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Numerous invasive viral infections pose a growing threat to rice yield. Rice viruses encode multifunctional effector proteins to evade or counter plant immunity and eventually establish a successful infection. Phytohormones play an important role in the innate immune system, restricting broad-spectrum viral infections. Recent advances have revealed similar pathogenic strategies that have evolved convergently from several distinct plant RNA viruses by dampening host phytohormone signaling networks. Plants have developed very diverse strategies to defend themselves against viral pathogens, among which plant hormones play pivotal roles. In response, some viruses have also deployed multifunctional viral effectors that effectively hijack key component hubs to counter or evade plant immune surveillance. Although significant progress has been made toward understanding counter-defense strategies that manipulate plant hormone regulatory molecules, these efforts have often been limited to an individual virus or specific host target/pathway. This review provides new insights into broad-spectrum antiviral responses in rice triggered by key components of phytohormone signaling, and highlights the common features of counter-defense strategies employed by distinct rice-infecting RNA viruses. These strategies involve the secretion of multifunctional virulence effectors that target the sophisticated phytohormone system, dampening immune responses by engaging with the same host targets. Additionally, the review provides an in-depth exploration of various viral effectors, emphasizing tertiary structure-based research and shared host targets. Understanding these conserved characteristics in detail may pave the way for molecular drug design, opening new opportunities to enhance broad-spectrum antiviral trials through precise engineering. [ABSTRACT FROM AUTHOR]

Oligosaccharins, widely recognized as plant immunity inducers, have been applied and studied for enhancing antiviral defenses in rice over the years. However, due to the complex induction mechanism in rice, further studies are needed. In this study, we demonstrated that oligosaccharins enhanced rice resistance to southern rice black-streaked dwarf virus (SRBSDV) at both the symptomatic and molecular levels. RNA-seq analysis revealed that oligosaccharins enhanced rice antiviral defense by activating multiple defense pathways. Among them, the jasmonic acid (JA) signaling pathway, a crucial antiviral pathway in rice, was investigated in detail. Interestingly, RNA-seq data showed that genes related to JA signaling pathway were significantly induced after 1 h but not after 24 h of oligosaccharins treatment, suggesting that JA induction by oligosaccharins was rapid and sensitive. Furthermore, JA levels and sensitivity analysis showed that oligosaccharins induced JA accumulation, making treated rice plants more sensitive to methyl jasmonate (MeJA). Additionally, oligosaccharins treatment also induced a burst of reactive oxygen species (ROS) in rice. Notably, oligosaccharins demonstrated a low-dose effect, within a certain dilution range from 6000-fold to 1000-fold diluted solution of 5% oligosaccharins, with the 4000-fold diluted solution exhibiting a stronger ability to induce elevated production of JA and ROS. Moreover, the application of low-dose oligosaccharins also enhanced rice resistance to SRBSDV. These data suggest that low-dose of oligosaccharins can enhance rice antiviral defense by inducing multiple defense pathways, including the JA signaling pathway and ROS production. [ABSTRACT FROM AUTHOR]

Abstract Oligosaccharins, widely recognized as plant immunity inducers, have been applied and studied for enhancing antiviral defenses in rice over the years. However, due to the complex induction mechanism in rice, further studies are needed. In this study, we demonstrated that oligosaccharins enhanced rice resistance to southern rice black-streaked dwarf virus (SRBSDV) at both the symptomatic and molecular levels. RNA-seq analysis revealed that oligosaccharins enhanced rice antiviral defense by activating multiple defense pathways. Among them, the jasmonic acid (JA) signaling pathway, a crucial antiviral pathway in rice, was investigated in detail. Interestingly, RNA-seq data showed that genes related to JA signaling pathway were significantly induced after 1 h but not after 24 h of oligosaccharins treatment, suggesting that JA induction by oligosaccharins was rapid and sensitive. Furthermore, JA levels and sensitivity analysis showed that oligosaccharins induced JA accumulation, making treated rice plants more sensitive to methyl jasmonate (MeJA). Additionally, oligosaccharins treatment also induced a burst of reactive oxygen species (ROS) in rice. Notably, oligosaccharins demonstrated a low-dose effect, within a certain dilution range from 6000-fold to 1000-fold diluted solution of 5% oligosaccharins, with the 4000-fold diluted solution exhibiting a stronger ability to induce elevated production of JA and ROS. Moreover, the application of low-dose oligosaccharins also enhanced rice resistance to SRBSDV. These data suggest that low-dose of oligosaccharins can enhance rice antiviral defense by inducing multiple defense pathways, including the JA signaling pathway and ROS production.

Mitochondria are key orchestrators of antiviral responses that serve as platforms for the assembly and activation of innate immune-signaling complexes. In response to viral infection, mitochondria can be triggered to release immune-stimulatory molecules that can boost interferon production. These same molecules can be released by damaged mitochondria to induce pathogenic, antiviral-like immune responses in the absence of infection. This review explores how members of the tripartite motif-containing (TRIM) protein family, which are recognized for their roles in antiviral defense, regulate mitochondria-based innate immune activation. In antiviral defense, TRIMs are essential components of immune signal transduction pathways and function as directly acting viral restriction factors. TRIMs carry out conceptually similar activities when controlling immune activation related to mitochondria. First, they modulate immune-signaling pathways that can be activated by mitochondrial molecules. Second, they co-ordinate the direct removal of mitochondria and associated immune-activating factors through mitophagy. These insights broaden the scope of TRIM actions in innate immunity and may implicate TRIMs in diseases associated with mitochondria-derived inflammation. [ABSTRACT FROM AUTHOR]

Currently, there are approximately 6500 species of viruses known in the world, among which more than 1500 are plant viruses. Most of them are capable of causing epiphytoties, which lead to decreased yields, reduced product quality, and sometimes put valuable commercial varieties or even entire plant species at risk of extinction. The global spread of viruses leads to the need to strengthen phytosanitary and quarantine restrictions, which requires additional financial costs. Understanding of viral biology and the principles of its propagation is a key factor in the formation of strategies and methods for combating these pathogens. Among the newest approaches are the genetic engineering technologies. Their use made it possible to create a number of plant varieties with increased resistance to viruses. However, the problem of creating virus-resistant plants still remains one of the most urgent since viruses acquire the ability to bypass defense mechanisms with time and there is a need to obtain new resistant varieties. There are several main approaches for obtaining of transgenic plants with increased resistance to viruses. They are based on RNA interference, resistance associated with viral capsid proteins, RNA-satellites, antisense RNAs, replicases, RNA-dependent RNA polymerase, the action of ribonucleases, ribosome-inactivating proteins, hammerhead ribozymes, miRNAs, plant antibodies, etc. One of the approaches to creating virus-resistant plants is the use of ribonuclease genes. The genes encoding ribonucleases have different origin and belong to a wide range of hosts: bacteria, fungi, plants, and animals. In particular, extracellular ribonucleases are able to cut nonspecifically molecules of viral RNA in apoplast that allows for creating plants with increased resistance to various plant viruses. This review is focused on the study of various genetic engineering approaches and the prospects of their use for the creation of virus-resistant plants. Emphasis is placed on the study of heterologous ribonuclease genes influence. [ABSTRACT FROM AUTHOR]

