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Some local business owners expressed their feelings during this back-to-school season. They said it's not just about the boost in business, but getting the opportunity to interact with the students.
"This is where it's all at," said Daily Grind and Licks Unlimited Co-Owner Dana Dykes. "This is the busiest time of the year, is when the students are around. It's going to be exciting; we're looking forward to it."
"I just get so excited, and I think part of it is, you know, as a recent graduate from U of I, there's some nostalgia," said Nourish Yoga and Smoothie Co-Owner Jessica Thomas. "Like, I remember what it's like to be a freshman. I remember what it's like to come down to Moscow."
Washington State University Students will start classes next Monday, and the University of Idaho will start their fall semester on August 26th.


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Authorities crack down on drivers without insuranceUPDATED 7:49 AM CST Nov 19, 2012
Law enforcement agencies across the state are creating checkpoints to stop drivers to check for current car insurance coverage.
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The Human Herpesvirus-7 (HHV-7) U21 Immunoevasin Subverts NK-Mediated Cytoxicity through Modulation of MICA and MICB
Schneider, Christine L.
Hudson, Amy W.
PLoS Pathogens
Herpesviruses have evolved numerous immune evasion strategies to facilitate establishment of lifelong persistent infections. Many herpesviruses encode gene products devoted to preventing viral antigen presentation as a means of escaping detection by cytotoxic T lymphocytes. The human herpesvirus-7 (HHV-7) U21 gene product, for example, is an immunoevasin that binds to class I major histocompatibility complex molecules and redirects them to the lysosomal compartment. Virus infection can also induce the upregulation of surface ligands that activate NK cells. Accordingly, the herpesviruses have evolved a diverse array of mechanisms to prevent NK cell engagement of NK-activating ligands on virus-infected cells. Here we demonstrate that the HHV-7 U21 gene product interferes with NK recognition. U21 can bind to the NK activating ligand ULBP1 and reroute it to the lysosomal compartment. In addition, U21 downregulates the surface expression of the NK activating ligands MICA and MICB, resulting in a reduction in NK-mediated cytotoxicity. These results suggest that this single viral protein may interfere both with CTL-mediated recognition through the downregulation of class I MHC molecules as well as NK-mediated recognition through downregulation of NK activating ligands.
Author Summary
The long coevolution of herpesviruses with their hosts has resulted in the development of a diverse array of viral immune evasion strategies and host counter-strategies. The identification of viral proteins that impair the function of cellular immune-recognition receptors has proven fertile ground for the discovery of fundamental concepts in immunology and cell biology. While the cytomegaloviruses have demonstrated an extraordinary array of immunoevasive tactics, little is known about the immunoevasive strategies of the closely-related human herpesvirus-7 (HHV-7). We have previously demonstrated that the U21 gene product from HHV-7 likely interferes with viral antigen presentation to cytotoxic T cells by rerouting class I major histocompatibility molecules to lysosomes for degradation. In addition to the host's cytotoxic T cell response, virus infection also induces the expression of Natural-Killer (NK) activating ligands, alerting cytotoxic NK cells to identify and kill virus-infected cells. Here we describe a novel function for the same viral protein - U21 - in interfering with NK cell recognition. Our findings provide the first indication that HHV-7, too, may have found it necessary to strategize mechanisms of NK escape.
Related Articles
The p36 Isoform of Murine Cytomegalovirus m152 Protein Suffices for Mediating Innate and Adaptive Immune Evasion
Fink, Annette
Renzaho, Angeliqué
Reddehase, Matthias J.
Lemmermann, Niels A. W.
The MHC-class I (MHC-I)-like viral (MHC-Iv) m152 gene product of murine cytomegalovirus (mCMV) was the first immune evasion molecule described for a member of the β-subfamily of herpesviruses as a paradigm for analogous functions of human cytomegalovirus proteins. Notably, by interacting with classical MHC-I molecules and with MHC-I-like RAE1 family ligands of the activatory natural killer (NK) cell receptor NKG2D, it inhibits presentation of antigenic peptides to CD8 T cells and the NKG2D-dependent activation of NK cells, respectively, thus simultaneously interfering with adaptive and innate immune recognition of infected cells. Although the m152 gene product exists in differentially glycosylated isoforms whose individual contributions to immune evasion are unknown, it has entered the scientific literature as m152/gp40, based on the quantitatively most prominent isoform but with no functional justification. By construction of a recombinant mCMV in which all three N-glycosylation sites are mutated (N61Q, N208Q, and N241Q), we show here that N-linked glycosylation is not essential for functional interaction of the m152 immune evasion protein with either MHC-I or RAE1. These data add an important functional detail to recent structural analysis of the m152/RAE1γ complex that has revealed N-glycosylations at positions Asn61 and Asn208 of m152 distant from the m152/RAE1γ interface.
antigen presentation; BAC mutagenesis; CD8 T cells; cytomegalovirus; viral immune evasion; natural killer (NK) cells; N-linked glycosylation
Related Articles
Viral Inhibition of the Transporter Associated with Antigen Processing (TAP): A Striking Example of Functional Convergent Evolution
Verweij, Marieke C.
Horst, Daniëlle
Griffin, Bryan D.
Luteijn, Rutger D.
Davison, Andrew J.
Ressing, Maaike E.
Wiertz, Emmanuel J. H. J.
PLoS Pathogens
Herpesviruses are large DNA viruses that are highly abundant within their host populations. Even in the presence of a healthy immune system, these viruses manage to cause lifelong infections. This persistence is partially mediated by the virus entering latency, a phase of infection characterized by limited viral protein expression. Moreover, herpesviruses have devoted a significant part of their coding capacity to immune evasion strategies. It is believed that the close coexistence of herpesviruses and their hosts has resulted in the evolution of viral proteins that specifically attack multiple arms of the host immune system. Cytotoxic T lymphocytes (CTLs) play an important role in antiviral immunity. CTLs recognize their target through viral peptides presented in the context of MHC molecules at the cell surface. Every herpesvirus studied to date encodes multiple immune evasion molecules that effectively interfere with specific steps of the MHC class I antigen presentation pathway. The transporter associated with antigen processing (TAP) plays a key role in the loading of viral peptides onto MHC class I molecules. This is reflected by the numerous ways herpesviruses have developed to block TAP function. In this review, we describe the characteristics and mechanisms of action of all known virus-encoded TAP inhibitors. Orthologs of these proteins encoded by related viruses are identified, and the conservation of TAP inhibition is discussed. A phylogenetic analysis of members of the family Herpesviridae is included to study the origin of these molecules. In addition, we discuss the characteristics of the first TAP inhibitor identified outside the herpesvirus family, namely, in cowpox virus. The strategies of TAP inhibition employed by viruses are very distinct and are likely to have been acquired independently during evolution. These findings and the recent discovery of a non-herpesvirus TAP inhibitor represent a striking example of functional convergent evolution.
Related Articles
The Viral KSHV Chemokine vMIP-II Inhibits the Migration of Naive and Activated Human NK Cells by Antagonizing Two Distinct Chemokine Receptors
Yamin, Rachel
Kaynan, Noa S.
Glasner, Ariella
Vitenshtein, Alon
Tsukerman, Pinchas
Bauman, Yoav
Ophir, Yael
Elias, Shlomo
Bar-On, Yotam
Gur, Chamutal
Mandelboim, Ofer
PLoS Pathogens
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 (CD56Dim CD16Pos) while the remaining 10% are CD16 negative and express CD56 in high levels (CD56Bright CD16Neg). 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 CD56Dim CD16Pos 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.
Author Summary
NK cells belong to the innate immune system, able to rapidly kill tumors and various pathogens. They reside in the blood and in various tissues and traffic to different infected organs through the usage of different chemokines and chemokine receptors. KSHV is a master of immune evasion, and around a quarter of the KSHV encoded genes are dedicated to interfere with immune cell recognition. Here, we investigate the role played by the KSHV derived cytokine and chemokines (vIL-6, vMIP-I, vMIP-II, vMIP-III) in modulating NK cell activity. We show that vMIP-II binds and inhibits the activity of two different receptors, CX3CR1 and CCR5, expressed by naïve NK cells and by activated NK cells, respectively. Thus, we demonstrate 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.
Related Articles
Epstein-Barr Virus Evades CD4+ T Cell Responses in Lytic Cycle through BZLF1-mediated Downregulation of CD74 and the Cooperation of vBcl-2
Zuo, Jianmin
Thomas, Wendy A.
Haigh, Tracey A.
Fitzsimmons, Leah
Long, Heather M.
Hislop, Andrew D.
Taylor, Graham S.
Rowe, Martin
PLoS Pathogens
Evasion of immune T cell responses is crucial for viruses to establish persistence in the infected host. Immune evasion mechanisms of Epstein-Barr virus (EBV) in the context of MHC-I antigen presentation have been well studied. In contrast, viral interference with MHC-II antigen presentation is less well understood, not only for EBV but also for other persistent viruses. Here we show that the EBV encoded BZLF1 can interfere with recognition by immune CD4+ effector T cells. This impaired T cell recognition occurred in the absence of a reduction in the expression of surface MHC-II, but correlated with a marked downregulation of surface CD74 on the target cells. Furthermore, impaired CD4+ T cell recognition was also observed with target cells where CD74 expression was downregulated by shRNA-mediated inhibition. BZLF1 downregulated surface CD74 via a post-transcriptional mechanism distinct from its previously reported effect on the CIITA promoter. In addition to being a chaperone for MHC-II αβ dimers, CD74 also functions as a surface receptor for macrophage Migration Inhibitory Factor and enhances cell survival through transcriptional upregulation of Bcl-2 family members. The immune-evasion function of BZLF1 therefore comes at a cost of induced toxicity. However, during EBV lytic cycle induced by BZLF1 expression, this toxicity can be overcome by expression of the vBcl-2, BHRF1, at an early stage of lytic infection. We conclude that by inhibiting apoptosis, the vBcl-2 not only maintains cell viability to allow sufficient time for synthesis and accumulation of infectious virus progeny, but also enables BZLF1 to effect its immune evasion function.
