Escape of HIV-1-Infected Dendritic Cells from TRAIL-Mediated NK Cell Cytotoxicity during NK-DC Cross-Talk—A Pivotal Role of HMGB1

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

Identification of a biological signature for schizophrenia in serum

Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n = 71) and control (n = 59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60-75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of similar to 50% of MDD patients and 10-20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms. Molecular Psychiatry (2012) 17, 494-502; doi:10.1038/mp.2011.42; published online 12 April 201

Ecodynamic solutions for the protection of intertidal habitats: the use of oyster reefs

Ecosystem engineering processes are relevant to many environmental problems and management concerns. Within the program ‘‘Building with Nature’’ (www.ecoshape.nl) we investigate the use of bivalve reefs as ecodynamic measures to protect tidal flats against erosion, which poses a serious problem in the Oosterschelde estuary (Netherlands). Bivalve reefs are ecosystem engineers that influence tidal flow and wave action and therefore modify sediment transport patterns. The development of such infrastructural solutions that aim for an integration with the natural environment can only be achieved through experimentation and learning-by-doing. Artificial oyster reefs were constructed in different erosional intertidal environments in the Oosterschelde. Reefs consist of gabions filled with oyster shells (Crassostrea gigas), offering a stable substrate that allows for the settlement of oysters, while minimizing shell loss. Monitoring results indicate that artificial reefs can develop into self-maintaining, living oyster reefs which stabilize tidal flats. Site-specific effects in reef development (e.g. recruitment of oyster larvae) and in sediment dynamics were observed. Knowledge about local hydromorphological conditions and a thorough understanding of the ecosystem engineering properties and habitat requirements of C. gigas are needed to implement this concept in management practices. We present the concept, monitoring and modeling results and derive design rules from these

Ecodynamic solutions for the protection of intertidal habitats: the use of oyster reefs

Ecosystem engineering processes are relevant to many environmental problems and management concerns. Within the program ‘‘Building with Nature’’ (www.ecoshape.nl) we investigate the use of bivalve reefs as ecodynamic measures to protect tidal flats against erosion, which poses a serious problem in the Oosterschelde estuary (Netherlands). Bivalve reefs are ecosystem engineers that influence tidal flow and wave action and therefore modify sediment transport patterns. The development of such infrastructural solutions that aim for an integration with the natural environment can only be achieved through experimentation and learning-by-doing. Artificial oyster reefs were constructed in different erosional intertidal environments in the Oosterschelde. Reefs consist of gabions filled with oyster shells (Crassostrea gigas), offering a stable substrate that allows for the settlement of oysters, while minimizing shell loss. Monitoring results indicate that artificial reefs can develop into self-maintaining, living oyster reefs which stabilize tidal flats. Site-specific effects in reef development (e.g. recruitment of oyster larvae) and in sediment dynamics were observed. Knowledge about local hydromorphological conditions and a thorough understanding of the ecosystem engineering properties and habitat requirements of C. gigas are needed to implement this concept in management practices. We present the concept, monitoring and modeling results and derive design rules from these