Endogenous viral elements (EVEs) are common genetic passengers in various protists. Some EVEs represent viral fossils, whereas others are still active. The marine heterotrophic flagellate Cafeteria burkhardae contains several EVE types related to the virophage mavirus, a small DNA virus that parasitizes the lytic giant virus CroV. We hypothesized that endogenous virophages may act as an antiviral defense system in protists, but no protective effect of virophages in wild host populations has been shown so far. Here, we tested the activity of virophage EVEs and studied their impact on giant virus replication. We found that endogenous mavirus-like elements (EMALEs) from globally distributed Cafeteria populations produced infectious virus particles specifically in response to CroV infection. However, reactivation was stochastic, often inefficient, and poorly reproducible. Interestingly, only one of eight EMALE types responded to CroV infection, implying that other EMALEs may be linked to different giant viruses. We isolated and cloned several reactivated virophages and characterized their particles, genomes, and infection dynamics. All tested virophages inhibited the production of CroV during coinfection, thereby preventing lysis of the host cultures in a dose-dependent manner. Comparative genomics of different C. burkhardae strains revealed that inducible EMALEs are common and are not linked to specific geographic locations. We demonstrate that naturally occurring virophage EVEs reactivate upon giant virus infection, thus providing a striking example that eukaryotic EVEs can become active under specific conditions. Moreover, our results support the hypothesis that virophages can act as an adaptive antiviral defense system in protists. [ABSTRACT FROM AUTHOR]

The recent discovery of the CRISPR-Cas-mediated acquired immunity system highlights the fact that our knowledge of phage/virus defense mechanisms encoded in bacterial and archaeal genomes is far from complete. Indeed, new prokaryotic immune systems are now continually being discovered. A recent report described a novel glycosylase that recognizes α-glycosyl-hydroxymethyl cytosin (α-Glu-hmC), a modified base observed in the T4 phage genome, where it produces an abasic site, thereby inhibiting the phage propagation.

Viruses, causal agents of devastating diseases in plants, are obligate intracellular pathogens composed of a nucleic acid genome and a limited number of viral proteins. The diversity of plant viruses, their diminutive molecular nature, and their symplastic localization pose challenges to understanding the interplay between these pathogens and their hosts in the currently accepted framework of plant innate immunity. It is clear, nevertheless, that plants can recognize the presence of a virus and activate antiviral immune responses, although our knowledge of the breadth of invasion signals and the underpinning sensing events is far from complete. Below, I discuss some of the demonstrated or hypothesized mechanisms enabling viral recognition in plants, the step preceding the onset of antiviral immunity, as well as the strategies viruses have evolved to evade or suppress their detection. [ABSTRACT FROM AUTHOR]

ABSTRACTTank-binding kinase 1 (TBK1) plays a pivotal role as a cellular factor in regulating the immune response against herpes simplex virus type 1 (HSV-1). TBK1’s role in defending against HSV-1 is attributed to its capacity to induce the type I interferon response. Recent discoveries emphasize TBK1’s involvement in the regulation of optineurin (OPTN), an autophagy adaptor protein that plays a direct role in enhancing the antiviral response against HSV-1 through selective autophagy. Intriguingly, OPTN can also reciprocally regulate TBK1, leading to a limited understanding of the precise role of the OPTN-TBK1 axis in HSV-1 infection. In our study, we shed light on the relationship between OPTN and TBK1 in influencing the outcome of HSV-1 infection. Surprisingly, when TBK1 or OPTN was absent in cells, the spread and infectivity of HSV-1 did not align as expected. Furthermore, it was unexpected to note that cells lacking OPTN showed higher interferon expression compared to normal cells, yet they exhibited enhanced viral growth. Our investigations revealed that OPTN can directly degrade HSV-1 through autophagy even in the absence of active TBK1. Interestingly, we identified that another protein, Polo-like kinase 1 (PLK1), can compensate for the absence of TBK1 and trigger autophagy to restrict HSV-1. In summary, our findings highlight that OPTN significantly impacts the outcome of HSV-1 infection, regardless of the conventional antiviral response mediated by TBK1. Additionally, by introducing a new role for PLK1, this research provides valuable insights into the intricate interplay among OPTN, TBK1, and autophagy in shaping the course of HSV-1 infection.IMPORTANCEHerpes simplex virus type 1 (HSV-1) is globally prevalent, with latent infections observed in up to 80% of the population. The virus is known for subverting host defense mechanisms and infiltrating the nervous system to establish latency in peripheral ganglia. Multiple stressors can reactivate the virus, and recurrent herpes has been linked to vision loss and neurodegeneration. Identifying critical host factors that limit the spread of HSV-1 and the subsequent establishment of latent infection holds the potential to drive new intervention strategies for eradicating the virus. Numerous pieces of evidence underscore the significance of Tank-binding kinase 1 (TBK1) in restricting HSV-1. Reports have also suggested that phosphorylation of optineurin (OPTN) by TBK1 is required for triggering OPTN-mediated autophagy for HSV degradation. This report adds new insights into the roles of OPTN and TBK1 in HSV-1 infection and provides proof of a TBK1-independent HSV-1 restriction through OPTN. It confirms that TBK1 activation can be substituted by PLK1 to provide protection against HSV-1. In contrast, the activation of OPTN is likely an indispensable host defense mechanism for optimal defense against HSV-1.

Introduction: Tomato yellow leaf curl virus (TYLCV), which is a typical member of the genus Begomovirus, causes severe crop yield losses worldwide. RNA interference (RNAi) is an important antiviral defense mechanism in plants, but whether plant beneficial microbes used as biocontrol agents would modulate RNAi in defense against TYLCV remains unclear. Methods: Here, we employed whole-transcriptome, bisulfite, and small RNA sequencing to decipher the possible role of Bacillus amyloliquefaciens Ba13 as a bacterial biocontrol agent against TYLCV in RNAi modulation. Results: Potted tomato plants were exposed to whiteflies for natural viral infection 14 days after bacterial inoculation. Compared with non-inoculated controls, the abundance of TYLCV gene in the leaves of inoculated plants decreased by 70.1% at 28 days post-infection, which mirrored the pattern observed for plant disease index. The expression of the ARGONAUTE family genes (e.g., AGO3, AGO4, AGO5, and AGO7) involved in antiviral defense markedly increased by 2.44-6.73-fold following bacterial inoculation. The methylation level at CpG site 228 (in the open reading frame region of the RNA interference suppressing gene AV2) and site 461 (in the open reading frame regions of AV1 and AV2) was 183.1 and 63.0% higher in inoculated plants than in non-inoculated controls, respectively. The abundances of 10 small interfering RNAs matched to the TYLCV genome were all reduced in inoculated plants, accompanied by enhancement of photosystem and auxin response pathways. Discussion: The results indicate that the application of Ba. amyloliquefaciens Ba13 enhances plant resistance to TYLCV through RNAi modulation by upregulating RNAi-related gene expression and enhancing viral genome methylation. [ABSTRACT FROM AUTHOR]

CRISPR-Cas and prokaryotic Argonaute (pAgo) are nucleic acid (NA)-guided defense systems that protect prokaryotes against the invasion of mobile genetic elements. Previous studies established that they are directed by NA fragments (guides) to recognize invading complementary NA (targets), and that they cleave the targets to silence the invaders. Nevertheless, growing evidence indicates that many CRISPR-Cas and pAgo systems exploit the abortive infection (Abi) strategy to confer immunity. The CRISPR-Cas and pAgo Abi systems typically sense invaders using the NA recognition ability and activate various toxic effectors to kill the infected cells to prevent the invaders from spreading. This review summarizes the diverse mechanisms of these CRISPR-Cas and pAgo systems, and highlights their critical roles in the arms race between microbes and invaders. Many clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) (CRISPR-Cas) and Argonaute (Ago) systems mediate abortive infection as an immune response against viral invasion. These systems sense viral invasion via guide-directed target nucleic acid recognition. Target recognition results in activation of various toxic effectors. Bioinformatic analyses of the effectors suggest that more CRISPR-Cas and Ago systems mediate the abortive infection response. [ABSTRACT FROM AUTHOR]

