scholarly journals Zika Virus Infection Preferentially Counterbalances Human Peripheral Monocyte and/or NK Cell Activity

mSphere ◽  
2018 ◽  
Vol 3 (2) ◽  
Author(s):  
Fok-Moon Lum ◽  
David Lee ◽  
Tze-Kwang Chua ◽  
Jeslin J. L. Tan ◽  
Cheryl Y. P. Lee ◽  
...  
Keyword(s):  
Virus Infection ◽  
Nk Cells ◽  
Immune Cells ◽  
Zika Virus ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Cell Activity ◽  
High Density ◽  
Nk Cell Activity ◽  
Zikv Infection

ABSTRACTZika virus (ZIKV) has reemerged in the population and caused unprecedented global outbreaks. Here, the transcriptomic consequences of ZIKV infection were studied systematically first in human peripheral blood CD14+monocytes and monocyte-derived macrophages with high-density RNA sequencing. Analyses of the ZIKV genome revealed that the virus underwent genetic diversification, and differential mRNA abundance was found in host cells during infection. Notably, there was a significant change in the cellular response, with cross talk between monocytes and natural killer (NK) cells as one of the highly identified pathways. Immunophenotyping of peripheral blood from ZIKV-infected patients further confirmed the activation of NK cells during acute infection. ZIKV infection in peripheral blood cells isolated from healthy donors led to the induction of gamma interferon (IFN-γ) and CD107a—two key markers of NK cell function. Depletion of CD14+monocytes from peripheral blood resulted in a reduction of these markers and reduced priming of NK cells during infection. This was complemented by the immunoproteomic changes observed. Mechanistically, ZIKV infection preferentially counterbalances monocyte and/or NK cell activity, with implications for targeted cytokine immunotherapies.IMPORTANCEZIKV reemerged in recent years, causing outbreaks in many parts of the world. Alarmingly, ZIKV infection has been associated with neurological complications such as Guillain-Barré syndrome (GBS) in adults and congenital fetal growth-associated anomalies in newborns. Host peripheral immune cells are one of the first to interact with the virus upon successful transmission from an infected femaleAedesmosquito. However, little is known about the role of these immune cells during infection. In this work, the immune responses of monocytes, known target cells of ZIKV infection, were investigated by high-density transcriptomics. The analysis saw a robust immune response being elicited. Importantly, it also divulged that monocytes prime NK cell activities during virus infection. Removal of monocytes during the infection changed the immune milieu, which in turn reduced NK cell stimulation. This study provides valuable insights into the pathobiology of the virus and allows for the possibility of designing novel targeted therapeutics.

scholarly journals Zika virus infection preferentially counterbalances human peripheral monocyte and/or NK-cell activity

2017 ◽  
Author(s):  
Fok Moon Lum ◽  
David Lee ◽  
Tze-Kwang Chua ◽  
Jeslin J.L. Tan ◽  
Cheryl Y.P. Lee ◽  
...  
Keyword(s):  
Nk Cells ◽  
Zika Virus ◽  
Peripheral Blood ◽  
Cellular Response ◽  
Nk Cell ◽  
Acute Infection ◽  
Cell Activity ◽  
Host Cells ◽  
Nk Cell Activity ◽  
Zikv Infection

AbstractZika virus (ZIKV) has re-emerged in the population and caused unprecedented global outbreaks. Here, the transcriptomic consequences of ZIKV infection were studied systematically firstly in human peripheral blood CD14+ monocytes and monocyte-derived macrophages with high density RNA-sequencing. Analyses of the ZIKV genome revealed that the virus underwent genetic diversification and differential mRNA abundance was found in host cells during infection. Notably, there was a significant change in the cellular response with crosstalk between monocytes and natural killer (NK) cells as one of the highly identified pathway. Immune-phenotyping of peripheral blood from ZIKV-infected patients further confirmed the activation of NK cells during acute infection. ZIKV infection in peripheral blood cells isolated from healthy donors led to the induction of IFNγ and CD107a — two key markers of NK-cell function. Depletion of CD14+ monocytes from peripheral blood resulted in a reduction of these markers and reduced priming of NK cells during infection. This was complemented by the immunoproteomic changes observed. Mechanistically, ZIKV infection preferentially counterbalances monocyte and/or NK-cell activity, with implications for targeted cytokine immunotherapies.