Author Summary
Epstein-Barr virus (EBV) is a herpesvirus and an important human pathogen that can cause diseases ranging from non-malignant proliferative disease to fully malignant cancers of lymphocytes and epithelial cells. The persistence of EBV in healthy individuals relies on the balance between host immune responses and viral immune evasion. As CD4+ immune T cell responses include both helper and cytotoxic functions, viral mechanisms for interfering with MHC class II antigen presentation to CD4+ T cells have the potential to greatly influence the outcome of viral infections. Our work on Epstein-Barr virus provides a new paradigm for viral immune evasion of MHC-II presented antigen by targeting CD74. CD74 is a dual function protein; it serves as a surviving receptor as well as a chaperone for MHC-II antigen presentation. Therefore, downregulation of CD74 as a T cell evasion strategy comes at the cost of potentially inducing cell death. However, EBV also encodes a vBcl-2 to attenuate the toxicity associated with reduced CD74, thus enabling the immune-impairment function to be effected. We expect that future studies will identify other viruses utilizing a similar strategy to evade CD4+ immune T cell responses.
Related Articles
Escape of HIV-1-Infected Dendritic Cells from TRAIL-Mediated NK Cell Cytotoxicity during NK-DC Cross-Talk—A Pivotal Role of HMGB1
Melki, Marie-Thérèse
Saïdi, Héla
Dufour, Alexandre
Olivo-Marin, Jean-Christophe
Gougeon, Marie-Lise
PLoS Pathogens
Early stages of Human Immunodeficiency Virus-1 (HIV-1) infection are associated with local recruitment and activation of important effectors of innate immunity, i.e. natural killer (NK) cells and dendritic cells (DCs). Immature DCs (iDCs) capture HIV-1 through specific receptors and can disseminate the infection to lymphoid tissues following their migration, which is associated to a maturation process. This process is dependent on NK cells, whose role is to keep in check the quality and the quantity of DCs undergoing maturation. If DC maturation is inappropriate, NK cells will kill them ("editing process") at sites of tissue inflammation, thus optimizing the adaptive immunity. In the context of a viral infection, NK-dependent killing of infected-DCs is a crucial event required for early elimination of infected target cells. Here, we report that NK-mediated editing of iDCs is impaired if DCs are infected with HIV-1. We first addressed the question of the mechanisms involved in iDC editing, and we show that cognate NK-iDC interaction triggers apoptosis via the TNF-related apoptosis-inducing ligand (TRAIL)-Death Receptor 4 (DR4) pathway and not via the perforin pathway. Nevertheless, once infected with HIV-1, DCHIV become resistant to NK-induced TRAIL-mediated apoptosis. This resistance occurs despite normal amounts of TRAIL released by NK cells and comparable DR4 expression on DCHIV. The escape of DCHIV from NK killing is due to the upregulation of two anti-apoptotic molecules, the cellular-Flice like inhibitory protein (c-FLIP) and the cellular inhibitor of apoptosis 2 (c-IAP2), induced by NK-DCHIV cognate interaction. High-mobility group box 1 (HMGB1), an alarmin and a key mediator of NK-DC cross-talk, was found to play a pivotal role in NK-dependent upregulation of c-FLIP and c-IAP2 in DCHIV. Finally, we demonstrate that restoration of DCHIV susceptibility to NK-induced TRAIL killing can be obtained either by silencing c-FLIP and c-IAP2 by specific siRNA, or by inhibiting HMGB1 with blocking antibodies or glycyrrhizin, arguing for a key role of HMGB1 in TRAIL resistance and DCHIV survival. These findings provide evidence for a new strategy developed by HIV to escape immune attack, they challenge the question of the involvement of HMGB1 in the establishment of viral reservoirs in DCs, and they identify potential therapeutic targets to eliminate infected DCs.
Author Summary
Dendritic cells (DCs), the professional antigen presenting cells, are critical for host immunity by inducing specific immune responses against a broad variety of pathogens. Human Immunodeficiency Virus-1 (HIV-1) has evolved ways to exploit DCs, thereby facilitating viral dissemination and allowing evasion of antiviral immunity. In particular, infected DCs may function as cellular reservoirs for HIV-1, thus contributing to viral persistence in lymphoid tissues. The mechanisms involved in the constitution of HIV reservoirs in DCs are poorly understood. In this study, we reveal that DCs infected with HIV-1 (DCHIV) become resistant to killing by natural killer (NK) cells, early effectors of innate immunity involved in the destruction of virus infected cells or cancer cells. This protection of DCHIV from NK cytotoxicity is induced through a cross-talk between NK cells and DCHIV, which induces the upregulation in DCHIV of two inhibitors of cell death, i.e. cellular-Flice like inhibitory protein (c-FLIP) and cellular inhibitor of apoptosis 2 (c-IAP2). The molecule responsible for the induction of these inhibitors is High-mobility group box 1 (HMGB1), an alarmin involved in the functional maturation of DCs. Blocking HMGB1 restores DCHIV susceptibility to NK cell killing, arguing for a key role of HMGB1 in the persistence of DCHIV. These findings provide evidence of the crucial role of NK-DC cross-talk in promoting viral persistence, and they identify potential therapeutic targets to eliminate infected DCs.
Related Articles
The EBV Immunoevasins vIL-10 and BNLF2a Protect Newly Infected B Cells from Immune Recognition and Elimination
Jochum, Simon
Moosmann, Andreas
Lang, Stephan
Hammerschmidt, Wolfgang
Zeidler, Reinhard
PLoS Pathogens
Lifelong persistence of Epstein-Barr virus (EBV) in infected hosts is mainly owed to the virus' pronounced abilities to evade immune responses of its human host. Active immune evasion mechanisms reduce the immunogenicity of infected cells and are known to be of major importance during lytic infection. The EBV genes BCRF1 and BNLF2a encode the viral homologue of IL-10 (vIL-10) and an inhibitor of the transporter associated with antigen processing (TAP), respectively. Both are known immunoevasins in EBV's lytic phase. Here we describe that BCRF1 and BNLF2a are functionally expressed instantly upon infection of primary B cells. Using EBV mutants deficient in BCRF1 and BNLF2a, we show that both factors contribute to evading EBV-specific immune responses during the earliest phase of infection. vIL-10 impairs NK cell mediated killing of infected B cells, interferes with CD4+ T-cell activity, and modulates cytokine responses, while BNLF2a reduces antigen presentation and recognition of newly infected cells by EBV-specific CD8+ T cells. Together, both factors significantly diminish the immunogenicity of EBV-infected cells during the initial, pre-latent phase of infection and may improve the establishment of a latent EBV infection in vivo.
Author Summary
Despite strong cellular and humoral immune responses, herpesviruses persist in their hosts for a lifetime. Epstein-Barr virus (EBV) is a herpesvirus that infects human B cells. This results in a latent infection where only a minimal set of viral proteins is expressed and infected cells cannot be eradicated by immune cells. When the virus reactivates in order to produce progeny, many viral proteins are expressed that are potential targets of immunity, but the virus coexpresses viral "immunoevasins" that blunt immune responses. Similarly, in the very first phase of B cell infection by EBV, called the pre-latent phase, a rather wide spectrum of antigens is expressed. However, it has been unknown whether viral immunoevasion occurs in this phase. Here we show that two viral immunoevasins are active in the pre-latent phase and prevent immune recognition by a variety of mechanisms: they reduce the presentation of EBV antigens to CD8+ killer T cells, prevent an attack by natural killer cells, and reduce the function of CD4+ helper T cells. Thus, it seems to be important for the virus to shield itself from attack by immune cells during the pre-latent stage.
Related Articles
Varicellovirus UL49.5 Proteins Differentially Affect the Function of the Transporter Associated with Antigen Processing, TAP
Koppers-Lalic, Danijela
Verweij, Marieke C.
Lipińska, Andrea D.
Wang, Ying
Quinten, Edwin
Reits, Eric A.
Koch, Joachim
Loch, Sandra
Rezende, Marisa Marcondes
Daus, Franz
Bieńkowska-Szewczyk, Krystyna
Osterrieder, Nikolaus
Mettenleiter, Thomas C.
Heemskerk, Mirjam H. M.
Tampé, Robert
Neefjes, Jacques J.
Chowdhury, Shafiqul I.
Ressing, Maaike E.
Rijsewijk, Frans A. M.
Wiertz, Emmanuel J. H. J.
PLoS Pathogens
Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.
Author Summary
Herpesviruses have the conspicuous property that they persist for life in the infected host. This is also the case for varicelloviruses, a large subfamily of herpesviruses with representatives in humans (varicella zoster virus or VZV), cattle (bovine herpesvirus 1 or BHV-1), pigs (pseudorabies virus or PRV), and horses (equine herpesvirus or EHV type 1 and 4), among many others. Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in this process, as TAP imports peptides into the compartment where peptide loading of the MHC class I molecules takes place. In this study, we show that the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 all block the supply of peptides through the inhibition of TAP, but that the mechanisms employed by these proteins to inhibit TAP function exhibit surprising diversity. VZV UL49.5, on the other hand, binds to TAP, but does not interfere with peptide transport. Our study classifies the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.