ABSTRACT Prophages are bacteriophages integrated into the bacterial host’s chromosome. This research aims to analyze and characterize the existing prophages within a collection of 53 Pseudomonas aeruginosa strains from intensive care units (ICUs) in Portugal and Spain. A total of 113 prophages were localized in the collection, with 18 of them being present in more than one strain simultaneously. After annotation, five of them were discarded as incomplete, and the 13 remaining prophages were characterized. Of 13, 10 belonged to the siphovirus tail morphology group, 2 to the podovirus tail morphology group, and 1 to the myovirus tail morphology group. All prophages had a length ranging from 20,199 to 63,401 bp and a GC% between 56.2% and 63.6%. The number of open reading frames (ORFs) oscillated between 32 and 88, and in 3/13 prophages, more than 50% of the ORFs had an unknown function. With our findings, we show that prophages are present in the majority of the P. aeruginosa strains isolated from Portuguese and Spanish critically ill patients, many of them found in more than one circulating strain at the same time and following a similar clonal distribution pattern. Although a great sum of ORFs had an unknown function, number of proteins in relation to viral defense (anti-CRISPR proteins, toxin/antitoxin modules, proteins against restriction-modification systems) as well as to prophage interference into their host’s quorum sensing system and regulatory cascades were found. This supports the idea that prophages have an influence in bacterial pathogenesis and anti-phage defense. IMPORTANCE Despite being known for decades, prophages remain understudied when compared to the lytic phages employed in phage therapy. This research aims to shed some light into the nature, composition, and role of prophages found within a set of circulating strains of Pseudomas aeruginosa, with special attention to high-risk clones. Given the fact that prophages can effectively influence bacterial pathogenesis, prophage basic research constitutes a topic of growing interest. Furthermore, the abundance of viral defense and regulatory proteins within prophage genomes detected in this study evidences the importance of characterizing the most frequent prophages in circulating clinical strains and in high-risk clones if phage therapy is to be used.

Antiviral defense in ecdysozoan invertebrates requires Dicer with a helicase domain capable of ATP hydrolysis. But despite well-conserved ATPase motifs, human Dicer is incapable of ATP hydrolysis, consistent with a muted role in antiviral defense. To investigate this enigma, we used ancestral protein reconstruction to resurrect Dicer’s helicase in animals and trace the evolutionary trajectory of ATP hydrolysis. Biochemical assays indicated ancient Dicer possessed ATPase function, that like extant invertebrate Dicers, is stimulated by dsRNA. Analyses revealed that dsRNA stimulates ATPase activity by increasing ATP affinity, reflected in Michaelis constants. Deuterostome Dicer-1 ancestor, while exhibiting lower dsRNA affinity, retained some ATPase activity; importantly, ATPase activity was undetectable in the vertebrate Dicer-1 ancestor, which had even lower dsRNA affinity. Reverting residues in the ATP hydrolysis pocket was insufficient to rescue hydrolysis, but additional substitutions distant from the pocket rescued vertebrate Dicer-1’s ATPase function. Our work suggests Dicer lost ATPase function in the vertebrate ancestor due to loss of ATP affinity, involving motifs distant from the active site, important for coupling dsRNA binding to the active conformation. By competing with Dicer for viral dsRNA, RIG-I-like receptors important for interferon signaling may have allowed or actively caused loss of ATPase function.

Simple Summary: Three small RNA pathways, representing miRNAs, siRNAs and piRNAs, exist in insects. Of the three pathways, piRNAs and Piwi proteins appear to have the most complex biogenesis and functional roles. Significant progress has recently occurred in the understanding of the piRNA pathway in three major research areas, i.e., oogenesis and spermatogenesis in the fruitfly, antiviral response in mosquitoes and piRNA biogenesis in silkworm-derived BmN4 cells. Thus, it is timely to provide an overview of the knowledge accumulated so far. Studies in other insects are lagging behind but are highly anticipated since piRNAs and Piwi proteins are abundantly expressed not only in the germline but also in the somatic tissues. Due to the diversification of Piwi genes among insects, novel functions of piRNAs and Piwi proteins can be expected in the different species. This comprehensive review aimed to provide important background information about the current knowledge on piRNAs and Piwi proteins in insects that can function as a resource for future research. Research on Piwi proteins and piRNAs in insects has focused on three experimental models: oogenesis and spermatogenesis in Drosophila melanogaster, the antiviral response in Aedes mosquitoes and the molecular analysis of primary and secondary piRNA biogenesis in Bombyx mori-derived BmN4 cells. Significant unique and complementary information has been acquired and has led to a greater appreciation of the complexity of piRNA biogenesis and Piwi protein function. Studies performed in other insect species are emerging and promise to add to the current state of the art on the roles of piRNAs and Piwi proteins. Although the primary role of the piRNA pathway is genome defense against transposons, particularly in the germline, recent findings also indicate an expansion of its functions. In this review, an extensive overview is presented of the knowledge of the piRNA pathway that so far has accumulated in insects. Following a presentation of the three major models, data from other insects were also discussed. Finally, the mechanisms for the expansion of the function of the piRNA pathway from transposon control to gene regulation were considered. [ABSTRACT FROM AUTHOR]

Second-messenger-mediated signaling by cyclic oligonucleotides (cOs) composed of distinct base, ring size, and 3′-5′/2′-5′ linkage combinations constitutes the initial trigger resulting in activation of signaling pathways that have an impact on immune-mediated antiviral defense against invading viruses and phages. Bacteria and archaea have evolved CRISPR, CBASS, Pycsar, and Thoeris surveillance complexes that involve cO-mediated activation of effectors resulting in antiviral defense through either targeted nuclease activity, effector oligomerization-mediated depletion of essential cellular metabolites or disruption of host cell membrane functions. Notably, antiviral defense capitalizes on an abortive infection mechanism, whereby infected cells die prior to completion of the phage replication cycle. In turn, phages have evolved small proteins that target and degrade/sequester cOs, thereby suppressing host immunity. This review presents a structure-based mechanistic perspective of recent advances in the field of cO-mediated antiviral defense, in particular highlighting the ancient evolutionary adaptation by metazoans of bacterial cell-autonomous innate immune mechanisms. Patel and colleagues review the field of cyclic nucleotide (cO)-activated antiviral immune signaling by CRISPR, CBASS, Pycsar, and Thoeris surveillance pathways to highlight how these cell-autonomous innate immune systems elicit a potent innate immune response that originated in bacteria and evolved through evolutionary adaptation to metazoans. [ABSTRACT FROM AUTHOR]

Haematophagous arthropods can harbor various pathogens including viruses, bacteria, protozoa, and nematodes. Insects possess an innate immune system comprising of both cellular and humoral components to fight against various infections. Haemocytes, the cellular components of haemolymph, are central to the insect immune system as their primary functions include phagocytosis, encapsulation, coagulation, detoxification, and storage and distribution of nutritive materials. Plasmatocytes and granulocytes are also involved in cellular defense responses. Blood-feeding arthropods, such as mosquitoes and ticks, can harbour a variety of viral pathogens that can cause infectious diseases in both human and animal hosts. Therefore, it is imperative to study the virus-vector-host relationships since arthropod vectors are important constituents of the ecosystem. Regardless of the complex immune response of these arthropod vectors, the viruses usually manage to survive and are transmitted to the eventual host. A multidisciplinary approach utilizing novel and strategic interventions is required to control ectoparasite infestations and block vector-borne transmission of viral pathogens to humans and animals. In this review, we discuss the arthropod immune response to viral infections with a primary focus on the innate immune responses of ticks and mosquitoes. We aim to summarize critically the vector immune system and their infection transmission strategies to mammalian hosts to foster debate that could help in developing new therapeutic strategies to protect human and animal hosts against arthropod-borne viral infections.

