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in human influenza transmission, it is not extreme in nature; some diversity can be meaningfully retained between hosts. Copyright © 2020 Ghafari et al.Herpes simplex virus type 1 (HSV-1) is a leading cause of infectious blindness, highlighting the need for effective vaccines. A single-cycle HSV-2 strain deleted in glycoprotein D, ΔgD-2, completely protected mice from HSV-1 and HSV-2 skin or vaginal disease, and prevented latency following active or passive immunization in preclinical studies. The antibodies functioned primarily by activating Fc receptors to mediate antibody-dependent cellular cytotoxicity (ADCC). The ability of ADCC to protect the immune privileged eye, however, may differ from skin or vaginal infections. Thus, the current studies were designed to compare active and passive immunization with ΔgD-2 versus an adjuvanted gD subunit vaccine (rgD-2) in a primary lethal ocular murine model. ΔgD-2 provided significantly greater protection than rgD-2 following a two-dose vaccine regimen, although both vaccines were protective compared to mice immunized with an uninfected cell lysate. However, only immune serum from ΔgD-2-vaccinated, but not rgD-2-veged site. In these studies, we compared a single-cycle viral vaccine candidate, which is unique in that it elicits predominantly non-neutralizing antibodies that activate Fc receptors and bind complement, and a glycoprotein D subunit vaccine that elicits neutralizing, but not Fc receptor activating or complement binding responses. Only the single-cycle vaccine provided both active and passive protection against a lethal ocular challenge. These findings greatly expand our understanding of the types of immune responses needed to protect the eye and will inform future prophylactic and therapeutic strategies. Copyright © 2020 American Society for Microbiology.Respiratory syncytial virus (RSV) is a major cause of paediatric respiratory disease. Large numbers of neutrophils are recruited into the airways of children with severe RSV disease. It is not clear whether or how neutrophils enhance recovery from disease or contribute to its pathology.Using an in vitro model of the differentiated airway epithelium, we found that addition of physiological concentrations of neutrophils to RSV infected nasal cultures was associated with greater epithelial damage with lower ciliary activity, cilia loss, less tight junction expression (ZO-1) and more detachment of epithelial cells than seen with RSV infection alone. This was also associated with a decrease in infectious virus and fewer RSV positive cells in cultures after neutrophil exposure compared to pre-exposure. Epithelial damage in response to RSV infection was associated with neutrophil activation (within 1h), and neutrophil degranulation with significantly greater cellular expression of CD11b, MPO and higher neutrophil elastase and myeloperoxidase activity in apical surface medias compared to that from mock-infected AECs. We also recovered more apoptotic neutrophils from RSV infected cultures (>40%), compared to less then 5% in mock infected cultures after 4h.The results of this study could provide important insights into the role of neutrophils in host response in the airway.Importance This study shows that the RSV infected human airway drives changes in the behaviour of human neutrophils including increasing activation markers and delaying apoptosis that results in greater airway damage and viral clearance. Copyright © 2020 Deng et al.Virus infection leads to activation of the interferon-induced endoribonuclease, RNase L, which results in degradation of viral and cellular RNAs. Both cellular and viral RNA cleavage products of RNase L bind pattern recognition receptors (PRR) like Retinoic acid-inducible I (Rig-I) and or melanoma differentiation-associated protein 5 (MDA5) to further amplify interferon (IFN) production and antiviral response. Although much is known about the mechanics of ligand binding and PRR activation, how the cells coordinate RNA sensing to signaling response and interferon production remains unclear. We show that RNA cleavage products of RNase L activity induce formation of antiviral stress granule (avSG) by regulating activation of double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), and recruit antiviral proteins Rig-I, PKR, OAS and RNase L to avSG. Biochemical analysis of purified avSG showed interaction of key stress granule protein, G3BP1, with only PKR and Rig-I and not with OAS or RNase L. AvSG assembly N production. This study identifies a novel role of antiviral stress granules induced by RNase L as an antiviral signaling hub to coordinate the RNA ligands with cognate receptors to mount effective host response during viral infections. Copyright © 2020 Manivannan et al.During the replication of parainfluenza virus type 5 (PIV5) copyback defective virus genomes (DVGs) are erroneously produced and are packaged into "infectious" virus particles. Copyback DVGs are primary inducers of innate intracellular responses, including the interferon (IFN) response. Whilst DVGs can interfere with the replication of non-defective (ND) virus genomes and activate the IFN-induction cascade before ND PIV5 can block the production of IFN, we demonstrate that the converse is also true, i.e. RSL3 ic50 high levels of ND virus can block the ability of DVGs to activate the IFN-induction cascade. By following the replication and amplification of DVGs in A549 cells that are deficient in a variety of innate intracellular antiviral responses, we show that DVGs induce an uncharacterised IFN-independent innate response(s) that limits their replication. High throughput sequencing was used to characterise the molecular structure of copyback DVGs. Whilst there appears to be no sequence-specific break or rejoining poins, genome