NKp46 O-Glycan Sequences That Are Involved in the Interaction with Hemagglutinin Type 1 of Influenza Virus

Mendelson, Michal; Tekoah, Yoram; Zilka, Alon; Gershoni-Yahalom, Orly; Gazit, Roi; Achdout, Hagit; Bovin, Nicolai V.; Meningher, Tal; Mandelboim, Michal; Mandelboim, Ofer; David, Ayelet; Porgador, Angel

doi:10.1128/jvi.01815-09

Cited by 49 publications

(45 citation statements)

References 36 publications

(56 reference statements)

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“…This indicated that, similar to the binding of the influenza hemagglutinin lectin, NKp46 and NCR1 might bind to a lectin on the surface of Cg through the same sugar residue. The O-linked glycan on the NKp46/NCR1, Neu5Acα2-6 (Neu5Acα2-3Galβ1-3) GalNAc (Glasner et al, 2015; Mendelson et al, 2010), is shown in figure 3C. In Cg, the EPA genes encode a major family of glycan binding lectins, which mediate the attachment of the fungal cell to host cells.…”

Section: Resultsmentioning

confidence: 99%

NK Cell Recognition of Candida glabrata through Binding of NKp46 and NCR1 to Fungal Ligands Epa1, Epa6, and Epa7

Vitenshtein

Charpak-Amikam

Yamin

et al. 2016

Cell Host & Microbe

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Natural Killer (NK) cells form an important arm of the innate immune system and function to combat a wide range of invading pathogens, ranging from viruses to bacteria. However, the means by which NK cells accomplish recognition of pathogens with a limited repertoire of receptors remains largely unknown. In the current study, we describe the recognition of an emerging fungal pathogen, Candida glabrata, by the human NK cytotoxic receptor NKp46 and its mouse ortholog NCR1. Using NCR1 knockout mice, we observed that this receptor-mediated recognition was crucial for controlling C. glabrata infection in vitro and in vivo. Finally, we delineated the fungal ligands to be the C. glabrata adhesins Epa1, Epa6 and Epa7 and demonstrate that clearance of systemic C. glabrata infections in vivo depends on their recognition by NCR1. As NKp46 and NCR1 have been previously shown to bind viral adhesion receptors, we speculate that NKp46/NCR1 may be a novel type of pattern recognition receptor.

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Section: Resultsmentioning

confidence: 99%

NK Cell Recognition of Candida glabrata through Binding of NKp46 and NCR1 to Fungal Ligands Epa1, Epa6, and Epa7

Vitenshtein

Charpak-Amikam

Yamin

et al. 2016

Cell Host & Microbe

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“…Moreover, we found that intrahepatic frequency of NKp46 High NK cells inversely correlated with HCV loads. Whether NKp46 recognizes a HCV-derived protein [17][18][19][20][21] or interacts with a yet unknown NKp46 ligand, as has been suggested for malignant transformed cells, 40,41 remains to be clarified. However, blocking of NKp46 significantly reduced the capability of both circulating and intrahepatic NK cells to block HCV replication, suggesting a role of NKp46 in the regulation of anti-HCV immune responses.…”

Section: Nk Cells (Supportingmentioning

confidence: 99%

“…Moreover, NKp46 plays an important role in the killing of virus-infected cells by interacting with viral proteins. [17][18][19][20][21] Studies on NKp46 in HCV infection are controversial, because both reduced and increased surface expression have been reported. 5,[7][8][9] In this context, it is of interest that earlier studies showed that the surface expression of NKp46 may vary in different human peripheral blood NK cells, and that the NKp46 phenotype of NK clones correlates with cytolytic activity.…”