Related Articles
A Role for Host Activation-Induced Cytidine Deaminase in Innate Immune Defense against KSHV
Bekerman, Elena
Jeon, Diana
Ardolino, Michele
Coscoy, Laurent
PLoS Pathogens
Activation-induced cytidine deaminase (AID) is specifically induced in germinal center B cells to carry out somatic hypermutation and class-switch recombination, two processes responsible for antibody diversification. Because of its mutagenic potential, AID expression and activity are tightly regulated to minimize unwanted DNA damage. Surprisingly, AID expression has been observed ectopically during pathogenic infections. However, the function of AID outside of the germinal centers remains largely uncharacterized. In this study, we demonstrate that infection of human primary naïve B cells with Kaposi's sarcoma-associated herpesvirus (KSHV) rapidly induces AID expression in a cell intrinsic manner. We find that infected cells are marked for elimination by Natural Killer cells through upregulation of NKG2D ligands via the DNA damage pathway, a pathway triggered by AID. Moreover, without having a measurable effect on KSHV latency, AID impinges directly on the viral fitness by inhibiting lytic reactivation and reducing infectivity of KSHV virions. Importantly, we uncover two KSHV-encoded microRNAs that directly regulate AID abundance, further reinforcing the role for AID in the antiviral response. Together our findings reveal additional functions for AID in innate immune defense against KSHV with implications for a broader involvement in innate immunity to other pathogens.
Author Summary
Immune responses to pathogens rely heavily on the ability of B cells to generate a unique set of antibodies that can bind and eliminate the pathogen. Activation-induced cytidine deaminase (AID) is the enzyme specifically upregulated in activated B cells to diversify the antibody repertoire by introducing mutations within the antibody coding genes. Curiously, AID expression has been observed outside of activated B cells upon infection with a number of viral and bacterial pathogens. However, in such cases AID function is poorly characterized and often deemed inappropriate since its mutagenic activity can put the cell at risk for oncogenic transformation. In this study, we investigate the expression of AID in response to infection with an oncogenic human pathogen Kaposi's sarcoma-associated herpesvirus (KSHV) and the antibody-independent immune defense it exerts. We show that AID marks infected cells for elimination by natural killer (NK) cells and directly impinges on viral fitness. Furthermore, we uncover novel viral immune evasion strategies employed by KSHV to counteract AID. Together, our findings demonstrate a protective role for AID in the response to infection with an oncogenic virus such as KSHV and suggest that AID may actually limit transformation rather than serve as its culprit.
Related Articles
Human Cytomegalovirus UL18 Utilizes US6 for Evading the NK and T-Cell Responses
Kim, Youngkyun
Park, Boyoun
Cho, Sunglim
Shin, Jinwook
Cho, Kwangmin
Jun, Youngsoo
Ahn, Kwangseog
PLoS Pathogens
Human cytomegalovirus (HCMV) US6 glycoprotein inhibits TAP function, resulting in down-regulation of MHC class I molecules at the cell surface. Cells lacking MHC class I molecules are susceptible to NK cell lysis. HCMV expresses UL18, a MHC class I homolog that functions as a surrogate to prevent host cell lysis. Despite a high level of sequence and structural homology between UL18 and MHC class I molecules, surface expression of MHC class I, but not UL18, is down regulated by US6. Here, we describe a mechanism of action by which HCMV UL18 avoids attack by the self-derived TAP inhibitor US6. UL18 abrogates US6 inhibition of ATP binding by TAP and, thereby, restores TAP-mediated peptide translocation. In addition, UL18 together with US6 interferes with the physical association between MHC class I molecules and TAP that is required for optimal peptide loading. Thus, regardless of the recovery of TAP function, surface expression of MHC class I molecules remains decreased. UL18 represents a unique immune evasion protein that has evolved to evade both the NK and the T cell immune responses.
Author Summary
HCMV establishes a lifelong latent infection and causes serious disease in immunocompromised individuals. Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are the primary effectors for the immune defense against HCMV. However, HCMV has evolved to evade both the innate and adaptive cellular immunity to viral infection. HCMV US6 glycoprotein inhibits TAP function, resulting in down-regulation of MHC class I, while HCMV UL18 is an MHC class I homolog that functions as a surrogate to prevent host cell lysis. Despite significant sequence and structural homology between UL18 and MHC class I molecules, US6 down regulates surface expression of MHC class I, but not UL18. Here, we describe a mechanism by which UL18 circumvents the self-derived TAP inhibitor, US6. UL18 abrogates US6 inhibition of TAP-ATP binding and restores TAP-mediated peptide translocation, thereby making peptides available for the assembly and subsequent surface expression of UL18. Together UL18 and US6 inhibit binding of MHC class I to TAP, thus down regulating surface expression of MHC class I molecules. UL18 represents a unique immune evasion protein resistant to both the NK and T cell immune responses. Our data provide a molecular basis for persistent HCMV infection and will aid in the development of a therapeutic vaccine.
Related Articles
Two Novel Human Cytomegalovirus NK Cell Evasion Functions Target MICA for Lysosomal Degradation
Fielding, Ceri A.
Aicheler, Rebecca
Stanton, Richard J.
Wang, Eddie C. Y.
Han, Song
Seirafian, Sepehr
Davies, James
McSharry, Brian P.
Weekes, Michael P.
Antrobus, P. Robin
Prod'homme, Virginie
Blanchet, Fabien P.
Sugrue, Daniel
Cuff, Simone
Roberts, Dawn
Davison, Andrew J.
Lehner, Paul J.
Wilkinson, Gavin W. G.
Tomasec, Peter
PLoS Pathogens
NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an 'accordion' expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family.
Author Summary
Human cytomegalovirus (HCMV) is a herpesvirus that infects most people in the world, usually without producing symptoms. However, infection is life-long and must be kept in check by the immune system. When the immune system is weakened, the outcome of HCMV infection can be very serious. Thus, HCMV is the major cause of birth defects resulting from infection of the fetus during pregnancy, and it can cause severe disease in people with a weakened immune system, especially transplant recipients and HIV/AIDS patients. One type of immune cell, the natural killer (NK) cell, is crucial in controlling cells in the body that are abnormal. They do this by recognizing cells, which have special stress proteins on their surface, and killing them. When cells are infected with HCMV, they start to make these stress proteins. However, the virus has evolved ways to stop NK cells from killing infected cells by quickly stopping the stress proteins from reaching the surface. We have now identified two HCMV genes that target a major stress protein (called MICA) and cause its rapid destruction. Removing these two genes from HCMV renders infected cells very susceptible to killing by NK cells. This discovery might help the development of new ways to fight HCMV.
Related Articles
Mechanisms of virus immune evasion lead to development from chronic inflammation to cancer formation associated with human papillomavirus infection
Senba, Masachika
Mori, Naoki
Oncology Reviews
Human papillomavirus (HPV) has developed strategies to escape eradication by innate and adaptive immunity. Immune response evasion has been considered an important aspect of HPV persistence, which is the main contributing factor leading to HPV-related cancers. HPV-induced cancers expressing viral oncogenes E6 and E7 are potentially recognized by the immune system. The major histocompatibility complex (MHC) class I molecules are patrolled by natural killer cells and CD8+ cytotoxic T lymphocytes, respectively. This system of recognition is a main target for the strategies of immune evasion deployed by viruses. The viral immune evasion proteins constitute useful tools to block defined stages of the MHC class I presentation pathway, and in this way HPV avoids the host immune response. The long latency period from initial infection to persistence signifies that HPV evolves mechanisms to escape the immune response. It has now been established that there are oncogenic mechanisms by which E7 binds to and degrades tumor suppressor Rb, while E6 binds to and inactivates tumor suppressor p53. Therefore, interaction of p53 and pRb proteins can give rise to an increased immortalization and genomic instability. Overexpression of NF-κB in cervical and penile cancers suggests that NF-κB activation is a key modulator in driving chronic inflammation to cancer. HPV oncogene-mediated suppression of NF-κB activity contributes to HPV escape from the immune system. This review focuses on the diverse mechanisms of the virus immune evasion with HPV that leads to chronic inflammation and cancer.
human papillomavirus; immune evasion; cervical cancer; penile cancer.
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The Switch from Latent to Productive Infection in Epstein-Barr Virus-Infected B Cells Is Associated with Sensitization to NK Cell Killing▿
Pappworth, Isabel Y.
Wang, Eddie C.
Rowe, Martin
Journal of Virology
Following activation of Epstein-Barr virus (EBV)-infected B cells from latent to productive (lytic) infection, there is a concomitant reduction in the level of cell surface major histocompatibility complex (MHC) class I molecules and an impaired antigen-presenting function that may facilitate evasion from EBV-specific CD8+ cytotoxic T cells. In some other herpesviruses studied, most notably human cytomegalovirus (HCMV), evasion of virus-specific CD8+ effector responses via downregulation of surface MHC class I molecules is supplemented with specific mechanisms for evading NK cells. We now report that EBV differs from HCMV in this respect. While latently infected EBV-positive B cells were resistant to lysis by two NK lines and by primary polyclonal NK cells from peripheral blood, these effectors efficiently killed cells activated into the lytic cycle. Susceptibility to NK lysis coincided not only with downregulation of HLA-A, -B, and -C molecules that bind to the KIR family of inhibitory receptors on NK cells but also with downregulation of HLA-E molecules binding the CD94/NKG2A inhibitory receptors. Conversely, ULBP-1 and CD112, ligands for the NK cell-activating receptors NKG2D and DNAM-1, respectively, were elevated. Susceptibility of the virus-producing target cells to NK cell lysis was partially reversed by blocking ULBP-1 or CD112 with specific antibodies. These results highlight a fundamental difference between EBV and HCMV with regards to evasion of innate immunity.