region, size and structural preferences are selected for during their evolution and amplification. Copyright © 2020 Wignall-Fleming et al.Influenza A virus encodes a viral RNA-dependent RNA polymerase (FluPolA), which is responsible for transcribing and replicating the negative-sense viral RNA (vRNA) genome. FluPolA transcribes vRNA using a host capped mRNA primer, and replicates it by synthesising a positive-sense complementary RNA (cRNA) intermediate which is copied back into vRNA. To carry out these functions, FluPolA interacts with vRNA and cRNA using conserved promoter elements at the 5' and 3' termini. Recent structural studies have identified a new surface binding site for the 3' vRNA and cRNA promoters on FluPolA, referred to as the Mode B site. However, the role of this binding site in FluPolA function is unknown. In this study we used a combination of cell-based and biochemical assays to show that the Mode B site is important for both viral genome transcription and replication. Furthermore, we show that the Mode B site is not needed for initiating transcription in vitro but is required to synthesise a full-length product. This is consnome transcription by the influenza virus polymerase, and may be applicable to other related viruses. Copyright © 2020 American Society for Microbiology.Echovirus 30 (E30), a member of the enterovirus B species, is a major cause of viral meningitis, targeting children and adults alike. While it is a frequently isolated enterovirus and the cause of several outbreaks all over the world, suprisingly little is known regarding its entry and replication strategy within cells. In this study, we used E30 Bastianni (E30B) generated from an infectious cDNA clone in order to study early entry events during infection in human RD cells. E30B required the newly discovered Fc echovirus receptor (FcRn) for succesful infection, but not the Coxsackievirus and Adenovirus Receptor (CAR) or Decay-Accelerating Factor (DAF), although an interaction with DAF was observed. Double-stranded RNA replication intermediate was generated between 2 and 3 h post-infection (p.i.). and viral capsid production was initiated between 4 and 5 h p.i. The drugs affecting Rac1 (NSC 23766) and cholesterol (Filipin III) compromised infection, whereas bafilomycin A1, dyngo, U-73122, wortmannin and nocodaiscent of these viruses, e.g. by not relying on acidification for infectious entry. However, despite not using the clathrin entry pathway, E30 accumulates in classical early endosomes. Copyright © 2020 American Society for Microbiology.Histone deacetylase inhibitors (HDACi) are the most widely studied HIV latency reversing agents (LRAs). The HDACi suberoylanilidehydroxamic acid (vorinostat, VOR) has been employed in several clinical HIV latency reversal studies as well as in vitro models of HIV latency and shown to effectively induce HIV RNA and protein expression. Despite these findings, response to HDACi can vary, particularly with intermittent dosing, and information is lacking on the relationship between host transcriptional response and HIV latency reversal. Herein, we report on global gene expression responses to VOR and examined the longevity of the transcriptional response in various cellular models. We find many genes are modulated at 6 h post-VOR in HCT116, Jurkat and primary resting CD4 T cells yet return to baseline levels after an 18 h VOR-free period. With repeat exposure to VOR in resting CD4 T cells, we find similar and consistent transcriptional changes 6 h following each serial treatment. In addition, serial exposure in HIly exposures to VOR. Our study provides evidence that VOR induces a consistent level of host cell gene transcription, following intermittent exposure. In addition, a gene signature was identified in response to VOR exposure that was conserved across single and serial exposures both in vitro and in vivo, indicating that VOR can consistently and reproducibly modulate transcriptional host responses. However, as responses to HIV response to HDACis decline over time, other factors modulate viral reactivation in vivo despite robust HDAC activity. The identified host gene VOR biomarkers can be used for monitoring the pharmacodynamic activity of HDAC inhibitors. Copyright © 2020 Maxwell et al.Měnglà virus (MLAV), identified in Rousettus bats, is a phylogenetically distinct member of the family Filoviridae Because the filoviruses Ebola virus (EBOV) and Marburg virus (MARV) modulate host innate immunity, MLAV VP35, VP40 and VP24 proteins were compared with their EBOV and MARV homologs for innate immune pathway modulation. In human and Rousettus cells, MLAV VP35 behaved like EBOV and MARV VP35s, inhibiting virus-induced activation of the interferon (IFN)-β promoter and IRF3 phosphorylation. MLAV VP35 also interacted with PACT, a host protein engaged by EBOV VP35 to inhibit RIG-I signaling. MLAV VP35 also inhibits PKR activation. MLAV VP40 was demonstrated to inhibit type I IFN induced gene expression in human and bat cells. It blocked STAT1 tyrosine phosphorylation induced either by type I IFN or over-expressed Jak1, paralleling MARV VP40. MLAV VP40 also inhibited virus-induced IFNβ promoter activation, a property shared by MARV VP40 and EBOV VP24. A Jak kinase inhibitor did not recapitulate this inhy activities are possessed by MLAV VP35 and VP40, which parallels how MARV blocks IFN responses. However, whereas MARV activates cellular antioxidant responses through an interaction between its VP24 protein and host protein Keap1, MLAV VP24 lacks a Keap1 binding motif and fails to activate this cytoprotective response. These data indicate that MLAV possesses immune suppressing functions that could facilitate human infection. They also support the placement of MLAV in a different genus than either EBOV or MARV. Copyright © 2020 American Society for Microbiology.