The cytosolic RNA exosome, a 3→5 exoribonuclease complex, contributes to mRNA degradation in eukaryotes, limiting the accumulation of poorly-translated, improperly translated, or aberrant mRNA species. Disruption of cytosolic RNA exosome activity allows aberrant RNA species to accumulate, which can then be detected by host antiviral immune systems as a signature of pathogen infection, activating antiviral defenses. SKI7 is a critical component of the cytosolic RNA exosome in yeast, bridging the catalytic exoribonuclease core with the SKI2/SKI3/SKI8 adaptor complex that guides aberrant RNA substrates into the exosome. The ortholog of SKI7 was only recently identified in humans as an alternative splice form of the HBS1 gene, which encodes a decoding factor translational GTPase that rescues stalled ribosomes. Here, we identify the plant orthologs of HBS1/SKI7. We found that HBS1 and SKI7 are typically encoded by alternative splice forms of a single locus, although some plant lineages have evolved subfunctionalized genes that apparently encode only HBS1 or only SKI7. In all plant lineages examined, the SKI7 gene is subject to regulation by alternative splicing that can yield unproductive transcripts, either by removing deeply conserved SKI7 coding sequences, or by introducing premature stop codons that render SKI7 susceptible to nonsense-mediated decay. Taking a comparative, evolutionary approach, we define crucial features of the SKI7 protein shared by all eukaryotes, and use these deeply conserved features to identify SKI7 proteins in invertebrate lineages. We conclude that SKI7 is a conserved cytosolic RNA exosome subunit across eukaryotic lineages, and that SKI7 is consistently regulated by alternative splicing, suggesting broad coordination of nuclear and cytosolic RNA metabolism.

Rice (Oryza sativa L.) is one of the major staple foods for global consumption. A major roadblock to global rice production is persistent loss of crops caused by plant diseases, including rice blast, sheath blight, bacterial blight, and particularly various vector-borne rice viral diseases. Since the late 19th century, 19 species of rice viruses have been recorded in rice-producing areas worldwide and cause varying degrees of damage on the rice production. Among them, southern rice black-streaked dwarf virus (SRBSDV) and rice black-streaked dwarf virus (RBSDV) in Asia, rice yellow mottle virus (RYMV) in Africa, and rice stripe necrosis virus (RSNV) in America currently pose serious threats to rice yields. This review systematizes the emergence and damage of rice viral diseases, the symptomatology and transmission biology of rice viruses, the arm races between viruses and rice plants as well as their insect vectors, and the strategies for the prevention and control of rice viral diseases. [ABSTRACT FROM AUTHOR]

Influenza virus (IV) infection currently poses a serious and continuing threat to the global public health. Developing effective prevention strategies is important to defend against infection and spread of IV. Here, we developed a triple-protective nanoshield against IV infection in the lungs, formed by self-assembling DSPE-PEG amphiphilic polymers encapsulating the flu-preventive antiviral drug Arbidol internally. The preventive effect of the nanoshield against virus infection includes increasing the viscosity in the surrounding environment to physically defend against viral entry, forming a hydrated layer to block the interaction between viruses and cells, and inhibiting virus replication. Our finding suggested that a single inhalation of the nanoshield provides effective protection against IV infection for at least 8 h. Thus, this nanoshield may be a potential pandemic protection agent against IV, especially in viral environments, where no prophylactic or therapeutic measures are available.

Mixed lineage kinase domain‐like protein (MLKL) is the terminal effector of necroptosis, a form of regulated necrosis. Optimal activation of necroptosis, which eliminates infected cells, is critical for antiviral host defense. MicroRNAs (miRNAs) regulate the expression of genes involved in various biological and pathological processes. However, the roles of miRNAs in necroptosis‐associated host defense remain largely unknown. We screened a library of miRNAs and identified miR‐324‐5p as the most effective suppressor of necroptosis. MiR‐324‐5p downregulates human MLKL expression by specifically targeting the 3′UTR in a seed region‐independent manner. In response to interferons (IFNs), miR‐324‐5p is downregulated via the JAK/STAT signaling pathway, which removes the posttranscriptional suppression of MLKL mRNA and facilitates the activation of necroptosis. In influenza A virus (IAV)‐infected human primary macrophages, IFNs are induced, leading to the downregulation of miR‐324‐5p. MiR‐324‐5p overexpression attenuates IAV‐associated necroptosis and enhances viral replication, whereas deletion of miR‐324‐5p potentiates necroptosis and suppresses viral replication. Hence, miR‐324‐5p negatively regulates necroptosis by manipulating MLKL expression, and its downregulation by IFNs orchestrates optimal activation of necroptosis in host antiviral defense. Synopsis: Expression of MLKL, the terminal effector of necroptosis, is reduced by miR‐324‐5p. Interferon signaling decreases miR‐324‐5p levels via the JAK/STAT1 pathway, thereby stabilizing MLKL and potentiating necroptosis in influenza virus‐infected cells to limit viral replication. MiR‐324‐5p downregulates MLKL and thus inhibits necroptosis.MiR‐324‐5p targets MLKL in a seed region‐independent and species‐specific manner.IFN‐induced JAK‐STAT1‐mediated downregulation of miR‐324‐5p post‐transcriptionally promotes MLKL expression.The IFN‐miR‐324‐5p‐MLKL axis protects host cells against influenza A virus infection. [ABSTRACT FROM AUTHOR]

Autophagy is an intracellular degradation mechanism involved in antiviral defense, but the strategies employed by plant viruses to counteract autophagy‐related defense remain unknown for the majority of the viruses. Herein, we describe how the Chinese wheat mosaic virus (CWMV, genus Furovirus) interferes with autophagy and enhances its infection in Nicotiana benthamiana. Yeast two‐hybrid screening and in vivo/in vitro assays revealed that the 19 kDa coat protein (CP19K) of CWMV interacts with cytosolic glyceraldehyde‐3‐phosphate dehydrogenases (GAPCs), negative regulators of autophagy, which bind autophagy‐related protein 3 (ATG3), a key factor in autophagy. CP19K also directly interacts with ATG3, possibly leading to the formation of a CP19K–GAPC–ATG3 complex. CP19K–GAPC interaction appeared to intensify CP19K–ATG3 binding. Moreover, CP19K expression upregulated GAPC gene transcripts and reduced autophagic activities. Accordingly, the silencing of GAPC genes in transgenic N. benthamiana reduced CWMV accumulation, whereas CP19K overexpression enhanced it. Overall, our results suggest that CWMV CP19K interferes with autophagy through the promotion and utilization of the GAPC role as a negative regulator of autophagy. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections in infants and young children. Axl, a TAM family receptor tyrosine kinase, has been demonstrated to be a receptor mediating enveloped virus infection. Here we show that Axl functions as a suppressor of antiviral response during RSV infection. Knockdown of Axl expression in human cells resulted in cell resistance to RSV infection, although the treatment did not significantly affect RSV binding or cell entry. Mice deficient in Axl showed resistance to RSV infection, including reduction in viral load and in pulmonary injury. Although T lymphocyte and macrophage infiltration was reduced, more IFN-γ-producing cells were present in BAL fluid in Axl-/- mice. Fewer alternatively activated alveolar macrophages were found in the lungs of Axl-/- mice. Axl-/- mouse embryonic fibroblasts and siRNA-treated human cells had more robust IFN-b and IFN-stimulated gene induction of antiviral genes. Furthermore, reexpression of Axl using adenovirus-mediated Axl delivery repressed IFN-stimulated gene induction in Axl-null mouse embryonic fibroblasts by RSV infection. The results suggest that Axl, independent of being a virus entry receptor of RSV infection, negatively regulates IFN signaling to modulate host antiviral response against RSV infection. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) inflict a significant burden on the human population. The clinical manifestations caused by high-risk HPV types are cancers at anogenital sites, including cervical cancer, as well as head and neck cancers. Host cell defense mechanisms such as autophagy are initiated upon HPV entry. At the same time, the virus modulates cellular antiviral processes and structures such as promyelocytic leukemia nuclear bodies (PML NBs) to enable infection. Here, we uncover the autophagy adaptor p62, also known as p62/sequestosome-1, as a novel proviral factor in infections by the high-risk HPV type 16 (HPV16). Proteomics, imaging and interaction studies of HPV16 pseudovirus-treated HeLa cells display that p62 is recruited to virus-filled endosomes, interacts with incoming capsids, and accompanies the virus to PML NBs, the sites of viral transcription and replication. Cellular depletion of p62 significantly decreased the delivery of HPV16 viral DNA to PML NBs and HPV16 infection rate. Moreover, the absence of p62 leads to an increase in the targeting of viral components to autophagic structures and enhanced degradation of the viral capsid protein L2. The proviral role of p62 and formation of virus-p62-PML hybrid bodies have also been observed in human primary keratinocytes, the HPV target cells. Together, these findings suggest the previously unrecognized virus-induced formation of p62-PML hybrid bodies as a viral mechanism to subvert the cellular antiviral defense, thus enabling viral gene expression. [ABSTRACT FROM AUTHOR]

