Dynamic Co-evolution of Host and Pathogen: HCMV Downregulates the Prevalent Allele MICA∗008 to Escape Elimination by NK Cells

Seidel, Einat; Le, Vu Thuy Khanh; Bar-On, Yotam; Tsukerman, Pinchas; Enk, Jonatan; Yamin, Rachel; Stein, Natan; Schmiedel, Dominik; Djian, Esther; Weisblum, Yiska; Tirosh, Boaz; Šťastný, Peter; Wolf, Dana; Hengel, Hartmut; Mandelboim, Ofer

doi:10.1016/j.celrep.2015.01.029

Cited by 67 publications

(125 citation statements)

References 32 publications

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“…We confirmed that assumption, as we showed the staining with an NKG2D fusion was reduced upon infection. Another, less likely, explanation is that because MICA is highly polymorphic and since it was shown that HCMV possesses different mechanisms for different alleles (37), it may be possible that HHV-6 cannot target the specific MICA alleles expressed by SupT1 and MOLT-3 cells. Additionally, it is possible that the reactions of a transformed T cell and primary T cells following viral sensing vary tremendously.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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

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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...

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Section: Discussionmentioning

confidence: 99%

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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

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“…+ and DNAM-1 + cells (14)(15)(16)(17). In contrast, it is still debated whether and how HCMV upregulates NKG2DL, whereas for DNAM-1L it has not been investigated.…”

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confidence: 98%

Distinct Roles for Human Cytomegalovirus Immediate Early Proteins IE1 and IE2 in the Transcriptional Regulation of MICA and PVR/CD155 Expression

Pignoloni

Fionda

Dell’Oste

et al. 2016

The Journal of Immunology

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Elimination of virus-infected cells by cytotoxic lymphocytes is triggered by activating receptors, among which NKG2D and DNAM-1/CD226 play an important role. Their ligands, that is, MHC class I–related chain (MIC) A/B and UL16-binding proteins (ULBP)1–6 (NKG2D ligand), Nectin-2/CD112, and poliovirus receptor (PVR)/CD155 (DNAM-1 ligand), are often induced on virus-infected cells, although some viruses, including human CMV (HCMV), can block their expression. In this study, we report that infection of different cell types with laboratory or low-passage HCMV strains upregulated MICA, ULBP3, and PVR, with NKG2D and DNAM-1 playing a role in NK cell–mediated lysis of infected cells. Inhibition of viral DNA replication with phosphonoformic acid did not prevent ligand upregulation, thus indicating that early phases of HCMV infection are involved in ligand increase. Indeed, the major immediate early (IE) proteins IE1 and IE2 stimulated the expression of MICA and PVR, but not ULBP3. IE2 directly activated MICA promoter via its binding to an IE2-responsive element that we identified within the promoter and that is conserved among different alleles of MICA. Both IE proteins were instead required for PVR upregulation via a mechanism independent of IE DNA binding activity. Finally, inhibiting IE protein expression during HCMV infection confirmed their involvement in ligand increase. We also investigated the contribution of the DNA damage response, a pathway activated by HCMV and implicated in ligand regulation. However, silencing of ataxia telangiectasia mutated, ataxia telangiectasia and Rad3–related protein, and DNA-dependent protein kinase did not influence ligand expression. Overall, these data reveal that MICA and PVR are directly regulated by HCMV IE proteins, and this may be crucial for the onset of an early host antiviral response.

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“…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]).…”

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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

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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).

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Dynamic Co-evolution of Host and Pathogen: HCMV Downregulates the Prevalent Allele MICA∗008 to Escape Elimination by NK Cells

Cited by 67 publications

References 32 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

Distinct Roles for Human Cytomegalovirus Immediate Early Proteins IE1 and IE2 in the Transcriptional Regulation of MICA and PVR/CD155 Expression

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

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