Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antivi...

Double-Stranded RNA Sensors and Modulators in Innate Immunity.

N. Maclachlan, Edward J. Dubovi 602 pages, hardback, £78.99. Academic Press. 2016. ISBN 978 0 12800 946 8 

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A LOT has happened since the fourth edition of Fenner's Veterinary Virology was published in 2011, which probably accounts for the fifth edition being 15 per cent larger. The past five years have seen several new emergences and spillover events; some significant yet unnoticed by the general public. Schmallenberg virus was first identified in Germany in 2011 and confirmed to be present in the UK at the beginning of 2012. There were 266 outbreaks in the UK in that year. In recent years, outbreaks of African swine fever virus have been seen across six eastern European countries where farming practices and …

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Principles of virology

Cells have evolved highly specialized sentinels that detect viral infection and elicit an antiviral response. Among these, the stress-sensing protein kinase R, which is activated by double-stranded RNA, mediates suppression of the host translation machinery as a strategy to limit viral replication. Non-translating mRNAs rapidly condensate by phase separation into cytosolic stress granules, together with numerous RNA-binding proteins and components of signal transduction pathways. Growing evidence suggests that the integrated stress response, and stress granules in particular, contribute to antiviral defense. This review summarizes the current understanding of how stress and innate immune signaling act in concert to mount an effective response against virus infection, with a particular focus on the potential role of stress granules in the coordination of antiviral signaling cascades.

https://www.mdpi.com/1999-4915/12/9/984/pdf

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

Background Severe sepsis and septic shock remain significant public health concerns. Appropriate emergency department management includes early recognition, hemodynamic resuscitation, source control, and prompt antibiotic administration. Current international guidelines strongly recommend administration of early and appropriate antibiotics for patients with severe sepsis and septic shock. Interestingly, a recent Cochrane Review found insufficient evidence to provide a similar recommendation on antibiotic administration. The goal of this literature search was to systematically review the available literature on early and appropriate antimicrobial therapy and provide emergency physicians an evidence-based approach to antibiotic therapy for septic patients. Methods Four PubMed searches were completed to identify abstracts of relevant interest. We limited studies to those completed in adult humans that were composed in English between 2005 and 2015. Included studies were randomized controlled trials, meta-analyses, prospective trials, and retrospective cohort studies. These studies were identified by a rigorous search methodology. No review articles, case series, or case reports were included. Predefined criteria were used to evaluate the quality and appropriateness of selected articles as part of a structured review. Results A total of 1552 abstracts were evaluated for inclusion. After the review of these studies, 14 were included for formal review. The authors then systematically evaluated each study, which formed the basis for this clinical statement. Conclusions Patients with severe sepsis and septic shock should receive early and appropriate antibiotics in the emergency department. Patients with septic shock who received appropriate antimicrobial therapy within 1 h of recognition had the greatest benefit in mortality.

Does Early and Appropriate Antibiotic Administration Improve Mortality in Emergency Department Patients with Severe Sepsis or Septic Shock

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. Through this activity, they are implicated in almost every cellular process investigated to date. Hence, it is not surprising that miRNAs play diverse roles in regulation of viral infections and antiviral responses. Diverse families of DNA and RNA viruses have been shown to take advantage of cellular miRNAs or produce virally encoded miRNAs that alter host or viral gene expression. MiRNA-mediated changes in gene expression have been demonstrated to modulate viral replication, antiviral immune responses, viral latency, and pathogenesis. Interestingly, viruses mediate both canonical and non-canonical interactions with miRNAs to downregulate specific targets or to promote viral genome stability, translation, and/or RNA accumulation. In this review, we focus on recent findings elucidating several key mechanisms employed by diverse virus families, with a focus on miRNAs at the host⁻virus interface during herpesvirus, polyomavirus, retroviruses, pestivirus, and hepacivirus infections.

https://www.mdpi.com/1999-4915/10/8/440/pdf

The Diverse Roles of microRNAs at the Host⁻Virus Interface.