Dicer enzymes process virus-specific double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs) to initiate specific antiviral defense by related RNA interference (RNAi) pathways in plants, insects, nematodes, and mammals. Antiviral RNAi in Caenorhabditis elegans requires Dicer-related helicase 1 (DRH-1), not found in plants and insects but highly homologous to mammalian retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), intracellular viral RNA sensors that trigger innate immunity against RNA virus infection. However, it remains unclear if DRH-1 acts analogously to initiate antiviral RNAi in C. elegans Here, we performed a forward genetic screen to characterize antiviral RNAi in C. elegans Using a mapping-by-sequencing strategy, we uncovered four loss-of-function alleles of drh-1, three of which caused mutations in the helicase and C-terminal domains conserved in RLRs. Deep sequencing of small RNAs revealed an abundant population of Dicer-dependent virus-derived small interfering RNAs (vsiRNAs) in drh-1 single and double mutant animals after infection with Orsay virus, a positive-strand RNA virus. These findings provide further genetic evidence for the antiviral function of DRH-1 and illustrate that DRH-1 is not essential for the sensing and Dicer-mediated processing of the viral dsRNA replicative intermediates. Interestingly, vsiRNAs produced by drh-1 mutants were mapped overwhelmingly to the terminal regions of the viral genomic RNAs, in contrast to random distribution of vsiRNA hot spots when DRH-1 is functional. As RIG-I translocates on long dsRNA and DRH-1 exists in a complex with Dicer, we propose that DRH-1 facilitates the biogenesis of vsiRNAs in nematodes by catalyzing translocation of the Dicer complex on the viral long dsRNA precursors.IMPORTANCE The helicase and C-terminal domains of mammalian RLRs sense intracellular viral RNAs to initiate the interferon-regulated innate immunity against RNA virus infection. Both of the domains from human RIG-I can substitute for the corresponding domains of DRH-1 to mediate antiviral RNAi in C. elegans, suggesting an analogous role for DRH-1 as an intracellular dsRNA sensor to initiate antiviral RNAi. Here, we developed a forward genetic screen for the identification of host factors required for antiviral RNAi in C. elegans Characterization of four distinct drh-1 mutants obtained from the screen revealed that DRH-1 did not function to initiate antiviral RNAi. We show that DRH-1 acted in a downstream step to enhance Dicer-dependent biogenesis of viral siRNAs in C. elegans As mammals produce Dicer-dependent viral siRNAs to target RNA viruses, our findings suggest a possible role for mammalian RLRs and interferon signaling in the biogenesis of viral siRNAs.

Interleukin-26 (IL-26) is a proinflammatory cytokine that has properties atypical for a cytokine, such as direct antibacterial activity and DNA-binding capacity. We previously observed an accumulation of IL-26 in fibrotic and inflammatory lesions in the livers of patients with chronic HCV infection and showed that infiltrating CD3+ lymphocytes were the principal source of IL-26. Surprisingly, IL-26 was also detected in the cytoplasm of hepatocytes from HCV-infected patients, even though these cells do not produce IL-26, even when infected with HCV. Based on this observation and possible interactions between IL-26 and nucleic acids, we investigated the possibility that IL-26 controlled HCV infection independently of the immune system. We evaluated the ability of IL-26 to interfere with HCV replication in hepatocytes and investigated the mechanisms by which IL-26 exerts its antiviral activity. We showed that IL-26 penetrated HCV-infected hepatocytes, where it interacted directly with HCV double-stranded RNA replication intermediates, thereby inhibiting viral replication. IL-26 interfered with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA. These findings reveal a new role for IL-26 in direct protection against HCV infection, independently of the immune system, and increase our understanding of the antiviral defense mechanisms controlling HCV infection. Future studies should evaluate the possible use of IL-26 for treating other chronic disorders caused by RNA viruses, for which few treatments are currently available, or emerging RNA viruses. This study sheds new light on the body's arsenal for controlling hepatitis C virus (HCV) infection and identifies interleukin-26 (IL-26) as an antiviral molecule capable of blocking HCV replication. IL-26, which has unique biochemical and structural characteristics, penetrates infected hepatocytes and interacts directly with viral RNA, thereby blocking viral replication. IL-26 is, therefore, a new player in antiviral defenses, operating independently of the immune system. It is of considerable potential interest for treating HCV infection and other chronic disorders caused by RNA viruses for which few treatments are currently available, and for combating emerging RNA viruses. [Display omitted] • IL-26 is a new weapon in the antiviral arsenal, functioning independently of the immune system. • IL-26 penetrates HCV-infected cells and interacts with viral double-stranded RNA replication intermediates. • IL-26 interferes with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA. [ABSTRACT FROM AUTHOR]

Research on Piwi proteins and piRNAs in insects has focused on three experimental models: oogenesis and spermatogenesis in Drosophila melanogaster, the antiviral response in Aedes mosquitoes and the molecular analysis of primary and secondary piRNA biogenesis in Bombyx mori-derived BmN4 cells. Significant unique and complementary information has been acquired and has led to a greater appreciation of the complexity of piRNA biogenesis and Piwi protein function. Studies performed in other insect species are emerging and promise to add to the current state of the art on the roles of piRNAs and Piwi proteins. Although the primary role of the piRNA pathway is genome defense against transposons, particularly in the germline, recent findings also indicate an expansion of its functions. In this review, an extensive overview is presented of the knowledge of the piRNA pathway that so far has accumulated in insects. Following a presentation of the three major models, data from other insects were also discussed. Finally, the mechanisms for the expansion of the function of the piRNA pathway from transposon control to gene regulation were considered.

