Viral infection triggers an early host response through activation of pattern recognition receptors, including Toll-like receptors (TLR). TLR signaling cascades induce production of type I interferons and proinflammatory cytokines involved in establishing an anti-viral state as well as in orchestrating ensuing adaptive immunity. To allow infection, replication, and persistence, (herpes)viruses employ ingenious strategies to evade host immunity. The human gamma-herpesvirus Epstein-Barr virus (EBV) is a large, enveloped DNA virus persistently carried by more than 90% of adults worldwide. It is the causative agent of infectious mononucleosis and is associated with several malignant tumors. EBV activates TLRs, including TLR2, TLR3, and TLR9. Interestingly, both the expression of and signaling by TLRs is attenuated during productive EBV infection. Ubiquitination plays an important role in regulating TLR signaling and is controlled by ubiquitin ligases and deubiquitinases (DUBs). The EBV genome encodes three proteins reported to exert in vitro deubiquitinase activity. Using active site-directed probes, we show that one of these putative DUBs, the conserved herpesvirus large tegument protein BPLF1, acts as a functional DUB in EBV-producing B cells. The BPLF1 enzyme is expressed during the late phase of lytic EBV infection and is incorporated into viral particles. The N-terminal part of the large BPLF1 protein contains the catalytic site for DUB activity and suppresses TLR-mediated activation of NF-κB at, or downstream of, the TRAF6 signaling intermediate. A catalytically inactive mutant of this EBV protein did not reduce NF-κB activation, indicating that DUB activity is essential for attenuating TLR signal transduction. Our combined results show that EBV employs deubiquitination of signaling intermediates in the TLR cascade as a mechanism to counteract innate anti-viral immunity of infected hosts.

Viruses use a wide range of strategies to modulate the host immune response. The human gammaherpesvirus EBV, causative agent of infectious mononucleosis and several malignant tumors, encodes proteins that subvert immune responses, notably those mediated by T cells. Less is known about EBV interference with innate immunity, more specifically at the level of TLR-mediated pathogen recognition. The viral dsDNA sensor TLR9 is expressed on B cells, a natural target of EBV infection. Here, we show that EBV particles trigger innate immune signaling pathways through TLR9. Furthermore, using an in vitro system for productive EBV infection, it has now been possible to compare the expression of TLRs by EBV− and EBV+ human B cells during the latent and lytic phases of infection. Several TLRs were found to be differentially expressed either in latently EBV-infected cells or after induction of the lytic cycle. In particular, TLR9 expression was profoundly decreased at both the RNA and protein levels during productive EBV infection. We identified the EBV lytic-phase protein BGLF5 as a protein that contributes to downregulating TLR9 levels through RNA degradation. Reducing the levels of a pattern-recognition receptor capable of sensing the presence of EBV provides a mechanism by which the virus could obstruct host innate antiviral responses.

Staphylococcus aureus secretes several virulence factors modulating immune responses. Staphylococcal superantigenlike (SSL) proteins are a family of 14 exotoxins with homology to superantigens, but with generally unknown function. Recently, we showed that SSL5 binds to P-selectin glycoprotein ligand 1 dependently of sialyl Lewis X and inhibits Pselectin-dependent neutrophil rolling. Here, we show that SSL5 potently and specifically inhibits leukocyte activation by anaphylatoxins and all classes of chemokines. SSL5 inhibited calcium mobilization, actin polymerization, and chemotaxis induced by chemokines and anaphylatoxins but not by other chemoattractants. Antibody competition experiments showed that SSL5 targets several chemokine and anaphylatoxin receptors. IntroductionStaphylococcus aureus is a common human pathogen that causes severe community-acquired and nosocomial infections. This Grampositive bacterium produces a wide variety of virulence proteins that aid in its infection, colonization, and disease progress. These surface-associated and secreted proteins often target the immune system. 1 Chemotaxis inhibitory protein of S aureus (CHIPS) is such an excreted virulence factor of S aureus. CHIPS binds the formyl peptide receptor (FPR) and the C5a receptor (C5aR) and thereby inhibits cell activation by formylated peptides and C5a, respectively. 2,3 Consequently, it attenuates the initial activation and migration of neutrophils to the site of infection. Structurally, CHIPS shows homology to the C-terminal domain of staphylococcal superantigen-like (SSL) proteins. 4 SSLs are a family of 14 exoproteins. Eleven of them are encoded on staphylococcal pathogenicity island 2 present in all S aureus strains, and the remaining 3 are found on the immune evasion cluster 2. 5 They were identified through sequence and structural homology with superantigens, but they do not show superantigenic activity. 6 Latest evidence suggests that SSLs play a role in immune evasion by other means. SSL7 was described to bind C5 and immunoglobulin A (IgA) blocking the complement system and Fc␣RI binding, respectively. 7 Recently, we described that SSL5 binds to P-selectin glycoprotein ligand 1 (PSGL-1). 8 Thereby, SSL5 inhibits neutrophil rolling on endothelial cells by disrupting the interaction of PSGL-1 with its natural ligand P-selectin. Sugar moieties were shown to be crucial in this effect. Recently, the crystal structure of SSL5 in complex with sialyl Lewis X (sLex) was determined. 9 SSL11 was also shown to interact with sLex, 10 and both proteins bind sLex through their C-terminal domain. Therefore, at least a subset of SSLs affects the immune system by targeting glycoproteins.The immune response rapidly reacts to invading pathogens. The response is initiated by extravasation of leukocytes from the blood stream to the site of infection. It is regulated by various chemotactic factors that are produced endogenously by endothelial cells and leukocytes as well as exogenously by the invading pathogen. These comprise the chemoattracta...

Type I IFNs play critical roles in orchestrating the antiviral defense by inducing direct antiviral activities and shaping the adaptive immune response. Viruses have evolved numerous strategies to specifically interfere with IFN production or its downstream mediators, thereby allowing successful infection of the host to occur. The prototypic human gammaherpesvirus EBV, which is associated with infectious mononucleosis and malignant tumors, harbors many immune-evasion proteins that manipulate the adaptive and innate immune systems. In addition to proteins, the virus encodes >40 mature microRNAs for which the functions remain largely unknown. In this article, we identify EBV-encoded miR-BART16 as a novel viral immune-evasion factor that interferes with the type I IFN signaling pathway. miR-BART16 directly targets CREB-binding protein, a key transcriptional coactivator in IFN signaling, thereby inducing CREB-binding protein downregulation in EBV-transformed B cells and gastric carcinoma cells. miR-BART16 abrogates the production of IFN-stimulated genes in response to IFN-α stimulation and it inhibits the antiproliferative effect of IFN-α on latently infected BL cells. By obstructing the type I IFN-induced antiviral response, miR-BART16 provides a means to facilitate the establishment of latent EBV infection and enhance viral replication.

Staphylococcal superantigen-like 10 is a potential lead in the development of new anticancer compounds preventing metastasis by targeting CXCR4.