180 research outputs found
The regulation of type I interferon production by paramyxoviruses
No full textResearch supported by The Wellcome Trust (087751/A/08/Z)Experimentally, paramyxoviruses are conventionally considered good inducers of type I interferons (IFN-alpha/beta), and have been used as agents in the commercial production of human IFN-alpha. However, in the last few years it has become clear that viruses in general mount a major challenge to the IFN system, and paramyxoviruses are no exception. Indeed, most paramyxoviruses encode mechanisms to inhibit both the production of, and response to, type I IFN. Here we review our knowledge of the type I IFN-inducing signals (by so-called pathogen-associated molecular patterns, or PAMPs) produced during paramyxovirus infections, and discuss how paramyxoviruses limit the production of PAMPs and inhibit the cellular responses to PAMPs by interfering with the activities of the pattern recognition receptors (PRRs), mda-5, and RIG-I, as well as downstream components in the type I IFN induction cascades.Peer reviewe
Does sadness impair color perception? Flawed evidence and faulty methods
No full textHolcombe AO, Brown NJL, Goodbourn PT, Etz A, Geukes S. Does sadness impair color perception? Flawed evidence and faulty methods. F1000Research. 2016;5: 1778
Activation of the beta interferon promoter by paramyxoviruses in the absence of virus protein synthesis
No full textConflicting reports exist regarding the requirement for virus replication in interferon (IFN) induction by paramyxoviruses. Our previous work has demonstrated that pathogen-associated molecular patterns capable of activating the IFN-induction cascade are not normally generated during virus replication, but are associated instead with the presence of defective interfering (DI) viruses. We demonstrate here that DIs of paramyxoviruses, including parainfluenza virus 5, mumps virus and Sendai virus, can activate the IFN-induction cascade and the IFN-beta promoter in the absence of virus protein synthesis. As virus protein synthesis is an absolute requirement for paramyxovirus genome replication, our results indicate that these DI viruses do not require replication to activate the IFN-induction cascade.Peer reviewe
LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA.
No full textThe DExD/H box RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (mda-5) sense viral RNA in the cytoplasm of infected cells and activate signal transduction pathways that trigger the production of type I interferons (IFNs). Laboratory of genetics and physiology 2 (LGP2) is thought to influence IFN production by regulating the activity of RIG-I and mda-5, although its mechanism of action is not known and its function is controversial. Here we show that expression of LGP2 potentiates IFN induction by polyinosinic-polycytidylic acid [poly(I:C)], commonly used as a synthetic mimic of viral dsRNA, and that this is particularly significant at limited levels of the inducer. The observed enhancement is mediated through co-operation with mda-5, which depends upon LGP2 for maximal activation in response to poly(I:C). This co-operation is dependent upon dsRNA binding by LGP2, and the presence of helicase domain IV, both of which are required for LGP2 to interact with mda-5. In contrast, although RIG-I can also be activated by poly(I:C), LGP2 does not have the ability to enhance IFN induction by RIG-I, and instead acts as an inhibitor of RIG-I-dependent poly(I:C) signaling. Thus the level of LGP2 expression is a critical factor in determining the cellular sensitivity to induction by dsRNA, and this may be important for rapid activation of the IFN response at early times post-infection when the levels of inducer are low
Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures
No full textThe interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.</p
A daytime nap reduces the attentional blink
No full textThe attentional blink (AB) is an impairment in detecting the second of two targets that appear in close temporal succession. Previous research suggests that the AB is reduced after days of practice (Maki & Padmanabhan, 1994), but not after four consecutive blocks in one session (Taatgen et al., 2009). Here we investigate the role of sleep in modulating practice-dependent changes in the AB. We used a rapid serial visual presentation (RSVP) display comprising a stream of 26 English letters presented at 12 items/s. Two of the letters were targets cued by an annulus, and the number of items between the first target (T1) and second target (T2) was varied to yield a lag of 2, 5 or 10 items. Participants reported which two letters they thought were circled, and no feedback was provided. Participants completed the task at 9am, 12pm, 3pm and 5pm for a total of four sessions in one day. At 1pm, half the participants took a polysomnographically recorded nap for 60-90min, while the other participants went about their normal day or sat in a room quietly resting. Pooling the non-napping groups, we observed a significant increase in correct T2 reporting across sessions only within the nap group, and only for lag 2. The magnitude of improvement correlated positively with proportion of light stage two sleep, and negatively with proportion of deeper slow-wave sleep. We estimated the efficacy, latency and precision of attentional selection using a mixture model that considered the serial position of non-target items mistakenly reported as T2. These analyses indicated that the improvement observed in the nap group was due to increased efficacy (probability of reporting a T2-relevant item), with no change in latency or precision. Our results suggest that sleep, particularly stage two sleep, improves temporal attention
