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The source, timing, and geographical origin of the 1918–1920 pandemic influenza A virus have remained tenaciously obscure for nearly a century, as have the reasons for its unusual severity among young adults. Here, we reconstruct the origins of the pandemic virus and the classic swine influenza and (postpandemic) seasonal H1N1 lineages using a host-specific molecular clock approach that is demonstrably more accurate than previous methods. Our results suggest that the 1918 pandemic virus originated shortly before 1918 when a human H1 virus, which we infer emerged before ∼1907, acquired avian N1 neuraminidase and internal protein genes. We find that the resulting pandemic virus jumped directly to swine but was likely displaced in humans by ∼1922 by a reassortant with an antigenically distinct H1 HA. Hence, although the swine lineage was a direct descendent of the pandemic virus, the post-1918 seasonal H1N1 lineage evidently was not, at least for HA. These findings help resolve several seemingly disparate observations from 20th century influenza epidemiology, seroarcheology, and immunology. The phylogenetic results, combined with these other lines of evidence, suggest that the high mortality in 1918 among adults aged ∼20 to ∼40 y may have been due primarily to their childhood exposure to a doubly heterosubtypic putative H3N8 virus, which we estimate circulated from ∼1889–1900. All other age groups (except immunologically naive infants) were likely partially protected by childhood exposure to N1 and/or H1-related antigens. Similar processes may underlie age-specific mortality differences between seasonal H1N1 vs. H3N2 and human H5N1 vs. H7N9 infections.

The specificity of interferon effectors across an expanded range of viruses is studied, with results indicating that positive-sense single-stranded RNA viruses are more susceptible to interferon-stimulated gene activity than negative-sense RNA or DNA viruses; in addition, the DNA sensor cGAS is shown to have an unappreciated role in RNA virus inhibition. cGAS crucial to innate immunity This study reports the use of cell culture models to scan an extensive interferon-stimulated gene (ISG) library for activity against a broad spectrum of viruses. The scan reveals that positive-sense single-stranded (ss)RNA viruses are more susceptible to ISG activities than negative-sense ssRNA viruses or a DNA virus. The DNA sensor cyclic GMP-AMP synthase (cGAS) is shown to inhibit several RNA viruses. The authors also generated cGAS knockout mice and showed an in vivo requirement for cGAS in antiviral responses. The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors 1 , 2 , 3 . Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase ( cGAS , also known as MB21D1 ) as a gene whose expression also broadly inhibits several RNA viruses. In vitro , lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo , genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.

Viruses can infect all cell-based organisms, from bacteria to humans, animals, and plants. They are responsible for numerous cases of hospitalization, many deaths, and widespread crop destruction, all of which result in an enormous medical, economical, and biological burden. Each of the currently used decontamination methods has important drawbacks. Cold plasma (CP) has entered this field as a novel, efficient, and clean solution for virus inactivation. We present recent developments in this promising field of CP-mediated virus inactivation, and describe the applications and mechanisms of the inactivation. This is particularly relevant because viral pandemics, such as COVID-19, highlight the need for alternative virus inactivation methods to replace, complement, or upgrade existing procedures. Pathogenic viruses are becoming an increasing burden for health, agriculture, and the global economy. Classic disinfection methods have several drawbacks, and innovative solutions for virus inactivation are urgently needed.CP can be used as an environmentally friendly tool for virus inactivation. It can inactivate different human, animal, and plant viruses in various matrices.When using CP for virus inactivation it is important to set the correct parameters and to choose treatment durations that allow particles to interact with the contaminated material.Reactive oxygen and/or nitrogen species have been shown to be responsible for virus inactivation through effects on capsid proteins and/or nucleic acids. The development of more accurate methods will provide information on which plasma particles are crucial in each experiment, and how exactly they affect viruses.