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Quantitative Membrane Proteomics Reveals New Cellular Targets of Viral Immune Modulators
Bartee, Eric
McCormack, Ashley
Früh, Klaus
PLoS Pathogens
Immunomodulators of pathogens frequently affect multiple cellular targets, thus preventing recognition by different immune cells. For instance, the K5 modulator of immune recognition (MIR2) from Kaposi sarcoma–associated herpesvirus prevents activation of cytotoxic T cells, natural killer cells, and natural killer T cells by downregulating major histocompatibility complex (MHC) class I molecules, the MHC-like molecule CD1, the cell adhesion molecules ICAM-1 and PECAM, and the co-stimulatory molecule B7.2. K5 belongs to a family of viral- and cellular-membrane-spanning RING ubiquitin ligases. While a limited number of transmembrane proteins have been shown to be targeted for degradation by this family, it is unknown whether additional targets exist. We now describe a quantitative proteomics approach to identify novel targets of this protein family. Using stable isotope labeling by amino acids, we compared the proteome of plasma, Golgi, and endoplasmic reticulum membranes in the presence and absence of K5. Mass spectrometric protein identification revealed four proteins that were consistently underrepresented in the plasma membrane of K5 expression cells: MHC I (as expected), bone marrow stromal antigen 2 (BST-2, CD316), activated leukocyte cell adhesion molecule (ALCAM, CD166) and Syntaxin-4. Downregulation of each of these proteins was independently confirmed by immunoblotting with specific antibodies. We further demonstrate that ALCAM is a bona fide target of both K5 and the myxomavirus homolog M153R. Upon exiting the endoplasmic reticulum, ALCAM is ubiquitinated in the presence of wild-type, but not RING-deficient or acidic motif–deficient, K5, and is targeted for lysosomal degradation via the multivesicular body pathway. Since ALCAM is the ligand for CD6, a member of the immunological synapse of T cells, its removal by viral immune modulators implies a role for CD6 in the recognition of pathogens by T cells. The unbiased global proteome analysis therefore revealed novel immunomodulatory functions of pathogen proteins.
Viral immune modulators often target multiple cellular proteins for destruction. Presumably, this strategy enables viral pathogens to optimize evasion of multiple immune responses. To systematically identify such host cell targets in an unbiased fashion, Bartee et al. applied recently developed quantitative proteomics methods to identify novel targets for K5. K5 belongs to a family of viral ubiquitin ligases found in gamma-herpesviruses and poxviruses that target multiple cellular transmembrane proteins for destruction. Using stable isotope labeling combined with tandem mass spectrometry, the authors compared the abundance of proteins in membrane preparations from cells that expressed K5 to that in cells without K5. In their experiments, three novel membrane proteins (BST-2, Syntaxin-4, and ALCAM) were consistently found in lower abundance in K5-expressing cells. Importantly, the authors were able to confirm the K5-dependent downregulation of all of these proteins in independent experiments and by independent methods. ALCAM was chosen for a more in-depth analysis to firmly demonstrate that this protein is downregulated by K5 in a manner similar to other known targets. This proof-of-principle study demonstrates that novel targets of viral immune modulators can be identified with quantitative proteomics.
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Tim-3: An Activation Marker and Activation Limiter of Innate Immune Cells
Han, Gencheng
Chen, Guojiang
Shen, Beifen
Li, Yan
Frontiers in Immunology
Tim-3 was initially identified on activated Th1, Th17, and Tc1 cells and induces T cell death or exhaustion after binding to its ligand, Gal-9. The observed relationship between dysregulated Tim-3 expression on T cells and the progression of many clinical diseases has identified this molecule as an important target for intervention in adaptive immunity. Recent data have shown that it also plays critical roles in regulating the activities of macrophages, monocytes, dendritic cells, mast cells, natural killer cells, and endothelial cells. Although the underlying mechanisms remain unclear, dysregulation of Tim-3 expression on these innate immune cells leads to an excessive or inhibited inflammatory response and subsequent autoimmune damage or viral or tumor evasion. In this review, we focus on the expression and function of Tim-3 on innate immune cells and discuss (1) how Tim-3 is expressed and regulated on different innate immune cells; (2) how it affects the activity of different innate immune cells; and (3) how dysregulated Tim-3 expression on innate immune cells affects adaptive immunity and disease progression. Tim-3 is involved in the optimal activation of innate immune cells through its varied expression. A better understanding of the physiopathological role of the Tim-3 pathway in innate immunity will shed new light on the pathogenesis of clinical diseases, such as autoimmune diseases, chronic viral infections, and cancer, and suggest new approaches to intervention.
TIM-3; innate immunity; negative regulation; tolerance; homeostasis
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Quantitative Temporal Viromics: An Approach to Investigate Host-Pathogen Interaction
Weekes, Michael P.
Tomasec, Peter
Huttlin, Edward L.
Fielding, Ceri A.
Nusinow, David
Stanton, Richard J.
Wang, Eddie C.Y.
Aicheler, Rebecca
Murrell, Isa
Wilkinson, Gavin W.G.
Lehner, Paul J.
Gygi, Steven P.
A systematic quantitative analysis of temporal changes in host and viral proteins throughout the course of a productive infection could provide dynamic insights into virus-host interaction. We developed a proteomic technique called "quantitative temporal viromics" (QTV), which employs multiplexed tandem-mass-tag-based mass spectrometry. Human cytomegalovirus (HCMV) is not only an important pathogen but a paradigm of viral immune evasion. QTV detailed how HCMV orchestrates the expression of >8,000 cellular proteins, including 1,200 cell-surface proteins to manipulate signaling pathways and counterintrinsic, innate, and adaptive immune defenses. QTV predicted natural killer and T cell ligands, as well as 29 viral proteins present at the cell surface, potential therapeutic targets. Temporal profiles of >80% of HCMV canonical genes and 14 noncanonical HCMV open reading frames were defined. QTV is a powerful method that can yield important insights into viral infection and is applicable to any virus with a robust in vitro model.
Graphical Abstract
•>8,000 proteins quantified over eight time points, including 1,200 cell-surface proteins•Temporal profiles of 139/171 canonical HCMV proteins and 14 noncanonical HCMV ORFs•Multiple families of cell-surface receptors selectively modulated by HCMV•Multiple signaling pathways modulated during HCMV infection
The application of multiplexed tandem-mass-tag-based mass spectrometry to analyze temporal changes in the expression of host and viral proteins during infection reveals insights into viral pathogenesis and host immune responses.
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Pseudomonas Evades Immune Recognition of Flagellin in Both Mammals and Plants
Bardoel, Bart W.
van der Ent, Sjoerd
Pel, Michiel J. C.
Tommassen, Jan
Pieterse, Corné M. J.
van Kessel, Kok P. M.
van Strijp, Jos A. G.
PLoS Pathogens
The building blocks of bacterial flagella, flagellin monomers, are potent stimulators of host innate immune systems. Recognition of flagellin monomers occurs by flagellin-specific pattern-recognition receptors, such as Toll-like receptor 5 (TLR5) in mammals and flagellin-sensitive 2 (FLS2) in plants. Activation of these immune systems via flagellin leads eventually to elimination of the bacterium from the host. In order to prevent immune activation and thus favor survival in the host, bacteria secrete many proteins that hamper such recognition. In our search for Toll like receptor (TLR) antagonists, we screened bacterial supernatants and identified alkaline protease (AprA) of Pseudomonas aeruginosa as a TLR5 signaling inhibitor as evidenced by a marked reduction in IL-8 production and NF-κB activation. AprA effectively degrades the TLR5 ligand monomeric flagellin, while polymeric flagellin (involved in bacterial motility) and TLR5 itself resist degradation. The natural occurring alkaline protease inhibitor AprI of P. aeruginosa blocked flagellin degradation by AprA. P. aeruginosa aprA mutants induced an over 100-fold enhanced activation of TLR5 signaling, because they fail to degrade excess monomeric flagellin in their environment. Interestingly, AprA also prevents flagellin-mediated immune responses (such as growth inhibition and callose deposition) in Arabidopsis thaliana plants. This was due to decreased activation of the receptor FLS2 and clearly demonstrated by delayed stomatal closure with live bacteria in plants. Thus, by degrading the ligand for TLR5 and FLS2, P. aeruginosa escapes recognition by the innate immune systems of both mammals and plants.
Author Summary
Pseudomonas aeruginosa is a common environmental bacterium that can infect and cause disease in a wide variety of hosts, ranging from humans to plants. In healthy individuals, the innate immune system can counteract this microorganism effectively; however immunocompromised patients and cystic fibrosis patients suffer from severe infections with this bacterium. P. aeruginosa can propel itself through tissue by rotation of its long tail, called the flagellum, which is essential to establish colonization and infection of the host. The building blocks of the bacterial flagellum are over a thousand copies of the highly conserved protein flagellin. Mammals and plants have developed recognition systems to detect many different bacteria by sensing flagellin via Toll-like receptor 5 and Flagellin-sensitive 2, respectively. Bacteria actively try to interfere with this recognition (immune evasion). In this study, we describe a novel mechanism of P. aeruginosa to escape flagellin recognition. The secreted protein alkaline protease of P. aeruginosa, degrades immunity activating free flagellin. Bacterial motility is maintained, because flagellin present as building block of flagella is not degraded. In this way, the bacterium impairs recognition and hides itself from destruction by the immune system. Understanding these immune evasion strategies is of extreme importance for the development of new therapeutic approaches.
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Natural history of murine gamma-herpesvirus infection.