Abstract Rice viruses, known as “rice killer”, are vector-borne pathogens that cause severe disease and significant yield loss in rice production around the world. Rice virus disease is characterized by uncontrolled virus replication and the activation of host responses that contribute to pathogenesis. Underlying these phenomena is the potent suppression of rice antiviral responses, particularly the RNA silencing pathway and plant hormone pathways, which play vital roles in antiviral immunity. Classical rice virus disease control strategies include chemotherapeutics and use of disease resistance rice varieties. Here, we summarize recent advances in understanding the mechanisms behind the immune evasion and rice viral pathogenesis. Based on these mechanistic insights, we discuss how to combine different strategies for maintaining the effectiveness of rice resistance to viruses, and propose theoretical basis for the next generation of virus-resistant rice plants.

The annual steady increase of the herpesviral infections number in the human population is one of the most important interdisciplinary problems of modern medicine. Clinicians and laboratory diagnostics physicians face difficulties in clinical symptoms assessing, inadequate laboratory diagnostics and difficulties in interpretation of the obtained results. This is connected with a low awareness of atypical chronic active infection symptoms caused in particular by the Epstein-Barr virus (EBV), of the ability to fully diagnose, and of serious consequencescaused by prolonged activity of herpesviruses in the human body. Studies were carried out to determinethe functioning features of the antiviral defense system, as well as defects and disorders in the interferon system in patients suffering from various mono-, mixed herpesvirus infections and bacterial co-infections. The main clinical syndromes associated with these herpetic infections, as well as prevailing nosological forms of concomitant diseases, have been identified. Among the group of patients suffering from mono-herpesvirus infections, the leading position takes the allergic syndrome (55%), while the syndrome of chronic fatigue syndrome (85%) and the infectious syndrome (68%) prevail in the incidence of patients with mixed herpesvirus infections. Extended testing of the antiviral protection main mechanisms state made it possible to identify the most frequent defects in the functioning of antiviral immunity: disturbances in induced production of IFNα and IFNγ, deficiency of cytotoxic T lymphocytes, deficiency of natural killer cells, including EKT, and / or inadequate absence of their activation, neutropenia. The revealed clinical syndromes and functioning features of the antiviral defense system will allow us to further develop the concept of complex, individualized, etio- and immunopathogenetic therapy.

Sitobion miscanthi L-type symbiont (SMLS) is a bacterial symbiont commonly found in the wheat aphid S. miscanthi . A new aphid densovirus, S. miscanthi densovirus (SmDV), was recently identified in S. miscanthi . In this study, the similar cellular tropism of SmDV and SMLS in aphid embryos was uncovered using in situ hybridization. SmDV infection significantly decreased the longevity and number of S. miscanthi offspring. However, the SmDV titers were significantly suppressed after SMLS transmission, thus reducing the negative effects of SmDV infection on S. miscanthi fitness. Moreover, an integrative analysis of RNA-seq datasets showed that SMLS inhibited the expression of genes related to the phosphatidylinositol 3-kinase (Pl3K)/Akt pathways and further induced the expression of antiviral factors associated with the apoptosis and FoxO signaling pathways. These results indicate that SMLS mediates host antiviral defenses to inhibit the propagation of SmDV, which was further verified by an RNA interference assay.

Virophages can parasitize giant DNA viruses and may provide adaptive anti-giant virus defense in unicellular eukaryotes. Under laboratory conditions, the virophage mavirus integrates into the nuclear genome of the marine flagellate Cafeteria burkhardae and reactivates upon superinfection with the giant virus CroV. In natural systems, however, the prevalence and diversity of host-virophage associations has not been systematically explored. Here, we report dozens of integrated virophages in four globally sampled C. burkhardae strains that constitute up to 2% of their host genomes. These endogenous mavirus-like elements (EMALEs) separated into eight types based on GC-content, nucleotide similarity, and coding potential and carried diverse promoter motifs implicating interactions with different giant viruses. Between host strains, some EMALE insertion loci were conserved indicating ancient integration events, whereas the majority of insertion sites were unique to a given host strain suggesting that EMALEs are active and mobile. Furthermore, we uncovered a unique association between EMALEs and a group of tyrosine recombinase retrotransposons, revealing yet another layer of parasitism in this nested microbial system. Our findings show that virophages are widespread and dynamic in wild Cafeteria populations, supporting their potential role in antiviral defense in protists.

Breast cancer-associated gene 2 (BCA2) is an E3 ubiquitin and SUMO ligase with antiviral properties against HIV. Specifically, BCA2 (i) enhances the restriction imposed by BST2/Tetherin, impeding viral release; (ii) promotes the ubiquitination and degradation of the HIV protein Gag, limiting virion production; (iii) down-regulates NF-κB, which is necessary for HIV RNA synthesis; and (iv) activates the innate transcription factor IRF1. Due to its antiviral properties, ectopic expression of BCA2 in infected cells represents a promising therapeutic approach against HIV infection. However, BCA2 up-regulation is often observed in breast tumors. To date, the studies about BCA2 and cancer development are controversial, stating both pro- and anti-oncogenic roles. Here, we investigated the impact of BCA2 on cellular metabolic activity, cell proliferation, cell migration, and cell cycle progression. In addition, we also examined the ability of BCA2 to regulate NF-κB and IRF1 in transformed and non-tumor breast epithelial environments. Despite the fact that BCA2 promotes the transition from G1 to S phase of the cell cycle, it did not increase cell proliferation, migration nor metabolic activity. As expected, BCA2 maintains its enzymatic function at inhibiting NF-κB in different breast cancer cell lines. However, the effect of BCA2 on IRF1 differs depending on the cellular context. Specifically, BCA2 activates IRF1 in ER+ breast cell lines while it inhibits this transcription factor in ER– breast cancer cells. We hypothesize that the distinct actions of BCA2 over IRF1 may explain, at least in part, the different proposed roles for BCA2 in these cancers.

Rice (Oryza sativa L.) is one of the major staple foods for global consumption. A major roadblock to global rice production is persistent loss of crops caused by plant diseases, including rice blast, sheath blight, bacterial blight, and particularly various vector-borne rice viral diseases. Since the late 19th century, 19 species of rice viruses have been recorded in rice-producing areas worldwide and cause varying degrees of damage on the rice production. Among them, southern rice black-streaked dwarf virus (SRBSDV) and rice black-streaked dwarf virus (RBSDV) in Asia, rice yellow mottle virus (RYMV) in Africa, and rice stripe necrosis virus (RSNV) in America currently pose serious threats to rice yields. This review systematizes the emergence and damage of rice viral diseases, the symptomatology and transmission biology of rice viruses, the arm races between viruses and rice plants as well as their insect vectors, and the strategies for the prevention and control of rice viral diseases.

In villous trophoblasts, DROSHA is a key ribonuclease III enzyme that processes pri-microRNAs (pri-miRNAs) into pre-miRNAs at the placenta-specific, chromosome 19 miRNA cluster (C19MC) locus. However, little is known of its other functions. We performed formaldehyde crosslinking, immunoprecipitation, and sequencing (fCLIP-seq) analysis of terminal chorionic villi to identify DROSHA-binding RNAs in villous trophoblasts. In villous trophoblasts, DROSHA predominantly generated placenta-specific C19MC pre-miRNAs, including antiviral C19MC pre-miRNAs. The fCLIP-seq analysis also identified non-miRNA transcripts with hairpin structures potentially capable of binding to DROSHA (e.g. , SNORD100 and VTRNA1–1). Moreover, in vivo immunohistochemical analysis revealed DROSHA in the cytoplasm of villous trophoblasts. DROSHA was abundant in the cytoplasm of villous trophoblasts, particularly in the apical region of syncytiotrophoblast, in the full-term placenta. Furthermore, in BeWo trophoblasts infected with Sindbis virus (SINV), DROSHA translocated to the cytoplasm and recognized the genomic RNA of SINV. Therefore, in trophoblasts, DROSHA not only regulates RNA metabolism, including the biogenesis of placenta-specific miRNAs, but also recognizes viral RNAs. After SINV infection, BeWo DROSHA-binding VTRNA1–1 was significantly upregulated, and cellular VTRNA1–1 was significantly downregulated, suggesting that DROSHA soaks up VTRNA1–1 in response to viral infection. These results suggest that the DROSHA-mediated recognition of RNAs defends against viral infection in villous trophoblasts. Our data provide insight into the antiviral functions of DROSHA in villous trophoblasts of the human placenta. • Villous trophoblast DROSHA generated placenta-specific C19MC pre-miRNAs. • Villous trophoblast DROSHA also recognized non-miRNA transcripts (e.g., VTRNA1-1). • DROSHA was abundant in the cytoplasm of human placental villous trophoblasts. • BeWo cytoplasmic DROSHA was induced by Sindbis virus and clamped viral RNA. • Trophoblast DROSHA may act as a sponge of VTRNA1-1 in response to viral infection. [ABSTRACT FROM AUTHOR]

