The Human Herpesvirus-7 (HHV-7) U21 Immunoevasin Subverts NK-Mediated Cytoxicity through Modulation of MICA and MICB

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

Human cytomegalovirus infection of langerhans-type dendritic cells does not require the presence of the gH/gL/UL128-131A complex and is blocked after nuclear deposition of viral genomes in immature cells

Human cytomegalovirus (CMV) enters its host via the oral and genital mucosae. Langerhans-type dendritic cells (LC) are the most abundant innate immune cells at these sites, where they constitute a first line of defense against a variety of pathogens. We previously showed that immature LC (iLC) are remarkably resistant to CMV infection, while mature LC (mLC) are more permissive, particularly when exposed to clinical-strain-like strains of CMV, which display a pentameric complex consisting of the viral glycoproteins gH, gL, UL128, UL130, and UL131A on their envelope. This complex was recently shown to be required for the infection of immature monocyte-derived dendritic cells. We thus sought to establish if the presence of this complex is also necessary for virion penetration of LC and if defects in entry might be the source of iLC resistance to CMV. Here we report that the efficiency of LC infection is reduced, but not completely abolished, in the absence of the pentameric complex. While virion penetration and nuclear deposition of viral genomes are not impaired in iLC, the transcription of the viral immediate early genes UL122 and UL123 and of the delayed early gene UL50 is substantially lower than that in mLC. Together, these data show that the UL128, UL130, and UL131A proteins are dispensable for CMV entry into LC and that progression of the viral cycle in iLC is restricted at the step of viral gene expression

Roadmap on holography

From its inception holography has proven an extremely productive and attractive area of research. While specific technical applications give rise to 'hot topics', and three-dimensional (3D) visualisation comes in and out of fashion, the core principals involved continue to lead to exciting innovations in a wide range of areas. We humbly submit that it is impossible, in any journal document of this type, to fully reflect current and potential activity; however, our valiant contributors have produced a series of documents that go no small way to neatly capture progress across a wide range of core activities. As editors we have attempted to spread our net wide in order to illustrate the breadth of international activity. In relation to this we believe we have been at least partially successful

Variations in killer-cell immunoglobulin-like receptor and human leukocyte antigen genes and immunity to malaria

Malaria is one of the deadliest infectious diseases in the world. Immune responses to Plasmodium falciparum malaria vary among individuals and between populations. Human genetic variation in immune system genes is likely to play a role in this heterogeneity. Natural killer (NK) cells produce inflammatory cytokines in response to malaria infection, kill intraerythrocytic Plasmodium falciparum parasites by cytolysis, and participate in the initiation and development of adaptive immune responses to plasmodial infection. These functions are modulated by interactions between killer-cell immunoglobulin-like receptors (KIR) and human leukocyte antigens (HLA). Therefore, variations in KIR and HLA genes can have a direct impact on NK cell functions. Understanding the role of KIR and HLA in immunity to malaria can help to better characterize antimalarial immune responses. In this review, we summarize the different KIR and HLA so far associated with immunity to malaria.This work was supported through the DELTAS Africa Initiative (Grant no. 107743), that funded Stephen Tukwasibwe through PhD fellowship award, and Annettee Nakimuli through group leader award. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Science (AAS), Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (Grant no. 107743) and the UK government. Francesco Colucci is funded by Wellcome Trust grant 200841/Z/16/Z. The project received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. 695551) for James Traherne and John Trowsdale. Jyothi Jayaraman is a recipient of fellowship from the Centre for Trophoblast Research

Dental microwear texture gradients in guinea pigs reveal that material properties of the diet affect chewing behaviour

Dental microwear texture analysis (DMTA) is widely used for dietinferences in extant and extinct vertebrates. Often, a reference toothposition is analysed in extant specimens, while isolated teeth arelumped together in fossil datasets. It is therefore important to testwhether dentalmicrowear texture (DMT) istooth position specificand,ifso, what causes the differences in wear. Here, we present results fromcontrolled feeding experiments with 72 guinea pigs, which receivedeither fresh or dried natural plant diets of different phytolith content(lucerne, grass, bamboo) or pelleted diets with and without mineralabrasives (frequently encountered by herbivorous mammals in naturalhabitats). We tested for gradients in dental microwear texture along theupper cheek tooth row. Regardless of abrasive content, guinea pigs onpelleted diets displayed an increase in surface roughness along thetooth row, indicating that posterior tooth positions experience morewear compared with anterior teeth. Guinea pigs feedings on plants oflow phytolith content and low abrasiveness (fresh and dry lucerne,fresh grass) showed almost no DMT differences between toothpositions, while individuals feeding on more abrasive plants (drygrass, fresh and dry bamboo) showed a gradient of decreasing surfaceroughness along the tooth row. We suggest that plant feeding involvescontinuous intake and comminution by grinding, resulting in posteriortooth positions mainly processing food already partly comminuted andmoistened. Pelleted diets require crushing, which exerts higher loads,especially on posterior tooth positions, where bite forces are highest.These differences in chewing behaviour result in opposing weargradients for plant versus pelleted diets