Nash, A A
Dutia, B M
Stewart, J P
Davison, A J
Philosophical Transactions of the Royal Society of London. Series B
Murine gamma-herpesvirus 68 (MHV-68) is a natural pathogen of small rodents and insectivores (mice, voles and shrews). The primary infection is characterized by virus replication in lung epithelial cells and the establishment of a latent infection in B lymphocytes. The virus is also observed to persist in lung epithelial cells, dendritic cells and macrophages. Splenomegaly is observed two weeks after infection, in which there is a CD4+ T-cell-mediated expansion of B and T cells in the spleen. At three weeks post-infection an infectious mononucleosis-like syndrome is observed involving a major expansion of Vbeta4+CD8+ T cells. Later in the course of persistent infection, ca. 10% of mice develop lymphoproliferative disease characterized as lymphomas of B-cell origin. The genome from MHV-68 strain g2.4 has been sequenced and contains ca. 73 genes, the majority of which are collinear and homologous to other gamma-herpesviruses. The genome includes cellular homologues for a complement-regulatory protein, Bcl-2, cyclin D and interleukin-8 receptor and a set of novel genes M1 to M4. The function of these genes in the context of latent infections, evasion of immune responses and virus-mediated pathologies is discussed. Both innate and adaptive immune responses play an active role in limiting virus infection. The absence of type I interferon (IFN) results in a lethal MHV-68 infection, emphasizing the central role of these cytokines at the initial stages of infection. In contrast, type II IFN is not essential for the recovery from infection in the lung, but a failure of type II IFN receptor signalling results in the atrophy of lymphoid tissue associated with virus persistence. Splenic atrophy appears to be the result of immunopathology, since in the absence of CD8+ T cells no pathology occurs. CD8+ T cells play a major role in recovery from the primary infection, and also in regulating latently infected cells expressing the M2 gene product. CD4+ T cells have a key role in surveillance against virus recurrences in the lung, in part mediated through 'help' in the genesis of neutralizing antibodies. In the absence of CD4+ T cells, virus-specific CD8+ T cells are able to control the primary infection in the respiratory tract, yet surprisingly the memory CD8+ T cells generated are unable to inhibit virus recurrences in the lung. This could be explained in part by the observations that this virus can downregulate major histocompatibility complex class I expression and also restrict inflammatory cell responses by producing a chemokine-binding protein (M3 gene product). MHV-68 provides an excellent model to explore methods for controlling gamma-herpesvirus infection through vaccination and chemotherapy. Vaccination with gp150 (a homologue of gp350 of Epstein-Barr virus) results in a reduction in splenomegaly and virus latency but does not block replication in the lung, nor the establishment of a latent infection. Even when lung virus infection is greatly reduced following the action of CD8+ T cells, induced via a prime-boost vaccination strategy, a latent infection is established. Potent antiviral compounds such as the nucleoside analogue 2'deoxy-5-ethyl-beta-4'-thiouridine, which disrupts virus replication in vivo, cannot inhibit the establishment of a latent infection. Clearly, devising strategies to interrupt the establishment of latent virus infections may well prove impossible with existing methods.
Related Articles
Viral Infection: An Evolving Insight into the Signal Transduction Pathways Responsible for the Innate Immune Response
Kotwal, Girish J.
Hatch, Steven
Marshall, William L.
Advances in Virology
The innate immune response is initiated by the interaction of stereotypical pathogen components with genetically conserved receptors for extracytosolic pathogen-associated molecular patterns (PAMPs) or intracytosolic nucleic acids. In multicellular organisms, this interaction typically clusters signal transduction molecules and leads to their activations, thereby initiating signals that activate innate immune effector mechanisms to protect the host. In some cases programmed cell death—a fundamental form of innate immunity—is initiated in response to genotoxic or biochemical stress that is associated with viral infection. In this paper we will summarize innate immune mechanisms that are relevant to viral pathogenesis and outline the continuing evolution of viral mechanisms that suppress the innate immunity in mammalian hosts. These mechanisms of viral innate immune evasion provide significant insight into the pathways of the antiviral innate immune response of many organisms. Examples of relevant mammalian innate immune defenses host defenses include signaling to interferon and cytokine response pathways as well as signaling to the inflammasome. Understanding which viral innate immune evasion mechanisms are linked to pathogenesis may translate into therapies and vaccines that are truly effective in eliminating the morbidity and mortality associated with viral infections in individuals.
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Effect of NKG2D ligand expression on host immune responses
Champsaur, Marine
Lanier, Lewis L.
Immunological reviews
NKG2D (natural-killer group 2, member D) is an activating receptor present on the surface of natural killer (NK) cells, some NKT cells, CD8+ cytotoxic T cells, γδ T cells, and under certain conditions CD4+ T cells. Present in both humans and mice, this highly conserved receptor binds to a surprisingly diverse family of ligands that are distant relatives of MHC-class-I molecules. There is increasing evidence that ligand expression can result in both immune activation (tumor clearance, viral immunity, autoimmunity, and transplantation) and immune silencing (tumor evasion). In this review, we describe this family of NKG2D ligands and the various mechanisms that control their expression in stressed and normal cells. We also discuss the host response to both membrane-bound and secreted NKG2D ligands and summarize the models proposed to explain the consequences of this differential expression.
natural killer cell; NKG2D; NK cells; MIC; cytotoxicity; cancer; soluble ligands
Related Articles
Stage-Specific Inhibition of MHC Class I Presentation by the Epstein-Barr Virus BNLF2a Protein during Virus Lytic Cycle
Croft, Nathan P.
Shannon-Lowe, Claire
Bell, Andrew I.
Horst, Daniëlle
Kremmer, Elisabeth
Ressing, Maaike E.
Wiertz, Emmanuel J. H. J.
Middeldorp, Jaap M.
Rowe, Martin
Rickinson, Alan B.
Hislop, Andrew D.
PLoS Pathogens
The gamma-herpesvirus Epstein-Barr virus (EBV) persists for life in infected individuals despite the presence of a strong immune response. During the lytic cycle of EBV many viral proteins are expressed, potentially allowing virally infected cells to be recognized and eliminated by CD8+ T cells. We have recently identified an immune evasion protein encoded by EBV, BNLF2a, which is expressed in early phase lytic replication and inhibits peptide- and ATP-binding functions of the transporter associated with antigen processing. Ectopic expression of BNLF2a causes decreased surface MHC class I expression and inhibits the presentation of indicator antigens to CD8+ T cells. Here we sought to examine the influence of BNLF2a when expressed naturally during EBV lytic replication. We generated a BNLF2a-deleted recombinant EBV (ΔBNLF2a) and compared the ability of ΔBNLF2a and wild-type EBV-transformed B cell lines to be recognized by CD8+ T cell clones specific for EBV-encoded immediate early, early and late lytic antigens. Epitopes derived from immediate early and early expressed proteins were better recognized when presented by ΔBNLF2a transformed cells compared to wild-type virus transformants. However, recognition of late antigens by CD8+ T cells remained equally poor when presented by both wild-type and ΔBNLF2a cell targets. Analysis of BNLF2a and target protein expression kinetics showed that although BNLF2a is expressed during early phase replication, it is expressed at a time when there is an upregulation of immediate early proteins and initiation of early protein synthesis. Interestingly, BNLF2a protein expression was found to be lost by late lytic cycle yet ΔBNLF2a-transformed cells in late stage replication downregulated surface MHC class I to a similar extent as wild-type EBV-transformed cells. These data show that BNLF2a-mediated expression is stage-specific, affecting presentation of immediate early and early proteins, and that other evasion mechanisms operate later in the lytic cycle.
Author Summary
Epstein-Barr virus (EBV) is carried by approximately 90% of the world's population, where it persists and is chronically shed despite a vigorous specific immune response, a key component of which are CD8+ T cells that recognize and kill infected cells. The mechanisms the virus uses to evade these responses are not clear. Recently we identified a gene encoded by EBV, BNLF2a, that when expressed ectopically in cells inhibited their recognition by CD8+ T cells. To determine the contribution of BNLF2a to evasion of EBV-specific CD8+ T cell recognition and whether EBV encoded additional immune evasion mechanisms, a recombinant EBV was constructed in which BNLF2a was deleted. We found that cells infected with the recombinant virus were better recognized by CD8+ T cells specific for targets expressed co-incidently with BNLF2a, compared to cells infected with a non-recombinant virus. However, proteins expressed at late stages of the viral infection cycle were poorly recognised by CD8+ T cells, suggesting EBV encodes additional immune evasion genes to prevent effective CD8+ T cell recognition. This study highlights the stage-specific nature of viral immune evasion mechanisms.
Related Articles
Staphylococcus epidermidis Strategies to Avoid Killing by Human Neutrophils
Cheung, Gordon Y. C.
Rigby, Kevin
Wang, Rong
Queck, Shu Y.
Braughton, Kevin R.
Whitney, Adeline R.
Teintze, Martin
DeLeo, Frank R.
Otto, Michael
PLoS Pathogens
Staphylococcus epidermidis is a leading nosocomial pathogen. In contrast to its more aggressive relative S. aureus, it causes chronic rather than acute infections. In highly virulent S. aureus, phenol-soluble modulins (PSMs) contribute significantly to immune evasion and aggressive virulence by their strong ability to lyse human neutrophils. Members of the PSM family are also produced by S. epidermidis, but their role in immune evasion is not known. Notably, strong cytolytic capacity of S. epidermidis PSMs would be at odds with the notion that S. epidermidis is a less aggressive pathogen than S. aureus, prompting us to examine the biological activities of S. epidermidis PSMs. Surprisingly, we found that S. epidermidis has the capacity to produce PSMδ, a potent leukocyte toxin, representing the first potent cytolysin to be identified in that pathogen. However, production of strongly cytolytic PSMs was low in S. epidermidis, explaining its low cytolytic potency. Interestingly, the different approaches of S. epidermidis and S. aureus to causing human disease are thus reflected by the adaptation of biological activities within one family of virulence determinants, the PSMs. Nevertheless, S. epidermidis has the capacity to evade neutrophil killing, a phenomenon we found is partly mediated by resistance mechanisms to antimicrobial peptides (AMPs), including the protease SepA, which degrades AMPs, and the AMP sensor/resistance regulator, Aps (GraRS). These findings establish a significant function of SepA and Aps in S. epidermidis immune evasion and explain in part why S. epidermidis may evade elimination by innate host defense despite the lack of cytolytic toxin expression. Our study shows that the strategy of S. epidermidis to evade elimination by human neutrophils is characterized by a passive defense approach and provides molecular evidence to support the notion that S. epidermidis is a less aggressive pathogen than S. aureus.
