Neuraminidase-Mediated, NKp46-Dependent Immune-Evasion Mechanism of Influenza Viruses

Bar-On, Yotam; Glasner, Ariella; Meningher, Tal; Achdout, Hagit; Gur, Chamutal; Lankry, Dikla; Vitenshtein, Alon; Meyers, Adrienne F. A.; Mandelboim, Michal; Mandelboim, Ofer

doi:10.1016/j.celrep.2013.03.034

Cited by 52 publications

(67 citation statements)

References 21 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IgG fusion proteins containing the extracellular domain of NKG2D, NKp30, NKp44, or NKp46 were prepared and used for FACS staining of infected or uninfected SupT1 cells as previously described (35 At the indicated time points, cells were stained with anti-ULBP1, anti-ULBP2, anti-ULBP3, anti-MICA, anti-MICB, and anti-B7-H6 antibodies (all obtained from R&D Systems) as well as the mouse isotype IgG2b antibody (BioLegend). Anti-CD48 was obtained from Santa Cruz.…”

Section: Methodsmentioning

confidence: 99%

“…The inhibitory signal is mostly dependent on the recognition of MHC class I on target cells by appropriate NK inhibitory receptors (29,30). NK cells also possess numerous activating receptors that are able to recognize stressinduced self-ligands via the receptor NKG2D (31), immune regulatory self-molecules (for instance, the recognition of B7-H6 by the NKp30 receptor [32] or of CD48 by the 2B4 receptor [33]), or viral ligands such as the influenza virus-derived hemagglutinin that is recognized by both the NKp46 and NKp44 receptors (34,35). We and other groups have described several diverse viral mechanisms that manipulate cellular ligands for NK cells to escape the immune system (34,(36)(37)(38)(39)(40)(41)(42)(43)(44); however, knowledge about the interaction of HHV-6-infected cells with NK cells is currently missing.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

Schmiedel

Tai

Levi‐Schaffer

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

The Herpesviridae family consists of eight viruses, most of which infect a majority of the human population. One of the lessstudied members is human herpesvirus 6 (HHV-6) (Roseolovirus), which causes a mild, well-characterized childhood disease. Primary HHV-6 infection is followed by lifelong latency. Reactivation frequently occurs in immunocompromised patients, such as those suffering from HIV infection or cancer or following transplantation, and causes potentially life-threatening complications. In this study, we investigated the mechanisms that HHV-6 utilizes to remain undetected by natural killer (NK) cells, which are key participants in the innate immune response to infections. We revealed viral mechanisms which downregulate ligands for two powerful activating NK cell receptors: ULBP1, ULBP3, and MICB, which trigger NKG2D, and B7-H6, which activates NKp30. Accordingly, this downregulation impaired the ability of NK cells to recognize HHV-6-infected cells. Thus, we describe for the first time immune evasion mechanisms of HHV-6 that protect lytically infected cells from NK elimination. IMPORTANCEHuman herpesvirus 6 (HHV-6) latently infects a large portion of the human population and can reactivate in humans lacking a functional immune system, such as cancer or AIDS patients. Under these conditions, it can cause life-threatening diseases. To date, the actions and interplay of immune cells, and particularly cells of the innate immune system, during HHV-6 infection are poorly defined. In this study, we aimed to understand how cells undergoing lytic HHV-6 infection interact with natural killer (NK) cells, innate lymphocytes constituting the first line of defense against viral intruders. We show that HHV-6 suppresses the expression of surface proteins that alert the immune cells by triggering two major receptors on NK cells, NKG2D and NKp30. As a consequence, HHV-6 can replicate undetected by the innate immune system and potentially spread infection throughout the body. This study advances the understanding of HHV-6 biology and the measures it uses to successfully escape immune elimination. Human herpesvirus 6 (HHV-6) (Roseolovirus) was long neglected in research and medical diagnostics; however, in the past few years, it gained increasing attention. A variety of clinical complications were found to be associated with HHV-6 infection, especially concerning immunocompromised patients, in whom it has the ability to cause severe morbidity and mortality (1, 2). HHV-6 is subclassified into two distinct variants, HHV-6A and HHV-6B, which are considered independent viruses but share major genome sequence homologies and epidemiologies (3,4). Similarly to other members of the herpesvirus family, HHV-6 causes a relatively short and mild primary disease called roseola infantum, usually in children up to the age of 2 years, with a sudden rise of fever and rash as major symptoms (5). Following this initial infection, HHV-6 establishes lifelong latency in about 90% of all individuals examined (2). Reactivation frequentl...

