The viral RNase E(rns) prevents IFN type-I triggering by pestiviral single- and double-stranded RNAs

Interferon (IFN) type-I is of utmost importance in the innate antiviral defence of eukaryotic cells. The cells express intra- and extracellular receptors that monitor their surroundings for the presence of viral genomes. Bovine viral diarrhoea virus (BVDV), a Pestivirus of the family Flaviviridae, is able to prevent IFN synthesis induced by poly(IC), a synthetic dsRNA. The evasion of innate immunity might be a decisive ability of BVDV to establish persistent infection in its host. We report that ds- as well as ssRNA fragments of viral origin are able to trigger IFN synthesis, and that the viral envelope glycoprotein E(rns), that is also secreted from infected cells, is able to inhibit IFN expression induced by these extracellular viral RNAs. The RNase activity of E(rns) is required for this inhibition, and E(rns) degrades ds- and ssRNA at neutral pH. In addition, cells infected with a cytopathogenic strain of BVDV contain more dsRNA than cells infected with the homologous non-cytopathogenic strain, and the intracellular viral RNA was able to excite the IFN system in a 5'-triphosphate-, i.e. RIG-I-, independent manner. Functionally, E(rns) might represent a decoy receptor that binds and enzymatically degrades viral RNA that otherwise might activate the IFN defence by binding to Toll-like receptors of uninfected cells. Thus, the pestiviral RNase efficiently manipulates the host's self-nonself discrimination to successfully establish and maintain persistence and immunotolerance.

Prolonged activity of the pestiviral RNase Erns as an interferon antagonist after uptake by clathrin-mediated endocytosis

The RNase activity of the envelope glycoprotein E(rns) of the pestivirus bovine viral diarrhea virus (BVDV) is required to block type I interferon (IFN) synthesis induced by single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) in bovine cells. Due to the presence of an unusual membrane anchor at its C terminus, a significant portion of E(rns) is also secreted. In addition, a binding site for cell surface glycosaminoglycans is located within the C-terminal region of E(rns). Here, we show that the activity of soluble E(rns) as an IFN antagonist is not restricted to bovine cells. Extracellularly applied E(rns) protein bound to cell surface glycosaminoglycans and was internalized into the cells within 1 h of incubation by an energy-dependent mechanism that could be blocked by inhibitors of clathrin-dependent endocytosis. E(rns) mutants that lacked the C-terminal membrane anchor retained RNase activity but lost most of their intracellular activity as an IFN antagonist. Surprisingly, once taken up into the cells, E(rns) remained active and blocked dsRNA-induced IFN synthesis for several days. Thus, we propose that E(rns) acts as an enzymatically active decoy receptor that degrades extracellularly added viral RNA mainly in endolysosomal compartments that might otherwise activate intracellular pattern recognition receptors (PRRs) in order to maintain a state of innate immunotolerance. IMPORTANCE The pestiviral RNase E(rns) was previously shown to inhibit viral ssRNA- and dsRNA-induced interferon (IFN) synthesis. However, the localization of E(rns) at or inside the cells, its species specificity, and its mechanism of interaction with cell membranes in order to block the host's innate immune response are still largely unknown. Here, we provide strong evidence that the pestiviral RNase E(rns) is taken up within minutes by clathrin-mediated endocytosis and that this uptake is mostly dependent on the glycosaminoglycan binding site located within the C-terminal end of the protein. Remarkably, the inhibitory activity of E(rns) remains for several days, indicating the very potent and prolonged effect of a viral IFN antagonist. This novel mechanism of an enzymatically active decoy receptor that degrades a major viral pathogen-associated molecular pattern (PAMP) might be required to efficiently maintain innate and, thus, also adaptive immunotolerance, and it might well be relevant beyond the bovine species.

Sēder teḥinnôt û-vaqqāšôt : ... ich hob ṭog un nochṭ iber der teḥinne giṭrochṭ un hob zi hiṭ wegn einr gimochṭ ...

[Mattatja Ben-Meir Sobotki]

Der Broyner bukh : ṿegn der unṭertsindung funem Raykhsṭag un ṿegn Hiṭlerishn ṭeror

Jidd., in hebr. Schr.

Position Errors Caused by GPS HI Blunders

Height of instrument (HI) blunders in GPS measurements cause position errors. These errors can be pure vertical, pure horizontal, or a mixture of both. There are different error regimes depending on whether both the base and the rover both have HI blunders, if just the base has an HI blunder, or just the rover has an HI blunder. The resulting errors are on the order of 30 cm for receiver separations of 1000 km for an HI blunder of 2 m. Given the complicated nature of the errors, we believe it would be difficult, if not impossible, to detect such errors by visual inspection. This serves to underline the necessity to enter GPS HIs correctly.

Idn un di milḥome miṭ Hiṭlern

Daṿid Bergelson

Toldot ha-defus ha-ʿIvri : be-ʿarim ha-eleh she-be-Eropah ; Aṿignyon, Izna, Amśṭerdam, Anṭṿerpen, Baziliʾah, Bruna, Dihrenfurṭ, Desauya, Hali, Ṿina, Ṭhingen, Yesnits, London, Laiden, Mets, Tsurikh, Ḳarlsru, Ḳoshṭants, Ḳiṭen, Ḳliṿa ṿe-Shṭrasburg me-reshit hiṿasdam ṿe-hitpatḥutam bi-shenat 276

me-et Ḥayim Doverish Fridberg

Clusters and Innovation: Beijing's Hi-technology Industry Cluster and Guangzhou's Automobile Industry Cluster

This paper proposes a flowchart approach to the automobile industry cluster policy and the hi-technology industry cluster policy to prioritize policy measures. First, in the automobile industry cluster, suppliers of parts and components to anchor firms such as Honda, Nissan and Toyota of Japanese assembly makers in Guangzhou, China, can innovate partly because the suppliers have become independent of their anchor firms in the Japanese Keiretsu system. Second, concerning the hi-technology industry clustering in Beijing, we show that the existence of universities is a precondition for the industrial cluster policy and that the leadership of the Zhongguancun Science Park Management Committee of Beijing Municipality is crucial to the success of the industrial cluster policy. The flowchart for the hi-technology industry is different from the one for the automobile industry cluster.

Désima I [Texto impreso] : en la primera desimeta no hiá qui em prive del dret ...

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