Author Summary
Staphylococcus epidermidis frequently causes chronic infections, indicating pronounced capacity to evade host defenses. However, S. epidermidis is in general much less aggressive than its close relative, S. aureus. Here we identify molecular underpinnings of that discrepancy by showing that S. epidermidis immune evasion mechanisms are limited to those involving molecules that protect against or eliminate antimicrobial agents secreted by white blood cells, while immune evasion mechanisms of virulent S. aureus include the production of destructive toxins. This is especially noteworthy, because we demonstrate here for the first time that S. epidermidis has the capacity to produce a toxin with great potential to destroy white blood cells, but keeps its production at a very limited level. Thus, our study shows that two closely related human pathogens have adapted specific molecular mechanisms to evade host defenses, reflecting the unique approach used by each to cause human disease.
Related Articles
Identification of DNA-Damage DNA-Binding Protein 1 as a Conditional Essential Factor for Cytomegalovirus Replication in Interferon-γ-Stimulated Cells
Trilling, Mirko
Le, Vu Thuy Khanh
Fiedler, Manuela
Zimmermann, Albert
Bleifuß, Elke
Hengel, Hartmut
PLoS Pathogens
The mouse cytomegaloviral (MCMV) protein pM27 represents an indispensable factor for viral fitness in vivo selectively, antagonizing signal transducer and activator of transcription 2 (STAT2)-mediated interferon signal transduction. We wished to explore by which molecular mechanism pM27 accomplishes this effect. We demonstrate that pM27 is essential and sufficient to curtail the protein half-life of STAT2 molecules. Pharmacologic inhibition of the proteasome restored STAT2 amounts, leading to poly-ubiquitin-conjugated STAT2 forms. PM27 was found in complexes with an essential host ubiquitin ligase complex adaptor protein, DNA-damage DNA-binding protein (DDB) 1. Truncation mutants of pM27 showed a strict correlation between DDB1 interaction and their ability to degrade STAT2. SiRNA-mediated knock-down of DDB1 restored STAT2 in the presence of pM27 and strongly impaired viral replication in interferon conditioned cells, thus phenocopying the growth attenuation of M27-deficient virus. In a constructive process, pM27 recruits DDB1 to exploit ubiquitin ligase complexes catalyzing the obstruction of the STAT2-dependent antiviral state of cells to permit viral replication.
Author Summary
Cytomegaloviruses are strictly species-specific. Mouse cytomegalovirus (MCMV) is a prototypical β-herpesvirus, infecting Mus musculus as natural host and is closely related to the human pathogenic cytomegalovirus (HCMV, HHV-5) which both establish lifelong infection. Thus, MCMV infection constitutes an important model for HCMV pathogenesis. Cytomegaloviral evasion from innate immunity has been observed in many respects, but the molecular mechanisms of most viral factors are still elusive. We recently identified the MCMV-encoded protein pM27 to be required for efficient viral replication in the presence of interferons in vitro and to be essential in vivo. We identified STAT2, a mediator of interferon signalling, as target of pM27. Here we identify the cellular machinery exploited by pM27 to reduce the STAT2 protein half-life. PM27 was sufficient to induce poly-ubiquitination of STAT2, tagging it for proteasomal degradation. Since pM27 lacks domains found within ubiquitin-ligases, we conducted a search for cellular co-factors. We found DDB1, an essential cellular ubiquitin-ligase complex adaptor protein, to associate with pM27. Ablation of DDB1 increased viral susceptibility towards interferon, phenocopying the attenuation of ΔM27-MCMV. This defines DDB1 as conditional essential host factor of CMV replication. Our findings exemplify how cytomegaloviruses exploit an essential host protein to circumvent innate immunity.
Related Articles
Enterovirus 71 Protease 2Apro Targets MAVS to Inhibit Anti-Viral Type I Interferon Responses
Wang, Bei
Xi, Xueyan
Lei, Xiaobo
Zhang, Xiaoyan
Cui, Sheng
Wang, Jianwei
Jin, Qi
Zhao, Zhendong
PLoS Pathogens
Enterovirus 71 (EV71) is the major causative pathogen of hand, foot, and mouth disease (HFMD). Its pathogenicity is not fully understood, but innate immune evasion is likely a key factor. Strategies to circumvent the initiation and effector phases of anti-viral innate immunity are well known; less well known is whether EV71 evades the signal transduction phase regulated by a sophisticated interplay of cellular and viral proteins. Here, we show that EV71 inhibits anti-viral type I interferon (IFN) responses by targeting the mitochondrial anti-viral signaling (MAVS) protein—a unique adaptor molecule activated upon retinoic acid induced gene-I (RIG-I) and melanoma differentiation associated gene (MDA-5) viral recognition receptor signaling—upstream of type I interferon production. MAVS was cleaved and released from mitochondria during EV71 infection. An in vitro cleavage assay demonstrated that the viral 2A protease (2Apro), but not the mutant 2Apro (2Apro-110) containing an inactivated catalytic site, cleaved MAVS. The Protease-Glo assay revealed that MAVS was cleaved at 3 residues between the proline-rich and transmembrane domains, and the resulting fragmentation effectively inactivated downstream signaling. In addition to MAVS cleavage, we found that EV71 infection also induced morphologic and functional changes to the mitochondria. The EV71 structural protein VP1 was detected on purified mitochondria, suggesting not only a novel role for mitochondria in the EV71 replication cycle but also an explanation of how EV71-derived 2Apro could approach MAVS. Taken together, our findings reveal a novel strategy employed by EV71 to escape host anti-viral innate immunity that complements the known EV71-mediated immune-evasion mechanisms.
Author Summary
Enterovirus 71 (EV71) is the causative pathogen of hand, foot, and mouth disease (HFMD). Since the 2008 outbreak of HFMD in Fuyang, Anhui province, China, HFMD has been a severe public health concern affecting children. The major obstacle hindering HFMD prevention and control efforts is the lack of targeted anti-viral treatments and preventive vaccines due to the poorly understood pathogenic mechanisms underlying EV71. Viral evasion of host innate immunity is thought to be a key factor in viral pathogenicity, and many viruses have evolved diverse antagonistic mechanisms during virus-host co-evolution. Here, we show that EV71 has evolved an effective mechanism to inhibit the signal transduction pathway leading to the production of type I interferon, which plays a central role in anti-viral innate immunity. This inhibition is carried out by an EV71-encoded 2A protease (2Apro) that cleaves MAVS—an adaptor molecule critical in the signaling pathway activated by the viral recognition receptors RIG-I and MDA-5—to escape host innate immunity. These findings provide new insights to understand EV71 pathogenesis.
Related Articles
Phase-Dependent Immune Evasion of Herpesviruses▿ †
Vider-Shalit, Tal
Fishbain, Vered
Raffaeli, Shai
Louzoun, Yoram
Journal of Virology
Viruses employ various modes to evade immune detection. Two possible evasion modes are a reduction of the number of epitopes presented and the mimicry of host epitopes. The immune evasion efforts are not uniform among viral proteins. The number of epitopes in a given viral protein and the similarity of the epitopes to host peptides can be used as a measure of the viral attempts to hide this protein. Using bioinformatics tools, we here present a genomic analysis of the attempts of four human herpesviruses (herpes simplex virus type 1-human herpesvirus 1, Epstein-Barr virus-human herpesvirus 4, human cytomegalovirus-human herpesvirus 5, and Kaposi's sarcoma-associated herpesvirus-human herpesvirus 8) and one murine herpesvirus (murine herpesvirus 68) to escape from immune detection. We determined the full repertoire of CD8 T-lymphocyte epitopes presented by each viral protein and show that herpesvirus proteins present many fewer epitopes than expected. Furthermore, the epitopes that are presented are more similar to host epitopes than are random viral epitopes, minimizing the immune response. We defined a score for the size of the immune repertoire (the SIR score) based on the number of epitopes in a protein. The numbers of epitopes in proteins expressed in the latent and early phases of infection were significantly smaller than those in proteins expressed in the lytic phase in all tested viruses. The latent and immediate-early epitopes were also more similar to host epitopes than were lytic epitopes. A clear trend emerged from the analysis. In general, herpesviruses demonstrated an effort to evade immune detection. However, within a given herpesvirus, proteins expressed in phases critical to the fate of infection (e.g., early lytic and latent) evaded immune detection more than all others. The application of the SIR score to specific proteins allows us to quantify the importance of immune evasion and to detect optimal targets for immunotherapy and vaccine development.
Related Articles
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Fairy-Tale Castles
Every princess needs her own plastic canvas castle!
Create a fantasy land of 4 exquisitely detailed miniature castles and accessories made with 7- and 10-count plastic canvas. Sizes: Knights' Castle is 4 3/4" x 7 3/4" x 7 3/4" tall; Ladies' Castle is 5" x 8 1/2" x 6 3/4" tall; Winter Ice Palace is 6 7/8" square x 6 1/4" tall; Arabian Tents are 3" x 3" x 4 1/4" tall.
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Dell Color Laser
Don't drive around looking for deals on laser toner for your Dell Color Laser printer. We've got all the laser toner you need right here at 4inkjets.com. Your laser toner will be delivered straight to your office so you won't have to hunt it down at office supply stores. Check our lists for your model.
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A "related Vibrio" was found in numerous stool cultures from a 16-month-old boy with chronic diarrhea. An outbreak of acute diarrhea occurred in the nursery frequented by this boy; the same Vibrio was isolated in the stool cultures of all symptomatic cases. Using a new device, the related Vibrio has also been isolated in intestinal aspirates at different levels of the gastrointestinal tract in several cases.