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

Schmiedel

Tai

Levi‐Schaffer

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…3F). To confirm that the HA Ig staining of the various Ncr1 proteins is specific, we generated fusion proteins of human NKp46, NKp44 (that were shown to bind viral HA) (20,22,25,38,39), and KIR2DL1. We then ran these proteins on SDS-PAGE gels (Fig.…”

Section: Ncr1-noe´is Activated Upon Tumor and Influenza Virus Recognimentioning

confidence: 99%

“…Using the Ncr1 gfp/gfp mice, it was revealed that Ncr1 is involved in controlling influenza virus infections (5,22,25), tumor and metastases eradication (6,7,10,24), the development of type I and type II diabetes (11,23,26,27), liver fibrosis (28), and bacterial infections (3,29). In all of these studies, the activity of the Ncr1 gfp/gfp NK cells was impaired in an Ncr1-dependent manner.…”

mentioning

confidence: 99%

Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé

Glasner¹,

Šimić

Miklić

et al. 2015

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

NK cells kill various cells using activating receptors, such as the natural cytotoxicity receptors (NCRs). NKp46 is a major NCR and is the only NCR expressed in mice (denoted Ncr1). Using Ncr1-deficient mice (Ncr1gfp/pfp) we demonstrated that Ncr1 controls various pathologies, and that in its absence Ncr1-related functions are impaired. In 2012, another Ncr1-related mouse was generated, named Noé, in which a random mutation, W32R, in position 32, impaired the Ncr1-Noé cell surface expression. Interestingly, in the Noé mice, Ncr1-dependent deficiencies were not observed. Additionally, the Noé-NK cells were hyperactivated, probably due to increased Helios expression, and the Noé mice demonstrate increased clearance of influenza and murine CMV. In contrast, in the Ncr1gfp/pfp mice infection with influenza was lethal and we show in the present study no difference in murine CMV infection between Ncr1gfp/pfp and wild-type (WT) mice. Because the foremost difference between the Noé and Ncr1gfp/gfp mice is the presence of a mutated Ncr1-Noé protein, we studied its properties. We show that Ncr1-Noé and various other Ncr1 mutants in position 32 can be expressed on the surface, albeit slowly and unstably, and that ligand recognition and function of the various Ncr1-Noé is similar to the WT Ncr1. We further show that the glycosylation pattern of Ncr1-Noé is aberrant, that the Ncr1-Noé proteins accumulate in the endoplasmic reticulum, and that the expression of Ncr1-Noé proteins, but not WT Ncr1, leads to increased Helios expression. Thus, we suggest that the NK hyperactivated phenotype observed in the Noé mice might result from the presence of the Ncr1-Noé protein.

show abstract

“…NK cells are known mostly for their role in controlling viral infections (20,21) and have been shown to be involved in cytomegalovirus (CMV) (22)(23)(24), influenza virus (6,(25)(26)(27)(28), Newcastle disease virus (29), vaccinia virus (30), and human metapneumovirus (HMPV) infections (31,32). NK cells express a large repertoire of inhibitory receptors, which mostly recognize major histocompatibility complex class I (MHC-I) molecules (missing self hypothesis [33]).…”

mentioning

confidence: 99%

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

Glasner

Oiknine‐Djian

Weisblum

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

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-␤). 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-␤-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.KEYWORDS Zika virus, MHC class I, NK cells, NK escape mechanisms N K cells are lymphocytes belonging to the innate immune system. NK cells participate in many immunological activities, from killing cancerous cells (1-7) and fighting bacteria (8-10) and fungi (11) to playing roles in allergy (12) and graft-versushost disease (13). NK cells also play roles in autoimmunity (14-18) and pregnancy (19).

show abstract

Neuraminidase-Mediated, NKp46-Dependent Immune-Evasion Mechanism of Influenza Viruses

Cited by 52 publications

References 21 publications

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé

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

Contact Info

Product

Resources

About