Abstract Mosquito-borne diseases are associated with major global health burdens. Aedes spp. and Culex spp. are primarily responsible for the transmission of the most medically important mosquito-borne viruses, including dengue virus, West Nile virus and Zika virus. Despite the burden of these pathogens on human populations, the interactions between viruses and their mosquito hosts remain enigmatic. Viruses enter the midgut of a mosquito following the mosquito’s ingestion of a viremic blood meal. During infection, virus recognition by the mosquito host triggers their antiviral defense mechanism. Of these host defenses, activation of the RNAi pathway is the main antiviral mechanism, leading to the degradation of viral RNA, thereby inhibiting viral replication and promoting viral clearance. However, whilst antiviral host defense mechanisms limit viral replication, the mosquito immune system is unable to effectively clear the virus. As such, these viruses can establish persistent infection with little or no fitness cost to the mosquito vector, ensuring life-long transmission to humans. Understanding of the mosquito innate immune response enables the discovery of novel antivectorial strategies to block human transmission. This review provides an updated and concise summary of recent studies on mosquito antiviral immune responses, which is a key determinant for successful virus transmission. In addition, we will also discuss the factors that may contribute to persistent infection in mosquito hosts. Finally, we will discuss current mosquito transmission-blocking strategies that utilize genetically modified mosquitoes and Wolbachia-infected mosquitoes for resistance to pathogens.

Plant pathogens, including viruses, negatively impact global crop production. Plants have evolved complex immune responses to pathogens. These responses are often controlled by nucleotide-binding leucine-rich repeat proteins (NLRs), which recognize intracellular, pathogen-derived proteins. Genetic resistance to plant viruses is often phenotypically characterized by programmed cell death at or near the infection site; a reaction termed the hypersensitive response. Although visualization of the hypersensitive response is often used as a hallmark of resistance, the molecular mechanisms leading to the hypersensitive response and associated cell death vary. Plants with extreme resistance to viruses rarely exhibit symptoms and have little to no detectable virus replication or spread beyond the infection site. Both extreme resistance and the hypersensitive response can be activated by the same NLR genes. In many cases, genes that normally provide an extreme resistance phenotype can be stimulated to cause a hypersensitive response by experimentally increasing cellular levels of pathogen-derived elicitor protein(s). The molecular mechanisms of extreme resistance and its relationship to the hypersensitive response are largely uncharacterized. Studies on potato and soybean cultivars that are resistant to strains of Potato virus Y (PVY), Potato virus X (PVX), and Soybean mosaic virus (SMV) indicate that abscisic acid (ABA)-mediated signaling and NLR nuclear translocation are important for the extreme resistance response. Recent research also indicates that some of the same proteins are involved in both extreme resistance and the hypersensitive response. Herein, we review and synthesize published studies on extreme resistance in potato and soybean, and describe studies in additional species, including model plant species, to highlight future research avenues that may bridge the gaps in our knowledge of plant antiviral defense mechanisms.

Summary: Persistent virus infections can cause pathogenesis that is debilitating or lethal. During these infections, virus-specific T cells fail to protect due to weakened antiviral activity or failure to persist. These outcomes are governed by histone modifications, although it is unknown which enzymes contribute to T cell loss or impaired function over time. In this study, we show that T cell receptor-stimulated CD8+ T cells increase their expression of UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome) to enhance gene expression. During chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, UTX binds to enhancers and transcription start sites of effector genes, allowing for improved cytotoxic T lymphocyte (CTL)-mediated protection, independent of its trimethylation of histone 3 lysine 27 (H3K27me3) demethylase activity. UTX also limits the frequency and durability of virus-specific CD8+ T cells, which correspond to increased expression of inhibitory receptors. Thus, UTX guides gene expression patterns in CD8+ T cells, advancing early antiviral defenses while reducing the longevity of CD8+ T cell responses.

Interferon (IFN) is a crucial first line of defense against viral infection. This cytokine induces the expression of several IFN-Stimulated Genes (ISGs), some of which act as restriction factors. Upon IFN stimulation, cells also express ISG15 and SUMO, two key ubiquitin-like (Ubl) modifiers that play important roles in the antiviral response. IFN itself increases the global cellular SUMOylation in a PML-dependent manner. Mass spectrometry-based proteomics enables the large-scale identification of Ubl protein conjugates to determine the sites of modification and the quantitative changes in protein abundance. Importantly, a key difference amongst SUMO paralogs is the ability of SUMO2/3 to form poly-SUMO chains that recruit SUMO ubiquitin ligases such RING finger protein RNF4 and RNF111, thus resulting in the proteasomal degradation of conjugated substrates. Crosstalk between poly-SUMOylation and ISG15 has been reported recently, where increased poly-SUMOylation in response to IFN enhances IFN-induced ISGylation, stabilizes several ISG products in a TRIM25-dependent fashion, and results in enhanced IFN-induced antiviral activities. This contribution will highlight the relevance of the global SUMO proteome and the crosstalk between SUMO, ubiquitin and ISG15 in controlling both the stability and function of specific restriction factors that mediate IFN antiviral defense.

The limited antiviral options and lack of an effective vaccine against human respiratory syncytial virus (RSV) highlight the need for a novel antiviral therapy. One alternative is to identify and target the host factors required for viral infection. Here, using RNA interference to knock down Rab proteins, we provide multiple lines of evidence that Rab5a is required for RSV infection: (i) Rab5a is upregulated both in RSV A2-infected A549 cells and RSV A2-challenged BALB/c mouse airway epithelial cells at early infection phase; (ii) short hairpin RNA (shRNA)-mediated knockdown of Rab5a is associated with reduced lung pathology in RSV A2-challenged mice; (iii) Rab5a expression is correlated with disease severity of RSV infection of infants. Knockdown of Rab5a increases lambda interferon (IFN-λ) production by mediating interferon regulatory factor 1 (IRF1) nuclear translocation. Our results highlight a new role for Rab5a in RSV infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity, which suggests that Rab5a is a potential target for novel therapeutics against RSV infection. [ABSTRACT FROM AUTHOR]

