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1.
Cell Host Microbe ; 20(4): 527-534, 2016 Oct 12.
Article in English | MEDLINE | ID: mdl-27736647

ABSTRACT

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 remain 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 demonstrated 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.


Subject(s)
Antigens, Ly/metabolism , Candida glabrata/immunology , Fungal Proteins/metabolism , Killer Cells, Natural/immunology , Natural Cytotoxicity Triggering Receptor 1/metabolism , Animals , Antigens, Ly/genetics , Candidiasis/immunology , Disease Models, Animal , Humans , Mice, Inbred BALB C , Mice, Knockout , Natural Cytotoxicity Triggering Receptor 1/genetics
2.
Cell Rep ; 15(11): 2331-9, 2016 06 14.
Article in English | MEDLINE | ID: mdl-27264178

ABSTRACT

Cells in our body can induce hundreds of antiviral genes following virus sensing, many of which remain largely uncharacterized. CEACAM1 has been previously shown to be induced by various innate systems; however, the reason for such tight integration to innate sensing systems was not apparent. Here, we show that CEACAM1 is induced following detection of HCMV and influenza viruses by their respective DNA and RNA innate sensors, IFI16 and RIG-I. This induction is mediated by IRF3, which bound to an ISRE element present in the human, but not mouse, CEACAM1 promoter. Furthermore, we demonstrate that, upon induction, CEACAM1 suppresses both HCMV and influenza viruses in an SHP2-dependent process and achieves this broad antiviral efficacy by suppressing mTOR-mediated protein biosynthesis. Finally, we show that CEACAM1 also inhibits viral spread in ex vivo human decidua organ culture.


Subject(s)
Antigens, CD/metabolism , Cell Adhesion Molecules/metabolism , Cytomegalovirus/physiology , Orthomyxoviridae/physiology , Animals , Cytomegalovirus Infections/metabolism , Cytomegalovirus Infections/virology , DEAD Box Protein 58/metabolism , DNA, Viral/metabolism , Humans , Influenza, Human/metabolism , Influenza, Human/virology , Interferon Regulatory Factor-3/metabolism , Mice , Organ Culture Techniques , Protein Biosynthesis , Receptors, Immunologic , TOR Serine-Threonine Kinases/metabolism , Virus Replication
3.
Oncotarget ; 7(27): 40953-40964, 2016 Jul 05.
Article in English | MEDLINE | ID: mdl-27029068

ABSTRACT

Natural Killer (NK) cells are innate immune lymphocytes specializing in recognition and killing of tumors and pathogens, using an array of activating and inhibitory receptors. NK inhibition is mediated by a large repertoire of inhibitory receptors, whereas a limited number of activating NK cell receptors execute NK cell activation. The ligands recognized by the activating receptors are stress-induced, pathogen derived, tumor specific and even self ligands. However, the full spectrum of NK cell receptors and ligands that control NK cell activity remains uncharacterized. Here we demonstrate that Paired Ig-Like type 2 Receptor Alpha (PILRα), binds a distinct human NK cell sub-population present in the peripheral blood and also in the decidua. We further demonstrate that the interaction of NK cells with PILRα expressing targets lead to elevated IFNγ secretion and cytotoxicity. In conclusion, we present here a novel NK activating ligand which binds and activates an unknown NK receptor expressed on a unique NK cell subset.


Subject(s)
CD56 Antigen/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Membrane Glycoproteins/metabolism , Receptors, Immunologic/metabolism , Receptors, Natural Killer Cell/metabolism , Cells, Cultured , Cytotoxicity, Immunologic , HEK293 Cells , Humans , Interferon-gamma/metabolism , Lymphocyte Activation , Protein Binding
4.
Elife ; 52016 Mar 16.
Article in English | MEDLINE | ID: mdl-26982091

ABSTRACT

Expression of the stress-induced ligands MICA, MICB and ULBP 1-6 are up-regulated as a cellular response to DNA damage, excessive proliferation or viral infection; thereby, they enable recognition and annihilation by immune cells that express the powerful activating receptor NKG2D. This receptor is present not exclusively, but primarily on NK cells. Knowledge about the regulatory mechanisms controlling ULBP expression is still vague. In this study, we report a direct interaction of the oncogenic RNA binding protein (RBP) IMP3 with ULBP2 mRNA, leading to ULBP2 transcript destabilization and reduced ULBP2 surface expression in several human cell lines. We also discovered that IMP3 indirectly targets MICB with a mechanism functionally distinct from that of ULBP2. Importantly, IMP3-mediated regulation of stress-ligands leads to impaired NK cell recognition of transformed cells. Our findings shed new light on the regulation of NKG2D ligands and on the mechanism of action of a powerful oncogenic RBP, IMP3.