Being opportunistic intracellular pathogens, viruses are dependent on the host for their replication. They hijack host cellular machinery for their replication and survival by targeting crucial cellular physiological pathways, including transcription, translation, immune pathways, and apoptosis. Immediately after translation, the host and viral proteins undergo a process called post-translational modification (PTM). PTMs of proteins involves the attachment of small proteins, carbohydrates/lipids, or chemical groups to the proteins and are crucial for the proteins’ functioning. During viral infection, host proteins utilize PTMs to control the virus replication, using strategies like activating immune response pathways, inhibiting viral protein synthesis, and ultimately eliminating the virus from the host. PTM of viral proteins increases solubility, enhances antigenicity and virulence properties. However, RNA viruses are devoid of enzymes capable of introducing PTMs to their proteins. Hence, they utilize the host PTM machinery to promote their survival. Proteins from viruses belonging to the family: Togaviridae, Flaviviridae, Retroviridae, and Coronaviridae such as chikungunya, dengue, zika, HIV, and coronavirus are a few that are well-known to be modified. This review discusses various host and virus-mediated PTMs that play a role in the outcome during the infection.

Deformed wing virus (DWV) and its vector, the mite Varroa destructor, are a major threat to the world's honeybees. Although the impact of Varroa on colony-level DWV epidemiology is evident, we have little understanding of wider DWV epidemiology and the role that Varroa has played in its global spread. A phylogeographic analysis shows that DWV is globally distributed in honeybees, having recently spread from a common source, the European honeybee Apis mellifera. DWV exhibits epidemic growth and transmission that is predominantly mediated by European and North American honeybee populations and driven by trade and movement of honeybee colonies. DWV is now an important reemerging pathogen of honeybees, which are undergoing a worldwide manmade epidemic fueled by the direct transmission route that the Varroa mite provides.

Interferons (IFNs) contribute to cell-intrinsic antiviral immunity by inducing hundreds of interferon-stimulated genes (ISGs). In a screen to identify antiviral ISGs, we unexpectedly found that LY6E, a member of the LY6/uPAR family, enhanced viral infection. Here, we show that viral enhancement by ectopically expressed LY6E extends to several cellular backgrounds and affects multiple RNA viruses. LY6E does not impair IFN antiviral activity or signaling, but rather promotes viral entry. Using influenza A virus as a model, we narrow the enhancing effect of LY6E to uncoating after endosomal escape. Diverse mammalian orthologs of LY6E also enhance viral infectivity, indicating evolutionary conservation of function. By structure-function analyses, we identify a single amino acid in a predicted loop region that is essential for viral enhancement. Our study suggests that LY6E belongs to a class of IFN-inducible host factors that enhance viral infectivity without suppressing IFN antiviral activity. The interferon-induced gene LY6E increases virus infection, but the underlying mechanism is poorly understood. Here, Mar et al. show that LY6E enhances uncoating of influenza A virus after endosomal escape and that viral enhancement by LY6E is conserved across evolution.

SignificanceRiboswitches are short RNA sequences for ligand-dependent modulation of gene expression in cis. This study demonstrates that an artificial riboswitch, a ligand-dependent self-cleaving ribozyme (aptazyme), can knockdown expression of an adeno- (DNA) virus early and a measles (RNA) virus structural gene, impacting biological outcomes, i.e. inhibiting viral genome replication and infectivity, respectively. It is the first report of riboswitches for replication control of human-pathogenic viruses and of their function in fully cytoplasmic (virus) systems. For future applications, aptazymes can be customized in other viruses facilitating analyses of viral gene functions or as a safety switch in oncolytic viruses. Because of their small size and RNA-intrinsic activity, we propose aptazymes as an alternative for inducible promoters in eukaryotic gene expression control. Aptazymes are small, ligand-dependent self-cleaving ribozymes that function independently of transcription factors and can be customized for induction by various small molecules. Here, we introduce these artificial riboswitches for regulation of DNA and RNA viruses. We hypothesize that they represent universally applicable tools for studying viral gene functions and for applications as a safety switch for oncolytic and live vaccine viruses. Our study shows that the insertion of artificial aptazymes into the adenoviral immediate early gene E1A enables small-molecule–triggered, dose-dependent inhibition of gene expression. Aptazyme-mediated shutdown of E1A expression translates into inhibition of adenoviral genome replication, infectious particle production, and cytotoxicity/oncolysis. These results provide proof of concept for the aptazyme approach for effective control of biological outcomes in eukaryotic systems, specifically in virus infections. Importantly, we also demonstrate aptazyme-dependent regulation of measles virus fusion protein expression, translating into potent reduction of progeny infectivity and virus spread. This not only establishes functionality of aptazymes in fully cytoplasmic genetic systems, but also implicates general feasibility of this strategy for application in viruses with either DNA or RNA genomes. Our study implies that gene regulation by artificial riboswitches may be an appealing alternative to Tet- and other protein-dependent gene regulation systems, based on their small size, RNA-intrinsic mode of action, and flexibility of the inducing molecule. Future applications range from gene analysis in basic research to medicine, for example as a safety switch for new generations of efficiency-enhanced oncolytic viruses.