Slight changes were observed in the jejunal mucosa of the child with chronic diarrhea.
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Two men connected to a Bucks County church were doing well after kidney transplant surgery at a Camden hospital Tuesday, according to a hospital spokeswoman.
Rob Chifokoyo, 30, and Michael Wortell, 22, were in good condition Wednesday, said Carol Lynn Daley, director of marketing at Our Lady of Lourdes Hospital.
Wortell, a member of Doylestown's Covenant Church, donated a kidney to Chifokoyo, a Zimbabwean mission partner of the church.
A CaringBridge web page maintained by Chifokoyo's wife was updated Wednesday afternoon, saying that Wortell was able to walk and eat a meal during the day and that Chifokoyo would hopefully move from the intensive care unit into a regular room overnight.


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Join the Friends of the Citrus County Library System for their Fall Mega Book Sale, September 28--October 2 at the Citrus County Auditorium on U.S. HWY 41 S. in Inverness.
Sale Hours:
October 2, Tuesday, 10am--3pm ($3 a bag day)
This is your chance to find some fantastic bargains in recycled reading--from thousands of fiction titles, cookbooks, history, audiobooks, CDs, DVDs, and more, there's something for everyone at this huge event. Don't miss out!
And thanks to a generous donation by Quest Wealth Management, visitors at the book sale can purchase raffle tickets to win a new Lenovo IdeaPad Laptop!
The Lenovo IdeaPad comes with Windows 7 Home Premium and has a 15.6" screen, built in wireless, 4GB of memory, a built-in fingerprint reader for sensitive information, a built-in webcam, and other great features. Raffle tickets are $5 and can be purchased at the book sale. The winner will be drawn at the end of the book sale on Tuesday afternoon, October 2. You do not have to be present to win.
To keep up with all the exciting things the Friends of the Citrus County Library System are doing, check out their website: http://www.foccls.org
From our Community Partners Blog
If you aren't familiar with Medicare or the other available resources, or if you just want to brush up on what you already know, SHINE... Read more
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Seven events will offer visitors an opportunity to participate in guided evening walks The Friends of the Crystal River Preserve State Parks, Inc., in partnership with... Read more
From our Community Partners Blog
Citrus County Parks & Recreation's P.L.A.Y. ProgramThe P.L.A.Y. program (Preparing Little Athletes Youth) is a comprehensive motor skills development program that will prepare you and... Read more
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Staff Assisted Services Schedule and Locations CareerSource will roll out its Mobile Resource Unit (MOBY1) to the Homosassa Public Library to help residents of Citrus County find... Read more
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The Citrus County Library System will promote the pursuit of knowledge and deliver quality education to the community, embracing the power of information, imagination, and ideas.


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/ NEWS: Upcoming Film Festivals - are you going?
UKClimbing will be running a group test of climbers' skin care products in 2017. Here Ellie Fuller looks at just one, Climbskin... Read more
Mick Ward used to dream of a secret crag: \'It was never in the same place twice. And, when I\'d wake up, it seemed so real, yet... Read more
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Cronin and Morris Break Their Own Program Records
Dec. 3, 2011
BALTIMORE - Junior Brennan Morris and sophomore Caitlin Cronin each broke their own school records Saturday at the Mangione Aquatics Center in the Loyola University Maryland swimming and diving team's Metro Atlantic Athletic Conference opener against Iona, Marist and Saint Peter's. In addition, freshman Joe Wise set a new S10 Paralympic American record in the 50-yard butterfly.
As a team, Loyola's men swept Iona (240-124), Marist (193-175) and Saint Peter's (257-106), while the women defeated Iona (222-147) and Saint Peter's (298-54), but fell to Marist, 251-119.
Morris set a new school record in the 400-yard individual medley, clocking in at 3:48.81 to break his old record of 3:49.71 from last year's MAAC Championships. His time currently ranks third in the country and is an NCAA B cut time.
Morris also swam an NCAA B cut time in the 1650-yard freestyle, touching first in 15:21.50. That time currently ranks 10th in the NCAA.
Wise set a new S10 Paralympic American record by finishing the first 50 yards of the 100-yard freestyle in 28.85.
On the women's side, Cronin broke her own school record in the 200-yard freestyle from last year's MAAC Championships (1:52.88), winning today's event with a time of 1:52.04. Her 100-yard freestyle time of 51.81 was just shy of her school record of 51.64.
Senior Courtney Trivino also won an individual event for the Greyhounds, taking top honors in the 400-yard individual medley with a time of 4:37.23.
In the other events, junior Jeffrey Rowe finished second in the 100-yard butterfly in 51.30, while he took third in the 100-yard breaststroke in 59.84.
Junior Patrick Mukri finished third in the 100-yard backstroke in 52.97, while he clocked in second in the 200-yard backstroke (1:54.76).
In the 100-yard freestyle, Brice took second with a time of 48.16 and in the 100-yard backstroke, Henkels touched second in 1:00.18.
Senior Meghan Barry took third in the 200-yard backstroke in 2:10.54, sophomore Courtney Chenet was third in the 2:30.26 and junior Ryan Shovlin was third in the 200-yard butterfly (1:56.28).
In diving events, sophomore Elle Mixa and sophomore Michael Brown both finished third in their respective 1-meter and 3-meter events. Mixa scored 201.15 points in the 1-meter diving and 188.10 points in the 3-meter diving, while Brown scored 201.15 in the 1-meter and 208.25 in the 3-meter diving events.
In relay events, Loyola's men were victorious in the 200-yard freestyle relay, the 200-yard medley relay and the 400-yard freestyle relay.
Sophomore Julien Brice, sophomore Zachary Eller, sophomore Michael Kelly and Rowe combined to win the 200-yard freestyle relay in 1:25.55, while Morris, Rowe, Mukri and Brice won the 200-yard medley relay in 1:33.74.
In the 400-yard freestyle relay, Brice, Mukri, Morris and Rowe combined for a time of 3:07.42.
Loyola will return to action after the new year when it heads to Rider for a head-to-head meet on Saturday, Jan. 14.
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Saturday, Oct 1 EVENT LOCATION TIME COVERAGE Green vs. Grey Mangione Pool at the Fitness & Aquatic Center 10:00 AM Friday, Oct 7 EVENT LOCATION TIME COVERAGE American Mangione Pool at the Fitness & Aquatic Center 6:00 PM Saturday, Oct 8 EVENT LOCATION TIME COVERAGE Alumni Meet Mangione Pool at the Fitness & Aquatic Center 4:00 PM Saturday, Oct 15 EVENT LOCATION TIME COVERAGE Colgate Mangione Pool at the Fitness & Aquatic Center 1:00 PM Saturday, Oct 22 EVENT LOCATION TIME COVERAGE Lafayette Mangione Pool at the Fitness & Aquatic Center 1:00 PM Friday, Oct 28 EVENT LOCATION TIME COVERAGE Johns Hopkins Mangione Pool at the Fitness & Aquatic Center 5:00 PM
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Imagine you are one of the 30,000 people coming to Christ every day in China. The underground church you attend only has one copy of the life giving Word of God for every 300 people. You are given 10 pages of the Bible, told to memorize what you can and then pass it on to others in need. The pastor of your Church doesn't even have a complete Bible.
The goal of the ministry is to serve the worldwide church by providing the necessary tools and training for the local people to fulfill Christ's "Great Commission" in their own countries.
There are over 100 million believers in China alone! If you combine that with the other believers in countries that are closed to the Gospel, there is a tremendous need to not only preach the Gospel but to equip these believers to do the work of the Lord. Vision Beyond Borders has been committed to meeting the needs of hurting people for over 20 years. Having begun missions in 1984 at the age of 21 years old, Patrick Klein went to Israel to share the Gospel. Then in 1987, he went on a trip to SE Asia with a group from Christ For the Nations Institute (CFNI). After carrying Bibles into China, he sensed the call of God to begin working in Asia to reach people with the Gospel and to strengthen the persecuted Church. Following this direction in August 1994, Pat began a ministry in Casper, Wyoming called Asian Vision, which specialized in taking Bibles into China and other parts of Asia.
The ministry gradually grew and began work in other countries outside of Asia, including Cuba, Turkey, Morocco, and Romania. Then in 2001, a few years after the ministry's headquarters relocated to Sheridan, Wyoming, the name Asian Vision was changed to Vision Beyond Borders, better describing the work it does throughout the world.
The goal of the ministry is to serve the worldwide church by providing the necessary tools and training for the local people to fulfill Christ's "Great Commission" in their own countries. This is done by supplying them with native language Bibles, training materials, seeds, clothing, medical supplies, prayer teams and evangelism to children. Last year alone, Vision Beyond Borders helped to ship and deliver over 96,000 Bibles to numerous countries in all types of languages. Patrick Klein has been involved in missions work for more than 20 years and has spent several years living overseas in places such as Israel, Singapore, Hong Kong, the Philippines, and China. He has helped to deliver over 1,000,000 Bibles around the world, providing God's Word to those who are hungry and thirsty for the words of life.


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King David scores well with inspectors
Manchester's King David Primary School has received glowing inspection reports, with Ofsted impressed by the successful completion of a complex merger of junior and infant schools.
The two sections, with a total of 422 pupils, merged in September 2010. The primary then moved to the £22 million premises shared with King David High.
Ofsted rated the primary as "good", with "examples of outstanding practice" in its teaching. "The head-teacher's strong sense of purpose has been central to the school's success since the merger."
The school has also received an "outstanding" Pikuach report for its Jewish studies provision.