Subject(s)
Histocompatibility Antigens Class I/metabolism , RNA-Binding Proteins/metabolism , Tumor Escape , Cell Line, Tumor , GPI-Linked Proteins/antagonists & inhibitors , Humans , Intercellular Signaling Peptides and Proteins , Killer Cells, Natural/immunology , NK Cell Lectin-Like Receptor Subfamily K/metabolism
5.
Oncotarget ; 7(13): 15369-81, 2016 Mar 29.
Article in English | MEDLINE | ID: mdl-26992229

ABSTRACT

Polyomaviruses are a diverse family of viruses which are prevalent in the human population. However, the interactions of these viruses with the immune system are not well characterized. We have previously shown that two human polyomaviruses, JC and BK, use an identical microRNA to evade immune attack by Natural Killer (NK) cells. We showed that this viral microRNA suppresses ULBP3 expression, a stress induced ligand for the killer receptor NKG2D. Here we show that Simian Virus 40 (SV40) also evades NK cell attack through the down regulation of another stress-induced ligand of NKG2D, ULBP1. These findings indicate that NK cells play an essential role in fighting polyomavirus infections and further emphasize the importance of various members of the ULBP family in controlling polyomavirus infection.


Subject(s)
Cytotoxicity, Immunologic/immunology , Immune Evasion/immunology , Intracellular Signaling Peptides and Proteins/biosynthesis , Killer Cells, Natural/immunology , Polyomavirus Infections/immunology , Tumor Virus Infections/immunology , Animals , Cell Line , Down-Regulation , GPI-Linked Proteins/biosynthesis , Humans , Simian virus 40/immunology
6.
PLoS Pathog ; 9(8): e1003568, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23966863

ABSTRACT

Natural killer (NK) cells are innate immune cells able to rapidly kill virus-infected and tumor cells. Two NK cell populations are found in the blood; the majority (90%) expresses the CD16 receptor and also express the CD56 protein in intermediate levels (CD56(Dim) CD16(Pos)) while the remaining 10% are CD16 negative and express CD56 in high levels (CD56(Bright) CD16(Neg)). NK cells also reside in some tissues and traffic to various infected organs through the usage of different chemokines and chemokine receptors. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human virus that has developed numerous sophisticated and versatile strategies to escape the attack of immune cells such as NK cells. Here, we investigate whether the KSHV derived cytokine (vIL-6) and chemokines (vMIP-I, vMIP-II, vMIP-III) affect NK cell activity. Using transwell migration assays, KSHV infected cells, as well as fusion and recombinant proteins, we show that out of the four cytokine/chemokines encoded by KSHV, vMIP-II is the only one that binds to the majority of NK cells, affecting their migration. We demonstrate that vMIP-II binds to two different receptors, CX3CR1 and CCR5, expressed by naïve CD56(Dim) CD16(Pos) NK cells and activated NK cells, respectively. Furthermore, we show that the binding of vMIP-II to CX3CR1 and CCR5 blocks the binding of the natural ligands of these receptors, Fractalkine (Fck) and RANTES, respectively. Finally, we show that vMIP-II inhibits the migration of naïve and activated NK cells towards Fck and RANTES. Thus, we present here a novel mechanism in which KSHV uses a unique protein that antagonizes the activity of two distinct chemokine receptors to inhibit the migration of naïve and activated NK cells.


Subject(s)
Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , Cell Movement/drug effects , Chemokines/pharmacology , Herpesvirus 8, Human/chemistry , Killer Cells, Natural/drug effects , Receptors, Chemokine/antagonists & inhibitors , CX3C Chemokine Receptor 1 , Cells, Cultured , Chemokine CCL5/metabolism , Chemokine CX3CL1/metabolism , Cytokines/genetics , Cytokines/metabolism , Humans , Immunoblotting , Interleukin-6 , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Polymerase Chain Reaction , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism
7.
Cancer Res ; 72(21): 5463-72, 2012 Nov 01.
Article in English | MEDLINE | ID: mdl-22915757

ABSTRACT

Natural killer cells (NK) are a component of innate immunity well known for their potent ability to kill virus-infected or neoplastically transformed cells following stimulation of the NK cell receptor NKG2D. One of the various ligands of NKG2D is MICB, a stress-induced ligand that has been found to be upregulated on the surface of tumor cells. However, there is little knowledge about how this upregulation may occur or how it may be selected against in tumors as a mechanism of immune escape. Here, we report that the metastasis-associated microRNA (metastamir) miR-10b directly binds to the 3' untranslated region of MICB and downregulates its expression. Notably, antagonizing miR-10b action enhanced NKG2D-mediated killing of tumor cells in vitro and enhanced clearance of tumors in vivo. Conversely, overexpression of miR-10b downregulated MICB and impaired elimination of tumor cells. Together, our results define MICB as a novel immune target of miR-10b, implying a direct link between metastasis capability and immune escape from NK cells.