scholarly journals Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Ariella Glasner ◽  
Esther Oiknine-Djian ◽  
Yiska Weisblum ◽  
Mohammad Diab ◽  
Amos Panet ◽  
...  
Keyword(s):  
Virus Infection ◽  
Nk Cells ◽  
Mhc Class I ◽  
Zika Virus ◽  
Nk Cell ◽  
Cell Activity ◽  
Class I ◽  
Mhc I ◽  
Zika Virus Infection ◽  
Activating Receptors

ABSTRACT NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-β). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus. IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus infection is largely unknown. Here we demonstrate that Zika virus infection is almost undetected by NK cells, as evidenced by the fact that the expression of activating ligands for NK cells is not induced following Zika infection. We identified a mechanism whereby Zika virus sensing via the RIGI-IRF3 pathway resulted in IFN-β-mediated upregulation of MHC-I molecules and inhibition of NK cell activity. Countering MHC class I upregulation and boosting NK cell activity may be employed as prophylactic measures to combat Zika virus infection.

scholarly journals Altered NKp30, NKp46, NKG2D, and DNAM-1 Expression on Circulating NK Cells Is Associated with Tumor Progression in Human Gastric Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Bin Han ◽  
Fang-yuan Mao ◽  
Yong-liang Zhao ◽  
Yi-pin Lv ◽  
Yong-sheng Teng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Progression ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Cell Activity ◽  
Human Gastric Cancer ◽  
Nk Cell Activity ◽  
Activating Receptors ◽  
Cell Suppression

Natural killer (NK) cell activity is influenced by a complex integration of signaling pathways activated downstream of both activating and inhibitory surface receptors. The tumor microenvironment can suppress NK cell activity, and there is a great clinical interest in understanding whether modulating tumor-mediated NK cell suppression and/or boosting preexisting NK cell numbers in cancer patients is therapeutically viable. To this light, we characterized the surface receptor phenotypes of peripheral blood NK cells and examined their clinical relevance to human gastric cancer (GC). We found that the proportion of peripheral blood NK cells which expressed the activating receptors NKp30, NKp46, NKG2D, and DNAM-1 was significantly decreased in GC patients compared to healthy donors, and that this decrease was positively associated with tumor progression. At the same time, plasma TGF-β1 concentrations were significantly increased in GC patients and negatively correlated with the proportion of NKp30, NKp46, NKG2D, and DNAM-1 expressing NK cells. Furthermore, TGF-β1 significantly downregulated the expression of NKp30, NKp46, NKG2D, and DNAM-1 on NK cells in vitro, and the addition of galunisertib, an inhibitor of the TGF-β receptor subunit I, reversed this downregulation. Altogether, our data suggest that the decreased expression of activating receptors NKp30, NKp46, NKG2D, and DNAM-1 on peripheral blood NK cells is positively associated with GC progression, and that TGF-β1-mediated NK cell suppression may be a therapeutically targetable characteristic of GC.

scholarly journals CD56dim/CD56bright NK cell subpopulations and CD16/CD57 expression correlated with tumor development stages

2016 ◽  
Vol 2016 ◽  
pp. 1 ◽  
Author(s):  
Cornel Ursaciuc ◽  
Mihaela Surcel ◽  
Radu Huică ◽  
Dan Ciotaru ◽  
Maria Dobre ◽  
...  
Keyword(s):  
Nk Cells ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Cell Activity ◽  
Tumor Development ◽  
Nk Cell Activity ◽  
Double Positive ◽  
Development Stages ◽  
Phenotype Analysis ◽  
Cell Subpopulations

BACKGROUND: NK cells are characterized by cytotoxic activity against tumor cells and CD3-CD16+CD56+ phenotype. Two distinct subpopulations of NK cells were characterized in the peripheral blood: NK-CD56dim representing over 95% of NK cells and involved in antitumor cytotoxicity, and NK-CD56bright representing approximately 10% of NK cells and involved in secretion of cytokines.AIM: The aim of the study was to compare the presence of NK-CD56dim/NK-CD56bright subpopulations and their CD16/CD57 expression in peripheral blood NK cells during the particular development stages of malignancy: primary tumor (PT), lymph node invasion (LNI) and distant sites metastases (Mt). MATERIAL AND METHODS: We have analyzed by flow-cytometry peripheral blood samples from total 36 cancer patients: 24 patients with PT, 6 patients with LNI and 6 patients with Mt.RESULTS: The presence of the overall NK cells showed no significant variation between patients in different stages of tumor development. The phenotype analysis showed that CD16+ and/or CD57+ cells were lower in LNI patients compared to PT or Mt patients. Double-positive CD16+CD57+ cells were found decreased in patients with Mt, compared to patients with PT. During the stages of tumor development, NK-CD56bright subpopulation increased progressively (7% in PT patients, 13% in LNI patients, 65% in Mt patients), whereas NK-CD56dim subpopulation gradually decreased (92%, 86%, and 35% respectively). CD16/CD57 expression decreased in NK-CD56dim and increased in NK-CD56bright cells over the three studied stages.CONCLUSION: Our results show changes in NK cells characteristics during tumor development: reversal of NK-CD56dim/NK-CD56brightdistribution and modification of CD16/CD57 expression. Both types of changes can concur in reducing the efficiency of NK cell activity in patients with progressive tumors. 

