Upregulation of <scp>HLA</scp>‐E by dengue and not Zika viruses

Drews, Elena; Adam, Awadalkareem; Htoo, Phone; Townsley, Elizabeth; Mathew, Anuja

doi:10.1002/cti2.1039

Cited by 8 publications

(11 citation statements)

References 26 publications

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“…In this study, we used an in vitro model of co-culture to analyze the cellular and molecular events required for the control of DENV-2 infection by NK cells. We demonstrated that infection of Mo-DCs by DENV-2 induced autologous NK cells to produce IFN-γ and TNFα specifically, and did not mediate degranulation, in accordance with data previously observed with ex vivo NK cells of infected patients [12][13][14]; this is possibly explained by the upregulation of MHC class-1 molecules, and HLA-E in DENV-2 infection, confirmed herein and previously described [26,27,32]. However, we cannot exclude that the cytotoxic functions of NK cells are modulated differently in the function of the DENV serotype.…”

Section: Discussionsupporting

confidence: 92%

“…4A), as described previously for different flaviviruses, and unlike many other viruses that down‐regulate MHC class‐1 expression on infected cells . Concomitantly, HLA‐E expression was significantly increased in DENV‐2‐infected cells, as described . Moreover, the frequency and surface‐expression of the MHC class‐1‐related chain (MIC)‐A and MIC‐B, two ligands of NKG2D, were significantly induced in DENV‐2‐infected Mo‐DCs ( p = 0.0015), but not in bystander Mo‐DCs, when compared to non‐infected cells (Fig.…”

Section: Resultssupporting

confidence: 73%

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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

et al. 2019

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Dengue virus (DENV) is the most widespread arbovirus worldwide and is responsible for major outbreaks. The host's immune response plays a crucial role in controlling this infection but might also contribute to the promotion of viral spread and immunopathology. In response to DENV infection, NK cells preferentially produce cytokines and are cytotoxic in the presence of specific antibodies. Here, we identified that DENV‐2 inhibits glycogen synthase kinase 3 (GSK‐3) activity to subsequently induce MHC class‐1‐related chain (MIC) A and MIC‐B expression and IL‐12 production in monocyte‐derived DCs, independently of the STAT‐3 pathway. The inhibition of GSK‐3 by DENV‐2 or small molecules induced MIC‐A/B expression on monocyte‐derived DCs, resulting in autologous NK cells of a specific increase in IFN‐γ and TNF‐α production, in the absence of direct cytotoxicity. Together, these findings identified GSK‐3 as a regulator of MIC‐A/B expression and suggested its role in DENV‐2 infection to specifically induce cytokine production by NK cells.

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Section: Discussionsupporting

confidence: 92%

Section: Resultssupporting

confidence: 73%

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

et al. 2019

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“…Although the mechanism underlying this phenomenon is unclear, some of these responses have been attributed to elevated HLA-E expression (28). The upregulation of HLA-E, the ligand of NKG2C, is a common feature found in viral infections, such as dengue, hantavirus, and HIV (28,45,46). The engagement of NKG2C, the signature activating receptor of CD57 + /NKG2C high NK cells, leads to polyfunctional responses characterized by degranulation of cytolytic molecules as well as TNF-α and IFN-γ release (29).…”

Section: Discussionmentioning

confidence: 99%

NK Cell Activity and CD57+/NKG2Chigh Phenotype Are Increased in Men Who Have Sex With Men at High Risk for HIV

et al. 2020

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Introduction: The HIV-exposed seronegative (HESN) status is for individuals who remain seronegative despite repeated exposure to HIV. One of the main cohorts within this group is men who have sex with men (MSM). Studies of this cohort have revealed different immunological and genetic mechanisms that can explain the phenomenon of natural HIV resistance. NK cells' higher effector capacity is related to natural resistance to HIV. Besides, a new population of NK cells with adaptive features was described recently. These cells are increased in some HESN cohorts and appear to be involved in better control of viral replication in primarily HIV-infected subjects. The present study evaluated the role of NK cells in the natural resistance to HIV-1 infection in MSM. Methodology: Phenotypic and functional features were evaluated in NK cells from two groups of MSM, at different risks of HIV infection, according to the number of sexual partners. The production of IFN-γ and β-chemokines was included in the analysis, as well as the cytotoxic capacity and adaptive NK cell frequency. Genetic features, such as HLA and KIR allele frequencies, were also explored. Results: High-risk MSM exhibit an increased frequency of fully mature and CD57 + /NKG2C high NK cells. These individuals also show higher cytotoxic capacity and IFN-γ production in response to K562 stimuli. NK cells with a CD107a + /IFN-γ + functional profile were found more frequently and displayed higher IFN-γ production capacity among high-risk MSM than among low-risk MSM. The protective allele HLA-B * 18 was only present in the high-risk MSM group as well as HLA-B * 39. The protective phenotype KIR3DL1/S1-HLA-B * Bw4, in a homozygous state, was particularly abundant in the high-risk population. Notably, some of these functional features were related to higher frequencies of mature and CD57 + /NKG2C high NK cells, which, in turn, were associated with a higher number of sexual partners. Conclusion: The changes observed in the NK cell compartment can be driven by the magnitude of sexual exposure and immunological challenges of high-risk individuals, which could influence their resistance/susceptibility to HIV infection.

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“…Several NK cell receptors, namely DNAM-1, NKG2D, and NKp44 have been implicated in this direct recognition of DENV-infected cells (Beltrán and López-Vergès, 2014; Petitdemange et al, 2014; Costa et al, 2017; Mathew, 2018). However, DENV may also evade the NK cell response, most notably through upregulation of HLA class I (Lobigs et al, 1996; Momburg et al, 2001; Hershkovitz et al, 2008; Glasner et al, 2017; Drews et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Viruses can evade NK cell recognition by taking advantage of these inhibitory interactions. In vitro studies have shown flaviviruses, including DENV, upregulate total HLA class I as well as HLA-E, leading to inhibition of NK cell activation (Lobigs et al, 1996; Momburg et al, 2001; Hershkovitz et al, 2008; Glasner et al, 2017; Drews et al, 2018). Immune cells, particularly monocytes, are the main targets of DENV infection in vivo (Durbin et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

HLA Upregulation During Dengue Virus Infection Suppresses the Natural Killer Cell Response

McKechnie

Beltran

Pitti

et al. 2019

Front. Cell. Infect. Microbiol.

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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.

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Upregulation of HLA‐E by dengue and not Zika viruses

Cited by 8 publications

References 26 publications

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

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

NK Cell Activity and CD57+/NKG2Chigh Phenotype Are Increased in Men Who Have Sex With Men at High Risk for HIV

HLA Upregulation During Dengue Virus Infection Suppresses the Natural Killer Cell Response

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