Enteric Virome Sensing-Its Role in Intestinal Homeostasis and Immunity

Pattern recognition receptors (PRRs) sensing commensal microorganisms in the intestine induce tightly controlled tonic signaling in the intestinal mucosa, which is required to maintain intestinal barrier integrity and immune homeostasis. At the same time, PRR signaling pathways rapidly trigger the innate immune defense against invasive pathogens in the intestine. Intestinal epithelial cells and mononuclear phagocytes in the intestine and the gut-associated lymphoid tissues are critically involved in sensing components of the microbiome and regulating immune responses in the intestine to sustain immune tolerance against harmless antigens and to prevent inflammation. These processes have been mostly investigated in the context of the bacterial components of the microbiome so far. The impact of viruses residing in the intestine and the virus sensors, which are activated by these enteric viruses, on intestinal homeostasis and inflammation is just beginning to be unraveled. In this review, we will summarize recent findings indicating an important role of the enteric virome for intestinal homeostasis as well as pathology when the immune system fails to control the enteric virome. We will provide an overview of the virus sensors and signaling pathways, operative in the intestine and the mononuclear phagocyte subsets, which can sense viruses and shape the intestinal immune response. We will discuss how these might interact with resident enteric viruses directly or in context with the bacterial microbiome to affect intestinal homeostasis

The TLR signalling adaptor TRIF/TICAM-1 has an N-terminal helical domain with structural similarity to IFIT proteins

TRIF/TICAM-1 (TIR domain-containing adaptor inducing interferon-beta/TIR domain-containing adaptor molecule 1) is the adaptor protein in the Toll-like receptor (TLR) 3 and 4 signalling pathway that leads to the production of type 1 interferons and cytokines. The signalling involves TIR (Toll/interleukin-1 receptor) domain-dependent TRIF oligomerization. A protease-resistant N-terminal region is believed to be involved in self-regulation of TRIF by interacting with its TIR domain. Here, the structural and functional characterization of the N-terminal domain of TRIF (TRIF-NTD) comprising residues 1-153 is reported. The 2.22 angstrom resolution crystal structure was solved by single-wavelength anomalous diffraction (SAD) using selenomethionine-labelled crystals of TRIF-NTD containing two additional introduced Met residues (TRIF-NTDA66M/L113M). The structure consists of eight antiparallel helices that can be divided into two subdomains, and the overall fold shares similarity to the interferon-induced protein with tetratricopeptide repeats (IFIT) family of proteins, which are involved in both the recognition of viral RNA and modulation of innate immune signalling. Analysis of TRIF-NTD surface features and the mapping of sequence conservation onto the structure suggest several possible binding sites involved in either TRIF auto-regulation or interaction with other signalling molecules or ligands. TRIF-NTD suppresses TRIF-mediated activation of the interferon-beta promoter, as well as NF-kappa B-dependent reporter-gene activity. These findings thus identify opportunities for the selective targeting of TLR3- and TLR4-mediated inflammation

Retrospektive Analyse eines VACM-Behandlungsmanuals (vacuum-assisted closure and mesh-mediated fascial traction) beim temporären Bauchdeckenverschluss - Ergebnisse von 58 konsekutiven Patienten

Introduction: The optimal treatment concept for temporary abdominal closure (TAC) in critically ill visceral surgery patients with open abdomen (OA) continues to be unclear. The VACM (vacuum-assisted closure and mesh-mediated fascial traction) therapy seems to permit higher delayed primary fascial closure rates (FCR) than other TAC procedures. Material and methods: Patients of our clinic (n=58) who were treated by application of a VAC/VACM treatment manual in the period from 2005 to 2008 were retrospectively analysed. Results: The overall FCR of all patients was 48.3% (95% confidence interval: 34.95-61.78). An FCR of 61.3% was achieved in patients who had a vicryl mesh implanted at the fascial level (VACM therapy) in the course of treatment. Mortality among patients treated with VACM therapy was 45.2% (95% CI: 27.32-63.97).Conclusions: The results of our own study confirm the results of previous studies which showed an acceptable FCR among non-trauma patients who were treated with VACM therapy. VACM therapy currently appears to be the treatment regime of choice for patients with OA requiring TAC.Einleitung: Das optimale Behandlungskonzept eines temporären Bauchdeckenverschlusses (temporary abdominal closure, TAC) bei kritisch kranken viszeralchirurgischen Patienten mit offenem Abdomen ("open abdomen", OA) ist weiterhin unklar. Durch eine VACM-Therapie (vacuum-assisted closure and mesh-mediated fascial traction) scheinen sich gegenüber anderen Verfahren des TAC höhere Faszienverschlussraten (delayed primary fascial closure rate, FCR) realisieren zu lassen. Material und Methoden: Patienten unserer Klinik (n=58), welche in den Jahren 2005 bis 2008 mittels eines VAC/VACM-Behandlungsmanuals behandelt wurden, wurden retrospektiv analysiert. Ergebnisse: Die FCR aller Patienten betrug insgesamt 48,3% (95%-Konfidenzintervall: 34,95-61,78). Bei Patienten, bei denen im Verlauf ein Vicryl-Netz auf Faszienebene implantiert wurde (VACM-Therapie), konnte eine FCR von 61,3% realisiert werden. Die Letalität der mittels VACM therapierten Patienten betrug 45,2% (95%-KI: 27,32-63,97).Schlussfolgerung: Die Ergebnisse der eigenen Untersuchung bestätigen bisherige Studienergebnisse, die eine akzeptable FCR bei non-trauma-Patienten durch Anwendung der VACM-Therapie zeigen konnten. Die VACM-Therapie scheint aktuell Therapiekonzept der ersten Wahl bei Patienten mit OA und Indikation zum TAC zu sein

Virus-associated activation of innate immunity induces rapid disruption of Peyer’s patches in mice

Early in the course of infection, detection of pathogen-associated molecular patterns by innate immune receptors can shape the subsequent adaptive immune response. Here we investigate the influence of virus-associated innate immune activation on lymphocyte distribution in secondary lymphoid organs. We show for the first time that virus infection of mice induces rapid disruption of the Peyer's patches but not of other secondary lymphoid organs. The observed effect was not dependent on an active infectious process but due to innate immune activation and could be mimicked by virus-associated molecular patterns such as the synthetic double-stranded RNA poly(I:C). Profound histomorphological changes in Peyer's patches were associated with depletion of organ cellularity, most prominent among the B cell subset. We demonstrate that the disruption is entirely dependent on type I interferon. At the cellular level, we show that virus-associated immune activation by IFN-α blocks B-cell trafficking to the Peyer's patches by downregulating expression of the homing molecule α4β7-integrin. In summary, our data identify a mechanism that results in type I IFN-dependent rapid but reversible disruption of intestinal lymphoid organs during systemic viral immune activation. We propose that such re-routed lymphocyte trafficking may impact the development of B cell immunity to systemic viral pathogens