In a statement, the school noted that "the mammoth task of moving from our old buildings and settling in the pupils in our new surroundings is something to be proud of. Year six pupils attained wonderful SATs results, finishing 18th in the country."


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Asus ET2702 All-In-One PC - Intel Core i7-4770 3.40GHz, 8GB Memory, 2TB HDD, Blu-Ray, 2GB AMD Radeon HD 8890A, 27" Touchscreen, Windows 8 64-bit - ET2702-03Item#: YYT1-11160056 | Model#: ET2702-03
Currently Out Of Stock!
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Asus ET2702 All-In-One PC Product Details
Asus ET2702 All-In-One PC
Experience a more interactive multimedia experience when you purchase the Asus ET2702 All-In-One PC! The Asus ET2702 All-In-One PC comes in an ultra-slim design that allows you to put more of your stuff on your desk. It features a beautiful 27 Full HD Multi-Touch Widescreen that provides you with amazing visuals and a very intuitive user interface. It supports a maximum resolution of 2560 x 1440, allowing you to play your high-definition content with full detail. It runs on a 4th generation Intel Core i7-4770 3.40GHz processor that delivers quick processing speeds for your various tasks. It also comes with 8GB of DDR3 memory to help you multitask through several processes while having a smooth computing experience. Its 2TB HDD allows you to save lots of your photos, videos, and other files. Avail of the Asus ET2702 All-In-One PC now!
What It Is And Why You Need It:
- Ultra-slim design; saves lots of space on your desk
- 27" Full HD Multi-Touch Widescreen; provides you with a very intuitive user interface while displaying amazing visuals
- 2560 x 1440 maximum resolution; supports playback of 1080p content
- 4th generation Intel Core i7-4770 3.40GHz processor; delivers quick processing speeds
- 8GB of DDR3 memory; allows you to multitask through several processes
- 2TB HDD; lets you save lots of your photos, videos, and other files
Additional Resources: Product Manuals
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text: Europe cannot get its act together. Debt deals to figure out what the plan will be to bail out Greece have not been agreed upon yet. Angela Merkel of Germany and the backwards French government cannot find the correct budget or the correct plan of action. The Royal Bank of Canada (RBC) reported last evening that they project a mini recession in Europe (of which the Europeans … [Read more...]


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Company's Profile
Products & Services
Package for SIC
Project Experience
Major Customers
Live demo
India Offices
Hydromet Systems Private Limited is a wholly owned subsidiary company of
Corporation, 22400 Davis Drive, Sterling, Virginia, USA 20164. Sutron is operating directly in India since 2001. The Indian operations of Sutron started as a branch office with the permission of RBI in 2001. Subsequently, in 2005, Sutron Corporation USA incorporated a wholly owned subsidiary company under Indian Companies Act 1956.
is dedicated to providing reliable remote monitoring equipment that meets or exceeds WMO standards in India.
USA - an ISO 9001:2000 Certified company, supplies real-time data collection, telemetry, and technical expertise to monitor, control, manage, model, and forecast in areas of hydrology, meteorology, and water management. Since 1975, Sutron has produced systems, equipment and software that collect, store, and transmit from extreme locales to PDAs, desktop or laptop computers located anywhere on the planet using satellite, internet, radio or telephone communications.
Hydro-Met Systems Pvt. Ltd. has provided state-of-the-art technology to India for over 10 years. During this time we have designed and integrated over 1000 Real-Time Hydro-Met Monitoring Stations and 7 Digital Earth Receive Stations for reception of remote site data through INSAT / KALPANA satellite for the India Meteorological Department, the Central Water Commission, the Government of Andhra Pradesh (Cyclone Forecast and Mitigation Project), the Snow and Avalanche Study Establishment, the Ministry of Defense, BBMB and other Government of India agencies.
Sutron has unique advantages over all other manufacturer for following reasons:
Sutron designs, develops and manufactures its own loggers and satellite transmitter.,
Sutron has 6 offices in India and 20 engineers working full-time to support our customers throughout the nation.
Sutron has provided over 1000 remote monitoring stations in India.
Sutron provides annual maintenance to IMD, CWC and GOAP.
Sutron equipment is very user-friendly.
Easy to use
Sutron has been working with customers in India approximately 15 years. Sutron understands the climatic conditions and operating environment in India.
Sutron has installed more WMO-Compliant AWS Stations using various multiple communications techniques such as INSAT, GSM/GPRS, LOS Radio, IP-Based Systems than any other Hydro-Met Monitoring vendor in India.
Sutron has a record of completing most projects ON-TIME.
Sutron Hydromet Systems Pvt. Ltd., New Delhi / Sutron Corporation, Branch Office, New Delhi D-128-129, 1st Floor, Okhla Industrial Area, Phase – I, New Delhi – 110020 Tel. No.: 011-41759224 / 41759750 Fax: 011-41759225 Email: firstname.lastname@example.com
Copyright © "SUTRON" All Rights Reserved.


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A Trip To Remember
July 3, 2015 by admin
Filed under Featured Post, Reflections, Skin Care Education, Skin Care Science, Skin Care Tips
It has been a whirlwind of activity for me in the past few weeks as we continue to present our newest groundbreaking facial treatment, the Hydra 4® Red-Out™ Facial with Micro Silver and Anti-Oxidants for Hypersensitive Skin as well as the new at-home products, the Hydra 4® Red-Out™ Calming Cleanser and Serum, and the exciting, […]
Anthony P. Scott and Company Limited Launches New! Repechage Biolight
November 22, 2011 by admin
Filed under Press & Media, Skin Care Education
(from right to left: Lydia Sarfati, CEO/ Founder Repechage and Lauren Streeter, Corporate Educator) Monday, October 10, 2011– Anthony P. Scott and Company Limited welcomed Repêchage CEO and Founder, Lydia Sarfati, for a special presentation of the New! Repêchage Biolight Collection at the Hyatt in Trinidad and Tobago. For over 30 years, Anthony P. Scott […]


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After weeks in limbo stemming from revelations of sexual misconduct by one of its stars, the TLC reality show "19 Kids and Counting" is officially dead.
TLC is not moving forward with an 11th season of "19 Kids" featuring the Duggars, whose show "will no longer appear on the air," the network told The Associated Press on Thursday.
"We spent the past month and a half in thoughtful consideration about what is the best way forward here," said Marjorie Kaplan, group president of TLC, Animal Planet and Velocity networks.
In a move to redirect the attention and public outcry, TLC also announced it has teamed with two prominent...


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Fun With Goth
Listening to Cuba-born, New York-based musician Voltaire may evoke a night aboard an 18th-century frigate, complete with freely flowing wine and bawdy, drunken sing-alongs. For others, his music, with its organic instrumentation (clarinet, trumpet, accordion, cello), might call to mind a dark Berlin cabaret, full of gothic theatricality sorta like a goofball version of Dresden Dolls or Tom Waits had Waits cut his teeth on comic books instead of bourbon.
The lightheartedly macabre (new genre: fun goth?) musician/graphic novelist/creator of the vinyl toy Deady will whip up some horror-fied high jinks when he and his seven-man band, Voltaire and the Skeletal Orchestra, perform at Club Mardi Gras & Voodoo Lounge. Along with gypsy pirate garb, expect to hear Voltaire perform BRAINS!, the song that put him on the map because of its appearance on the Cartoon Network series The Grim Adventures of Billy and Mandy.
Fri., April 10, 9 p.m., 2009
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Delivery Days/ Picker for Prestashop
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text: NAHA Behind the Cover - April 2011 July 11, 2011 | 3:03 am EDT UpvoteClick if you like this articleOne upvote per userLog in to upvoteComments Print The cover of Modern Salon (April 2011). Steve Elias is no stranger to working on editorial photoshoots. Named Editorial Stylist of the Year in 2010 by the North American Hairstyling Awards, Elias has a passion for creating beautiful looks that come alive on the pages of a magazine. For his âJoy of Springâ photo shoot, Elias was inspired by the soft textures and strong shapes that have dominated fashion shows in 2011. âI wanted to follow the runway trends and create versatile looks that reflect them,â he says. When he began to narrow his vision into a collection, shape was the name of the game. âThe hard and soft textures combining into one shape was my inspirationâIâm all about the yin and yang.â Choosing the perfect team to help make his vision come to life was a no-brainer. âBilly Winters (photographer) and I have been working together forever,â says Elias. âI trust his amazing fashion aesthetic. Jonathanâ my make-up artistâhas an amazing eye for details and, in a make-up artist, that is important!â But it is Elias himself who leads the way to success in his shoots. He is a firm believer in precise planning to achieve the best possible resultsâ âthose who fail to plan, plan to fail,â he says. And after many successful shoots, Elias has a firm grasp on the key to getting it right. âTrust in your creative vision, but always be open to accepting suggestions from your team,â he says. âYou are all artists, and someone might see something you donât.â For those whoâve never done an editorial shoot or are looking to improve their skills, Elias offers this advice: âStart off small and find people who are in the same place you are and are willing to collaborateâyouâll mutually benefit one another in the creative process. Build your book slowly, and you will be surprised how much you learn about hair and about yourself in the process!âSteve Elias winning his NAHA for Editorial Stylist of the Year at last yearâs North American Hairstyling Awards.Elias always has a good timeâno matter whose hair heâs doing!


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------I've been doing machine embroidery for 12 years, but I'm definitely a beginner at garment sewing.
UFOs completed in 2016: 9
Items started and completed in 2016: 34
Yards sewn up in 2016: 48.5
Days I did not sew in 2016: 50
The Amazing Bernina 720E 💝 1150MDA
✝The Lord is my Light and my Salvation: whom shall I fear? The Lord is the strength of my life; of whom shall I be afraid? Psalm 27:1✝
------Janome MC6600 Bernina 240 Juki MO735 Singer 201-2 Singer 221-1
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