ISG56/IFIT1 is primarily responsible for interferon-induced changes to patterns of parainfluenza virus type 5 transcription and protein synthesis
No full textThis work was supported by the Wellcome Trust.Interferon (IFN) induces an antiviral state in cells that results in alterations of the patterns and levels of parainfluenza virus type 5 (PIV5) transcripts and proteins. This study reports that IFN-stimulated gene 56/IFN-induced protein with tetratricopeptide repeats 1 (ISG56/IFIT1) is primarily responsible for these effects of IFN. It was shown that treating cells with IFN after infection resulted in an increase in virus transcription but an overall decrease in virus protein synthesis. As there was no obvious decrease in the overall levels of cellular protein synthesis in infected cells treated with IFN, these results suggested that ISG56/IFIT1 selectively inhibits the translation of viral mRNAs. This conclusion was supported by in vitro translation studies. Previous work has shown that ISG56/IFIT1 can restrict the replication of viruses lacking a 2'-O-methyltransferase activity, an enzyme that methylates the 2'-hydroxyl group of ribose sugars in the 5'-cap structures of mRNA. However, the data in the current study strongly suggested that PIV5 mRNAs are methylated at the 2'-hydroxyl group and thus that ISG56/IFIT1 selectively inhibits the translation of PIV5 mRNA by some as yet unrecognized mechanism. It was also shown that ISG56/IFIT1 is primarily responsible for the IFN-induced inhibition of PIV5.Peer reviewe
Paramyxovirus V proteins interact with the RNA helicase LGP2 to inhibit RIG-I-dependent interferon induction
No full textThis work was supported by the Wellcome Trust (grant AL087751/B)RIG-I and mda-5 are activated by viral RNA and stimulate type I interferon production. Laboratory of genetics and physiology 2 (LGP2) shares homology with RIG-I and mda-5 but lacks the CARD domains required for signaling. The V proteins of paramyxoviruses limit interferon induction by binding mda-5 and preventing its activation; however, they do not bind RIG-I and have not been considered inhibitors of RIG-I signaling. Here we uncover a novel mechanism of RIG-I inhibition in which the V protein of parainfluenzavirus type 5 (PIV5; formerly known as simian virus type 5 [SV5]) interacts with LGP2 and cooperatively inhibits induction by RIG-I ligands. A complex between RIG-I and LGP2 is observed in the presence of PIV5-V, and we propose that this complex is refractory to activation by RIG-I ligands. The V proteins from other paramyxoviruses also bind LGP2 and demonstrate LGP2-dependent inhibition of RIG-I signaling. This is significant, because it demonstrates a general mechanism for the targeting of the RIG-I pathway by paramyxoviruses.Peer reviewe
Sleep modulates temporal attention
No full textThe ability to allocate attentional resources in time is limited. In the attentional blink (AB) phenomenon, detection of the second of two targets that appear in close temporal succession is impaired (Martens & Wyble, 2010). Previous research suggests that the AB is reduced after days of practice (Maki & Padmanabhan, 1994), but not after four consecutive blocks within one session (Taatgen et al., 2009). Here we investigate the role of sleep in modulating practice-dependent changes in the AB. We used a rapid serial visual presentation (RSVP) display comprising a stream of 26 English letters presented at 12 items/s. Two of the letters were targets cued by an annulus, and the number of items between the first target (T1) and second target (T2) was varied to yield a lag of 2, 5 or 10 items. Participants reported which two letters they thought were cued, and no feedback was provided. Participants completed four sessions of the task at 9am, 12pm, 3pm and 5pm. At 1pm, half the participants took a polysomnographically-recorded nap for 60-90min, while the other participants went about their normal daytime activities. We observed increased T2 accuracy across sessions only within the nap group, and only for lag 2. The magnitude of improvement correlated positively with proportion of light stage two sleep, and negatively with proportion of deeper slow-wave sleep. We estimated the efficacy (probability of reporting a T2-relevant item), latency and precision of attentional selection using a mixture model that considered the serial position of non-target items mistakenly reported as T2. These analyses indicated that the improvement observed in the nap group was due to increased efficacy, with no change in latency or temporal precision. Our results suggest that sleep, particularly stage two sleep, improves temporal attention
Mapuera virus, a rubulavirus that inhibits interferon signalling in a wide variety of mammalian cells without degrading STATs
No full textMajouera virus (MPRV) is a paramyxovirus that was originally isolated from bats, but its host range remains unknown. It was classified as a member of the genus Rubulavirus on the basis of structural and genetic features. Like other rubulaviruses it encodes a V protein (MPRV/V) that functions as an interferon (IFN) antagonist. Here we show that MPRV/V differs from the IFN antagonists of other rubulaviruses in that it does not induce the proteasomal degradation of STAT proteins, key factors in the IFN signalling cascade. Rather, MPRV/V prevents the nuclear translocation of STATs in response to IFN stimulation and inhibits the formation of the transcription factor complex ISGF3. We also show that MPRV/V blocks IFN signalling in cells from diverse mammalian species and discuss the IFN response as a barrier to cross-species infections.</p
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