Subject(s)
Gene Expression Regulation, Neoplastic/genetics , Histocompatibility Antigens Class I/biosynthesis , Killer Cells, Natural/metabolism , MicroRNAs/metabolism , Neoplasms/metabolism , Animals , Cell Line, Tumor , Down-Regulation , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Killer Cells, Natural/immunology , Ligands , Male , Mice , Mice, Inbred C57BL , MicroRNAs/immunology , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/immunology , Neoplasms/genetics , Neoplasms/immunology , Real-Time Polymerase Chain Reaction , Tumor Escape/genetics , Tumor Escape/immunology
8.
RNA Biol ; 8(4): 591-4, 2011.
Article in English | MEDLINE | ID: mdl-21593609

ABSTRACT

Since miRNAs are considered non-immunogenic, it was not too surprising to discover that some herpesviruses, which are masters of immune evasion, developed their own unique miRNAs to escape immune elimination. In this point of view we discuss our recent findings in which we demonstrate that two polyomaviruses, JC and BK, use an identical miRNA to escape immune attack. This identical miRNA targets the stress-induced protein ULBP3, which is recognized by the killer receptor NKG2D and thus, through the usage of a miRNA, JCV and BKV avoid the NKG2D mediated elimination. We further compare the miRNA-based immune evasion mechanisms of herpes and polyomaviruses, offering new insights on the complexity of the stress induced ligands function and recognition. Lastly, we consider the possibility that other viral and cellular mechanisms are also involved in targeting ULBP3 and other NKG2D ligands.


Subject(s)
BK Virus/pathogenicity , Immune Evasion , JC Virus/pathogenicity , MicroRNAs/metabolism , Polyomavirus Infections/virology , RNA, Viral/metabolism , BK Virus/genetics , BK Virus/immunology , GPI-Linked Proteins/metabolism , Herpesviridae/genetics , Herpesviridae/immunology , Herpesviridae/pathogenicity , Humans , Intercellular Signaling Peptides and Proteins/metabolism , JC Virus/genetics , JC Virus/immunology , MicroRNAs/genetics , NK Cell Lectin-Like Receptor Subfamily K/immunology , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Polyomavirus Infections/genetics , Polyomavirus Infections/immunology , RNA, Viral/genetics
9.
Cell Host Microbe ; 9(2): 93-102, 2011 Feb 17.
Article in English | MEDLINE | ID: mdl-21320692

ABSTRACT

The human polyoma viruses JCV and BKV establish asymptomatic persistent infection in 65%-90% of humans but can cause severe illness under immunosuppressive conditions. The mechanisms by which these viruses evade immune recognition are unknown. Here we show that a viral miRNA identical in sequence between JCV and BKV targets the stress-induced ligand ULBP3, which is a protein recognized by the killer receptor NKG2D. Consequently, viral miRNA-mediated ULBP3 downregulation results in reduced NKG2D-mediated killing of virus-infected cells by natural killer (NK) cells. Importantly, when the activity of the viral miRNA was inhibited during infection, NK cells killed the infected cells more efficiently. Because NKG2D is also expressed by various T cell subsets, we propose that JCV and BKV use an identical miRNA that targets ULBP3 to escape detection by both the innate and adaptive immune systems, explaining how these viruses remain latent without being eliminated by the immune system.


Subject(s)
BK Virus/genetics , Immune Evasion , Intercellular Signaling Peptides and Proteins/genetics , JC Virus/genetics , MicroRNAs/genetics , Polyomavirus Infections/immunology , RNA, Viral/immunology , BK Virus/immunology , Base Sequence , Cell Line, Tumor , Down-Regulation , GPI-Linked Proteins/genetics , GPI-Linked Proteins/immunology , Humans , Intercellular Signaling Peptides and Proteins/immunology , JC Virus/immunology , Killer Cells, Natural/immunology , MicroRNAs/immunology , Molecular Sequence Data , NK Cell Lectin-Like Receptor Subfamily K/immunology , Polyomavirus Infections/genetics , Polyomavirus Infections/virology , RNA, Viral/genetics
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