late stages of the DENV replication cycle, where viral activation may promote apoptosis and release of viral particles.

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Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

Cited by 7 publications

References 57 publications

NK Cell Responses in Zika Virus Infection Are Biased towards Cytokine-Mediated Effector Functions

NK Cell Responses in Zika Virus Infection Are Biased towards Cytokine-Mediated Effector Functions

Interests of the Non-Human Primate Models for HIV Cure Research

Glycogen synthase kinase 3ß participates in late stages of Dengue virus-2 infection

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