scholarly journals Varicella-Zoster Virus and Herpes Simplex Virus 1 Differentially Modulate NKG2D Ligand Expression during Productive Infection

2015 ◽  
Vol 89 (15) ◽  
pp. 7932-7943 ◽  
Author(s):  
Tessa M. Campbell ◽  
Brian P. McSharry ◽  
Megan Steain ◽  
Barry Slobedman ◽  
Allison Abendroth
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Activity ◽  
Nkg2d Ligand ◽  
Nk Cell Activity ◽  
Herpes Simplex Virus 1 ◽  
Varicella Zoster ◽  
Ligand Expression ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTNatural killer (NK) cell-deficient patients are particularly susceptible to severe infection with herpesviruses, especially varicella-zoster virus (VZV) and herpes simplex virus 1 (HSV-1). The critical role that NK cells play in controlling these infections denotes an intricate struggle for dominance between virus and NK cell antiviral immunity; however, research in this area has remained surprisingly limited. Our study addressed this absence of knowledge and found that infection with VZV was not associated with enhanced NK cell activation, suggesting that the virus uses specific mechanisms to limit NK cell activity. Analysis of viral regulation of ligands for NKG2D, a potent activating receptor ubiquitously expressed on NK cells, revealed that VZV differentially modulates expression of the NKG2D ligands MICA, ULBP2, and ULBP3 by upregulating MICA expression while reducing ULBP2 and ULBP3 expression on the surface of infected cells. Despite being closely related to VZV, infection with HSV-1 produced a remarkably different effect on NKG2D ligand expression. A significant decrease in MICA, ULBP2, and ULBP3 was observed with HSV-1 infection at a total cellular protein level, as well as on the cell surface. We also demonstrate that HSV-1 differentially regulates expression of an additional NKG2D ligand, ULBP1, by reducing cell surface expression while total protein levels are unchanged. Our findings illustrate both a striking point of difference between two closely related alphaherpesviruses, as well as suggest a powerful capacity for VZV and HSV-1 to evade antiviral NK cell activity through novel modulation of NKG2D ligand expression.IMPORTANCEPatients with deficiencies in NK cell function experience an extreme susceptibility to infection with herpesviruses, in particular, VZV and HSV-1. Despite this striking correlation, research into understanding how these two alphaherpesviruses interact with NK cells is surprisingly limited. Through examination of viral regulation of ligands to the activating NK cell receptor NKG2D, we reveal patterns of modulation by VZV, which were unexpectedly varied in response to regulation by HSV-1 infection. Our study begins to unravel the undoubtedly complex interactions that occur between NK cells and alphaherpesvirus infection by providing novel insights into how VZV and HSV-1 manipulate NKG2D ligand expression to modulate NK cell activity, while also illuminating a distinct variation between two closely related alphaherpesviruses.

scholarly journals Immunosurveillance of Cancer and Viral Infections with Regard to Alterations of Human NK Cells Originating from Lifestyle and Aging

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 557
Author(s):  
Xuewen Deng ◽  
Hiroshi Terunuma ◽  
Mie Nieda
Keyword(s):  
Nk Cells ◽  
Viral Infections ◽  
Nk Cell ◽  
Healthy Lifestyle ◽  
Cell Activity ◽  
Nk Cell Activity ◽  
Effector Cells ◽  
Cell Dysfunction ◽  
Forest Bathing ◽  
Infected Cells

Natural killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating cancer cells and virus- infected cells. NK cells are critical effector cells in the immunosurveillance of cancer and viral infections. Patients with low NK cell activity or NK cell deficiencies are predisposed to increased risks of cancer and severe viral infections. However, functional alterations of human NK cells are associated with lifestyles and aging. Personal lifestyles, such as cigarette smoking, alcohol consumption, stress, obesity, and aging are correlated with NK cell dysfunction, whereas adequate sleep, moderate exercise, forest bathing, and listening to music are associated with functional healthy NK cells. Therefore, adherence to a healthy lifestyle is essential and will be favorable for immunosurveillance of cancer and viral infections with healthy NK cells.

