Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

Innate immune defences are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs). Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people worldwide. Infection is regulated by hepatic immune defences triggered by the cellular RIG-I helicase. RIG-I binds PAMP RNA and signals interferon regulatory factor 3 activation to induce the expression of interferon-alpha/beta and antiviral/interferon-stimulated genes (ISGs) that limit infection. Here we identify the polyuridine motif of the HCV genome 3' non-translated region and its replication intermediate as the PAMP substrate of RIG-I, and show that this and similar homopolyuridine or homopolyriboadenine motifs present in the genomes of RNA viruses are the chief feature of RIG-I recognition and immune triggering in human and murine cells. 5' terminal triphosphate on the PAMP RNA was necessary but not sufficient for RIG-I binding, which was primarily dependent on homopolymeric ribonucleotide composition, linear structure and length. The HCV PAMP RNA stimulated RIG-I-dependent signalling to induce a hepatic innate immune response in vivo, and triggered interferon and ISG expression to suppress HCV infection in vitro. These results provide a conceptual advance by defining specific homopolymeric RNA motifs within the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and demonstrate immunogenic features of the PAMP-RIG-I interaction that could be used as an immune adjuvant for vaccine and immunotherapy approaches.     

NLRX1 is a regulator of mitochondrial antiviral immunity

The RIG-like helicase (RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection. MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus-induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti-pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses.     

An inhibitor of Bcl-2 family proteins induces regression of solid tumours

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.     

Infrared radiation from an extrasolar planet

A class of extrasolar giant planets--the so-called 'hot Jupiters' (ref. 1)--orbit within 0.05 au of their primary stars (1 au is the Sun-Earth distance). These planets should be hot and so emit detectable infrared radiation. The planet HD 209458b (refs 3, 4) is an ideal candidate for the detection and characterization of this infrared light because it is eclipsed by the star. This planet has an anomalously large radius (1.35 times that of Jupiter), which may be the result of ongoing tidal dissipation, but this explanation requires a non-zero orbital eccentricity (approximately 0.03; refs 6, 7), maintained by interaction with a hypothetical second planet. Here we report detection of infrared (24 microm) radiation from HD 209458b, by observing the decrement in flux during secondary eclipse, when the planet passes behind the star. The planet's 24-microm flux is 55 +/- 10 microJy (1sigma), with a brightness temperature of 1,130 +/- 150 K, confirming the predicted heating by stellar irradiation. The secondary eclipse occurs at the midpoint between transits of the planet in front of the star (to within +/- 7 min, 1sigma), which means that a dynamically significant orbital eccentricity is unlikely.     

Calcium and magnesium deficiency and C3 fraction of complement]

The third (C3) and fourth (C4) components of complement and C3 proactivator (C3PA) were determined in 55 children with low serum levels of calcium and magnesium and 30 normal children. The concentrations of serum C3, C4 and C3PA were significantly reduced in children with double deficiences of calcium and magnesium. There were significant correlations between calcium and C3 and magnesium and C3PA. The relations between calcium, magnesium and the classical or alternate pathway of complement systems are discussed.     

United Kingdom: The Corporate Strategy for 1989 of the Medical Research Council (MRC)

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United Kingdom: The Corporate Strategy for 1989 of the Medical Research Council (MRC)     

Tetraradial symmetry in early poriferans

Here is currently little consensus on the branching order and phyletic status of the oldest metazoan groups, but sponges are widely believed to be the earliest- branching living metazoans. Porifera are thought to have diverged before the emergence of developmental charac- ters typical of Eumetazoa, such as well-defined symmetry; extant sponges show radial symmetry of indeterminate high order, or none, combined with polarisation along the axis. In contrast, other early-branching phyla include bilateral and tetraradial （Cnidaria） and biradial （Cte- nophora） symmetry, or none （Placozoa）. A variety of prismatic early fossil sponges had shown here where the shared symmetry has been overlooked, and also describe structural tetraradial symmetry in Cambrian sponges from South China. Based on this study, this symmetry is likely to have been a primitive feature of sponges, and that the earliest-known fossil sponges were highly organised, cel- lularly integrated individuals whose body form was under strict genetic control.