Effects of human cytomegalovirus infection on ligands for the activating NKG2D receptor of NK cells: upregulation of UL16-binding protein (ULBP)1 and ULBP2 is counteracted by the viral UL16 protein.

Abstract Human CMV (HCMV) interferes with NK cell functions at various levels. The HCMV glycoprotein UL16 binds some of the ligands recognized by the NK-activating receptor NKG2D, namely UL16-binding proteins (ULBP) 1 and 2 and MHC class I-related chain B, possibly representing another mechanism of viral immune escape. This study addressed the expression and function of these proteins in infected cells. HCMV induced the expression of all three ULBPs, which were predominantly localized in the endoplasmic reticulum of infected fibroblasts together with UL16. However, while at a lower viral dose ULBP1 and 2 surface expression was completely inhibited compared to ULBP3, at a higher viral dose cell surface expression of ULBP1 and ULBP2 was delayed. The induction of ULBPs correlated with an increased dependency on NKG2D for recognition; however, the overall NK sensitivity did not change (suggesting that additional viral mechanisms interfere with NKG2D-independent pathways for recognition). Infection with a UL16 deletion mutant virus resulted in a different pattern compared to the wild type: all three ULBP molecules were induced with similar kinetics at the cell surface, accompanied by a pronounced, entirely NKG2D-dependent increase in NK sensitivity. Together our findings show that upon infection with HCMV, the host cell responds by expression of ULBPs and increased susceptibility to the NKG2D-mediated component of NK cell recognition, but UL16 limits these effects by interfering with the surface expression of ULBP1 and ULBP2.</jats:p

Detailed investigation of the propagation rate of urethane acrylates

Temperature dependent propagation rate coefficients, kp, are determined for four acrylate monomers containing a carbamate moiety via the pulsed laser polymerization-size exclusion chromatography (PLP-SEC) technique. Therefore, the Mark-Houwink-Kuhn-Sakurada coefficients K and a of the respective polymers were additionally determined via triple-detection SEC. The monomers under investigation were synthesized from hydroxyethyl acrylate, hydroxyl(iso)propyl acrylate as well as phenyl isocyanate and hexyl isocyanate, respectively, in all four possible combinations. For 2-(phenylcarbamoyloxy)ethyl acrylate (PhCEA) an activation energy of 14.3 kJ mol-1 and a frequency factor of A = 1.2 × 107 L·mol-1 s-1 are obtained for kp. The MHKS parameters for poly(PhCEA) are K = 8.3 × 10-5 dL g-1 and a = 0.677. For 2-(phenylcarbamoyloxy)isopropyl acrylate (PhCPA) an activation energy of 14.2 kJ mol-1 and a frequency factor of A = 4.9 × 10 6 L mol-1 s-1 are found for kp and the MHKS parameters for poly(PhCPA) read K = 10.3 × 10-5 dL g-1 and a = 0.657. The activation parameters of kp of 2-(hexylcarbamoyloxy)ethyl acrylate (HCEA) are EA = 13.3 kJ mol -1 and A = 6.6 × 106 L mol-1 s -1 with K = 36.0 × 10-5 dL g-1 and a = 0.552 for poly(HCEA). For 2-(hexylcarbamoyloxy)isopropyl acrylate (HCPA) E A is 14.1 kJ mol-1 and A = 6.6 × 106 L mol-1 s-1 with K = 26.0 × 10-5 dL g -1 and a = 0.587 for poly(HCPA). All rate measurements were performed in 1 M solutions in butyl acetate. The fast propagating nature and reduced activation energy of the monomers may be understood on the basis of the increased nucleophilicity that is induced by the carbamate functionality present in all monomers. Rate-increasing effects from solvent polarity and/or from H-bonding can, however, not be excluded and might also contribute to the observed high propagation rates. © 2010 The Royal Society of Chemistry