scholarly journals miR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yan Feng ◽  
Yan Li ◽  
Ying Zhang ◽  
Bo-Hao Zhang ◽  
Hui Zhao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Nk Cells ◽  
Natural Killer ◽  
Brain Ischemia ◽  
Cell Activation ◽  
Nk Cell ◽  
Cell Activity ◽  
Passive Transfer ◽  
Immune Defense ◽  
Nk Cell Activity

Abstract Background Brain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate NK cell activation and cytotoxicity after ischemic stroke. Methods Using a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia. Results We observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice. Conclusions These findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain.

Thermal stresses reduce natural killer cell cytotoxicity

1995 ◽  
Vol 79 (3) ◽  
pp. 732-737 ◽  
Author(s):  
S. J. Won ◽  
M. T. Lin
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Target Cell ◽  
Nk Cell ◽  
Cell Activity ◽  
Cortisol Concentration ◽  
Target Cells ◽  
Nk Cell Activity ◽  
Colonic Temperature ◽  
Effector Target

The effects of different ambient temperatures (Ta) on the splenic natural killer (NK) cell activity, effector-target cell conjugation activity, and NK cell numbers were assessed in male inbred C3H/HeNCrj mice (7–10 wk old). The splenic NK cytotoxic activities were examined in a 4-h 51Cr release assay in mouse spleen cells that were obtained 1, 2, 4, 8, or 16 days after exposure to Ta of 22, 4, or 35 degrees C. The percentage of conjugating lymphocytes was calculated by counting the number of single lymphocytes bound to single target cells per 400 effector cells. The numbers of NK cells were expressed by the percentage of 5E6-positive cells. The 5E6 identifies only a subset of NK cells. It was found that the splenic NK cell activity, the effector-target cell conjugation activity, or the NK cell number began to fall 1 day after cold (Ta 4 degrees C) or heat (Ta 35 degrees C) stress. After a 16-day period of either cold or heat exposure, the fall in the splenic NK cell activity, the effector-target cell conjugation activity, or the number of 5E6-positive subsets of NK cells was still evident. Compared with those of the control group (Ta 22 degrees C), the cold-stressed mice had higher adrenal cortisol concentration and lower colonic temperature, whereas the heat-stressed animals had higher adrenal cortisol concentration and higher colonic temperature during a 16-day period of thermal exposure. However, neither cold nor heat stress affected both the body weight gain and the spleen weight in our mice.

scholarly journals Hitting More Birds with a Stone: Impact of TGF-β on ILC Activity in Cancer

2020 ◽  
Vol 9 (1) ◽  
pp. 143 ◽  
Author(s):  
Cinzia Fionda ◽  
Helena Stabile ◽  
Cristina Cerboni ◽  
Alessandra Soriani ◽  
Angela Gismondi ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Cancer Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Cell Activity ◽  
Lymphoid Cells ◽  
Receptor Expression ◽  
Nk Cell Activity ◽  
Group I

Transforming growth factor (TGF)-β is a central immunosuppressive cytokine within tumor microenvironment inhibiting the expansion and function of major cellular components of adaptive and innate immune system. Among them, compelling evidence has demonstrated that TGF-β is a key regulator of natural killer (NK) cells, innate lymphoid cells (ILCs) with a critical role in immunosurveillance against different kinds of cancer cells. A TGF-β rich tumor microenvironment blocks NK cell activity at multiple levels. This immunosuppressive factor exerts direct regulatory effects on NK cells including inhibition of cytokine production, alteration of activating/inhibitory receptor expression, and promotion of the conversion into non cytotoxic group I ILC (ILC1). Concomitantly, TGF-β can render tumor cells less susceptible to NK cell-mediated recognition and lysis. Indeed, accumulating evidence suggest that changes in levels of NKG2D ligands, mainly MICA, as well as an increase of immune checkpoint inhibitors (e.g., PD-L1) and other inhibitory ligands on cancer cells significantly contribute to TGF-β-mediated suppression of NK cell activity. Here, we will take into consideration two major mechanisms underlying the negative regulation of ILC function by TGF-β in cancer. First, we will address how TGF-β impacts the balance of signals governing NK cell activity. Second, we will review recent advances on the role of this cytokine in driving ILC plasticity in cancer. Finally, we will discuss how the development of therapeutic approaches blocking TGF-β may reverse the suppression of host immune surveillance and improve anti-tumor NK cell response in the clinic.

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