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confidence: 99%

Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

et al. 2012

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Natural killer (NK) cells play a role in the early control and natural course of hepatitis C virus (HCV) infection. NK cell function is regulated by a multitude of receptors, including activating NKp46 receptor. However, reports on NKp46 in hepatitis C are controversial. Therefore, we investigated the hepatic recruitment and function of NKp46(1) NK cells, considering differential surface expression of NKp46 resulting in NKp46 High and NKp46 Dim subsets. Intra-and extrahepatic NK-cell subsets from HCV-infected patients were characterized by flow cytometry. Cytotoxic activity and interferon-gamma (IFN-c) secretion were studied using K-562, P815, and primary hepatic stellate cells as targets. Anti-HCV activity of NK-cell subsets was studied using the replicon system. Density of NKp46 surface expression clearly segregated NKp46 Dim and NKp46 High subsets, which differed significantly with respect to the coexpression of maturation markers and NK-cell receptors. More important, NKp46 High NK cells showed a higher cytolytic activity and stronger IFN-c secretion than NKp46 Dim NK cells. Accordingly, NKp46 High NK cells efficiently blocked HCV replication in vitro. Blocking experiments confirmed an important role for the NKp46 receptor. Furthermore, we found an intrahepatic accumulation of NKp46 High NK cells. Of note, high cytolytic activity of NKp46 High NK cells was also confirmed in the intrahepatic NK-cell population, and the frequency of intrahepatic NKp46 High NK cells was inversely correlated with HCV-RNA levels and fibrosis stage. Conclusions: NKp46 High expression defines a specific NK-cell subset that may be involved in both the suppression of HCV replication and HCV-associated liver damage underpinning the role of NK cells in the immunopathogenesis of HCV. (HEPATOLOGY 2012;56:1201-1213 See Editorial on Page 1197 I nfection with the hepatitis C virus (HCV) often results in chronic liver disease. Elimination of HCV infection requires the coordinated function of the innate and the adaptive immune system. Natural killer (NK) cells constitute a major component of the intrahepatic lymphocyte pool. In contrast to the peripheral blood, which contains approximately 5%-10% NK cells, intrahepatic lymphocytes comprise approximately 30% NK cells, and the percentage of intrahepatic NK cells may increase >50% in liver diseases. 1 Immunogenetic analyses indicate that NK cells may influence the outcome of acute HCV infection as well as immunopathogenesis in chronic hepatitis C (CHC). 2 Accordingly, in vitro studies suggest that NK cells are able to recognize and kill HCV-infected hepatocytes in vivo. 3 However, published data on phenotype and function of NK cells in HCV infection are controversial. [4][5][6][7][8][9][10][11][12][13]

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“…Early work showed that the viral hemagglutinin (HA) of influenza virus on the surface of infected cells can readily engage with branched α-2,3- and α-2,6-sialylated O -glycan sequences conjugated on NKp46, and influenza-infected target cells can be killed by human NK cells in a NKp46-dependent manner (65–68). In fact, exposure of NK cells to influenza virions or free HA has been found to decrease NCR-mediated cytotoxicity, which was associated with loss of TCR-ζ protein expression (71).…”

Section: Ligands Of the Ncrsmentioning

confidence: 99%

Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

et al. 2017

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The natural cytotoxicity receptor (NCR) family is constituted by NKp46, NKp44, and NKp30 in humans, which are expressed mainly on natural killer (NK) cells and are encoded by the ncr1, ncr2, and ncr3 genes, respectively. NCRs have classically been defined as activating receptors that trigger cytotoxicity and cytokine responses by NK cells upon engaging with ligands on tumor cells. Several new findings, however, have challenged this model and identified alternative mechanisms regulating the function of NCRs. Recent reports indicate that ligand matters, since the interaction of NKp44 with distinct ligands on target cells can either activate or inhibit NK cells. Also, the NCRs have been found to interact with distinct specificities to various heparan sulfate glycosaminoglycans, which are complex polysaccharides found in extracellular matrix or on cell surface heparan sulfate proteoglycans (HSPGs). The NCRs can engage with HSPGs in trans as a co-ligand on the target cells or in cis on the NK cell surface to regulate receptor–ligand interactions and NK cell activation. A number of splice variants of ncr2 and ncr3 have also been identified, and a predominant expression of certain variants results in inhibitory signaling through NKp44 and NKp30. Several recent studies have found that the selective expression of some of these inhibitory splice variants can significantly influence outcome in the contexts of cancer, infection, and pregnancy. These findings establish that NCR functions are more diverse than originally thought, and better understanding of their splice variant expression profiles and ligand interactions are needed to establish their functional regulation in the context of human health.

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NKp46 O-Glycan Sequences That Are Involved in the Interaction with Hemagglutinin Type 1 of Influenza Virus

Abstract: Natural killer (NK) cells serve as a crucial first-line defense against tumors and virus-infected cells. We previously showed that lysis of influenza virus (IV)-infected cells is mediated

Cited by 49 publications

References 36 publications

NK Cell Recognition of Candida glabrata through Binding of NKp46 and NCR1 to Fungal Ligands Epa1, Epa6, and Epa7

NK Cell Recognition of Candida glabrata through Binding of NKp46 and NCR1 to Fungal Ligands Epa1, Epa6, and Epa7

Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

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