Interferon-inducible transmembrane (IFITM) protein 3 is shown to be an innate defence mechanism against viral infection in vivo ; furthermore, a subset of the patients hospitalized during the H1N1 2009 pandemic carried a variant form of the IFITM3 gene. Immune defence against flu virus Interferon-inducible transmembrane (IFITM) proteins restrict the replication of certain pathogenic viruses, but no in vivo role for these proteins has been known until now. Paul Kellam and colleagues now report that IFITM3 is essential for protecting mice infected with influenza viruses from developing fulminant viral pneumonia. The authors further find that a small subset of humans hospitalized for infection with pandemic H1N1/09 swine flu or seasonal influenza virus carried a variant of IFITM3 with reduced antiviral activity. These results suggest that IFITM3 has a pivotal role in defence against influenza infection. The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses 1 , 2 , 3 , 4 , 5 , 6 , 7 . Both the magnitude and breadth of the IFITM proteins’ in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model 8 , we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo . Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 ‘Spanish’ influenza 9 , 10 . Similar increased viral replication is seen in vitro , with protection rescued by the re-introduction of Ifitm3 . To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro . Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.

Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fcγ receptor (FcγR)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcγR-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon FcγR engagement and review the available experimental evidence supporting the role of FcγRs in antiviral protection and pathogenesis through ADE. We explore FcγR engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.Antibody-dependent enhancement (ADE) has been described as a mechanism that contributes to the pathogenesis of dengue virus infection. Limited evidence also suggests that it can also occur in other viral infections. Here, the authors explore the history of the ADE phenomenon, discuss the diversity of Fc effector functions and consider its potential relevance in the context of SARS-CoV-2 infection.

The 3.7 Å cryo-electron microscopy structure of Zika virus is presented, revealing a typical flavivirus architecture; in contrast to the related flavivirus dengue virus, Zika virus is thermally stable at 40 °C, and this structural stability may be a feature that helps it to survive in semen, saliva and urine. What makes Zika virus tough Shee-Mei Lok and colleagues provide a 3.7 Å cryo-electron microscopy view of Zika virus, revealing typical flavivirus architecture. They report that in contrast to the related flavivirus dengue virus, Zika virus is thermally stable at 40 °C, and speculate that this structural stability may contribute to the ability of the virus to survive in semen, saliva and urine. Zika virus (ZIKV), formerly a neglected pathogen, has recently been associated with microcephaly in fetuses 1 , and with Guillian–Barré syndrome in adults 2 . Here we present the 3.7 Å resolution cryo-electron microscopy structure of ZIKV, and show that the overall architecture of the virus is similar to that of other flaviviruses. Sequence and structural comparisons of the ZIKV envelope (E) protein with other flaviviruses show that parts of the E protein closely resemble the neurovirulent West Nile and Japanese encephalitis viruses, while others are similar to dengue virus (DENV). However, the contribution of the E protein to flavivirus pathobiology is currently not understood. The virus particle was observed to be structurally stable even when incubated at 40 °C, in sharp contrast to the less thermally stable DENV 3 . This is also reflected in the infectivity of ZIKV compared to DENV serotypes 2 and 4 (DENV2 and DENV4) at different temperatures. The cryo-electron microscopy structure shows a virus with a more compact surface. This structural stability of the virus may help it to survive in the harsh conditions of semen 4 , saliva 5 and urine 6 . Antibodies or drugs that destabilize the structure may help to reduce the disease outcome or limit the spread of the virus.