HIV-1 translation is modulated by the activation of the interferon (IFN)-inducible Protein Kinase RNA-activated (PKR). PKR phosphorylates its downstream targets, including the alpha subunit of the eukaryotic translation Initiation Factor 2 (eIF2α), which decreases viral replication. The PKR Activator (PACT) is known to activate PKR after a cellular stress. In lymphocytic cell lines, HIV-1 activates PKR only transiently and not when cells replicate the virus at high levels. The regulation of this activation is due to a combination of viral and cellular factors that have been only partially identified. PKR is transiently induced and activated in peripheral blood mononuclear cells after HIV-1 infection. The addition of IFN reduces viral replication, and induces both the production and phosphorylation of PKR. In lymphocytic Jurkat cells infected by HIV-1, a multiprotein complex around PKR contains the double-stranded RNA binding proteins (dsRBPs), adenosine deaminase acting on RNA (ADAR)1 and PACT. In HEK 293T cells transfected with an HIV-1 molecular clone, PACT unexpectedly inhibited PKR and eIF2α phosphorylation and increased HIV-1 protein expression and virion production in the presence of either endogenous PKR alone or overexpressed PKR. The comparison between different dsRBPs showed that ADAR1, TAR RNA Binding Protein (TRBP) and PACT inhibit PKR and eIF2α phosphorylation in HIV-infected cells, whereas Staufen1 did not. Individual or a combination of short hairpin RNAs against PACT or ADAR1 decreased HIV-1 protein expression. In the astrocytic cell line U251MG, which weakly expresses TRBP, PACT mediated an increased HIV-1 protein expression and a decreased PKR phosphorylation. In these cells, a truncated PACT, which constitutively activates PKR in non-infected cells showed no activity on either PKR or HIV-1 protein expression. Finally, PACT and ADAR1 interact with each other in the absence of RNAs. In contrast to its previously described activity, PACT contributes to PKR dephosphorylation during HIV-1 replication. This activity is in addition to its heterodimer formation with TRBP and could be due to its binding to ADAR1. HIV-1 has evolved to replicate in cells with high levels of TRBP, to induce the expression of ADAR1 and to change the function of PACT for PKR inhibition and increased replication.

/pdf/the-pkr-activator-pact-becomes-a-pkr-inhibitor-during-hiv-1-2hnc8k9v06.pdf

The PKR activator, PACT, becomes a PKR inhibitor during HIV-1 replication.

Several proteins and RNAs expressed by mammalian viruses have been reported to interfere with RNA interference (RNAi) activity. We investigated the ability of the HIV-1-encoded RNA elements Trans-Activation Response (TAR) and Rev-Response Element (RRE) to alter RNAi. MicroRNA let7-based assays showed that RRE is a potent suppressor of RNAi activity, while TAR displayed moderate RNAi suppression. We demonstrate that RRE binds to TAR-RNA Binding Protein (TRBP), an essential component of the RNA Induced Silencing Complex (RISC). The binding of TAR and RRE to TRBP displaces small interfering (si)RNAs from binding to TRBP. Several stem-deleted RRE mutants lost their ability to suppress RNAi activity, which correlated with a reduced ability to compete with siRNA-TRBP binding. A lentiviral vector expressing TAR and RRE restricted RNAi, but RNAi was restored when Rev or GagPol were coexpressed. Adenoviruses are restricted by RNAi and encode their own suppressors of RNAi, the Virus-Associated (VA) RNA elements. RRE enhanced the replication of wild-type and VA-deficient adenovirus. Our work describes RRE as a novel suppressor of RNAi that acts by competing with siRNAs rather than by disrupting the RISC. This function is masked in lentiviral vectors co-expressed with viral proteins and thus will not affect their use in gene therapy. The potent RNAi suppressive effects of RRE identified in this study could be used to enhance the expression of RNAi restricted viruses used in oncolysis such as adenoviruses.

https://www.tandfonline.com/doi/pdf/10.1080/15476286.2015.1014759

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

Aim RNA interference (RNAi) is a mechanism by which small double-stranded RNAs called micro(mi) or small interfering(si) RNAs bind messenger RNAs (mRNAs) to inhibit their expression. The mechanism involves the RNA-induced silencing complex (RISC) composed of Dicer, TRBP and Ago2 proteins in which TRBP loads miRNAs into the active complex [1]. Several mammalian viruses interfere with RNAi activity. Changes in miRNA and mRNA expression have been observed in patients infected by HIV-1, but the mechanisms are not understood. To explain part of the relationship between RNAi and HIV-1, we investigated the ability and the mechanism of the HIV-1-encoded RNA Rev-Response Element (RRE) to suppress RNAi.

/pdf/competition-between-hiv-1-encoded-rre-rna-and-mirna-trbp-341y71pfjv.pdf

Competition between HIV-1-encoded RRE RNA and miRNA-TRBP interactions alters RNA interference activity and gene expression

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The PKR activator, PACT, becomes a PKR inhibitor during HIV-1 replication.

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

Competition between HIV-1-encoded RRE RNA and miRNA-TRBP interactions alters RNA interference activity and gene expression