Plant pathogens, including viruses, negatively impact global crop production. Plants have evolved complex immune responses to pathogens. These responses are often controlled by nucleotide-binding leucine-rich repeat proteins (NLRs), which recognize intracellular, pathogen-derived proteins. Genetic resistance to plant viruses is often phenotypically characterized by programmed cell death at or near the infection site; a reaction termed the hypersensitive response. Although visualization of the hypersensitive response is often used as a hallmark of resistance, the molecular mechanisms leading to the hypersensitive response and associated cell death vary. Plants with extreme resistance to viruses rarely exhibit symptoms and have little to no detectable virus replication or spread beyond the infection site. Both extreme resistance and the hypersensitive response can be activated by the same NLR genes. In many cases, genes that normally provide an extreme resistance phenotype can be stimulated to cause a hypersensitive response by experimentally increasing cellular levels of pathogen-derived elicitor protein(s). The molecular mechanisms of extreme resistance and its relationship to the hypersensitive response are largely uncharacterized. Studies on potato and soybean cultivars that are resistant to strains of Potato virus Y (PVY), Potato virus X (PVX), and Soybean mosaic virus (SMV) indicate that abscisic acid (ABA)-mediated signaling and NLR nuclear translocation are important for the extreme resistance response. Recent research also indicates that some of the same proteins are involved in both extreme resistance and the hypersensitive response. Herein, we review and synthesize published studies on extreme resistance in potato and soybean, and describe studies in additional species, including model plant species, to highlight future research avenues that may bridge the gaps in our knowledge of plant antiviral defense mechanisms. [ABSTRACT FROM AUTHOR]

Bacteriophages or phages are viruses that infect bacterial cells (for the scope of this review we will also consider viruses that infect Archaea). The constant threat of phage infection is a major force that shapes evolution of microbial genomes. To withstand infection, bacteria had evolved numerous strategies to avoid recognition by phages or to directly interfere with phage propagation inside the cell. Classical molecular biology and genetic engineering had been deeply intertwined with the study of phages and host defenses. Nowadays, owing to the rise of phage therapy, broad application of CRISPR-Cas technologies, and development of bioinformatics approaches that facilitate discovery of new systems, phage biology experiences a revival. This review describes variety of strategies employed by microbes to counter phage infection. In the first part defense associated with cell surface, roles of small molecules, and innate immunity systems relying on DNA modification were discussed. The second part focuses on adaptive immunity systems, abortive infection mechanisms, defenses associated with mobile genetic elements, and novel systems discovered in recent years through metagenomic mining. [ABSTRACT FROM AUTHOR]

Plant viruses employ diverse virulence strategies to achieve successful infection, but there are few known general strategies of viral pathogenicity and transmission used by widely different plant viruses. Here, we report a class of independently evolved virulence factors in different plant RNA viruses which possess active transcriptional repressor activity. Rice viruses in the genera Fijivirus, Tenuivirus, and Cytorhabdovirus all have transcriptional repressors that interact in plants with the key components of jasmonic acid (JA) signaling, namely mediator subunit OsMED25, OsJAZ proteins, and OsMYC transcription factors. These transcriptional repressors can directly disassociate the OsMED25-OsMYC complex, inhibit the transcriptional activation of OsMYC, and then combine with OsJAZ proteins to cooperatively attenuate the JA pathway in a way that benefits viral infection. At the same time, these transcriptional repressors efficiently enhanced feeding by the virus insect vectors by repressing JA signaling. Our findings reveal a common strategy in unrelated plant viruses in which viral transcriptional repressors hijack and repress the JA pathway in favor of both viral pathogenicity and vector transmission. [ABSTRACT FROM AUTHOR]

Multilayered defense responses are activated upon pathogen attack. Viruses utilize a number of strategies to maximize the coding capacity of their small genomes and produce viral proteins for infection, including suppression of host defense. Here, we reveal translation leakage as one of these strategies: two viral effectors encoded by tomato golden mosaic virus, chloroplast-localized C4 (cC4) and membrane-associated C4 (mC4), are translated from two in-frame start codons and function cooperatively to suppress defense. cC4 localizes in chloroplasts, to which it recruits NbPUB4 to induce ubiquitination of the outer membrane; as a result, this organelle is degraded, and chloroplast-mediated defenses are abrogated. However, chloroplast-localized cC4 induces the production of singlet oxygen ( 1 O 2 ), which in turn promotes translocation of the 1 O 2 sensor NbMBS1 from the cytosol to the nucleus, where it activates expression of the CERK1 gene. Importantly, an antiviral effect exerted by CERK1 is countered by mC4, localized at the plasma membrane. mC4, like cC4, recruits NbPUB4 and promotes the ubiquitination and subsequent degradation of CERK1, suppressing membrane-based, receptor-like kinase-dependent defenses. Importantly, this translation leakage strategy seems to be conserved in multiple viral species and is related to host range. This finding suggests that stacking of different cellular antiviral responses could be an effective way to abrogate viral infection and engineer sustainable resistance to major crop viral diseases in the field., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The silkworm, a crucial model organism of the Lepidoptera, offers an excellent platform for investigating the molecular mechanisms underlying the innate immune response of insects toward pathogens. Over the years, researchers worldwide have identified numerous immune-related genes in silkworms. However, these identified silkworm immune genes are not well classified and not well known to the scientific community. With the availability of the latest genome data of silkworms and the extensive research on silkworm immunity, it has become imperative to systematically categorize the immune genes of silkworms with different database IDs. In this study, we present a meticulous organization of prevalent immune-related genes in the domestic silkworm, using the SilkDB 3.0 database as a reliable source for updated gene information. Furthermore, utilizing the available data, we classify the collected immune genes into distinct categories: pattern recognition receptors, classical immune pathways, effector genes and others. In-depth data analysis has enabled us to predict some potential antiviral genes. Subsequently, we performed antiviral experiments on selected genes, exploring their impact on Bombyx mori nucleopolyhedrovirus replication. The outcomes of this research furnish novel insights into the immune genes of the silkworm, consequently fostering advancements in the field of silkworm immunity research by establishing a comprehensive classification and functional understanding of immune-related genes in the silkworm. This study contributes to the broader understanding of insect immune responses and opens up new avenues for future investigations in the domain of host-pathogen interactions., (© 2024 Institute of Zoology, Chinese Academy of Sciences.)

Viruses have colonized the germ line of our ancestors on several occasions during evolution, leading to the integration in the human genome of viral sequences from over 30 retroviral groups and a few nonretroviruses. Among the recently emerged viruses infecting humans, several target the testis (e.g., human immunodeficiency virus [HIV], Zika virus, and Ebola virus). Here, we aimed to investigate whether human testicular germ cells (TGCs) can support integration by HIV, a contemporary retrovirus that started to spread in the human population during the last century. We report that albeit alternative receptors enabled HIV-1 binding to TGCs, HIV virions failed to infect TGCs in vitro. Nevertheless, exposure of TGCs to infected lymphocytes, naturally present in the testis from HIV men, led to HIV-1 entry, integration, and early protein expression. Similarly, cell-associated infection or bypassing viral entry led to HIV-1 integration in a spermatogonial cell line. Using DNAscope, HIV-1 and simian immunodeficiency virus (SIV) DNA were detected within a few TGCs in the testis from one infected patient, one rhesus macaque, and one African green monkey in vivo. Molecular landscape analysis revealed that early TGCs were enriched in HIV early cofactors up to integration and had overall low antiviral defenses compared with testicular macrophages and Sertoli cells. In conclusion, our study reveals that TGCs can support the entry and integration of HIV upon cell-associated infection. This could represent a way for this contemporary virus to integrate into our germ line and become endogenous in the future, as happened during human evolution for a number of viruses. [ABSTRACT FROM AUTHOR]

The tobacco RBP45 is a nuclear RNA binding protein (RBP). In this study, we identified that the gene expression of NtRBP45 was significantly up‐regulated upon the Tobacco mosaic virus infection and the central region of the protein accounted for its nuclear localization. In particular, using a green fluorescent protein‐based transient suppression assay, we uncovered that the transiently overexpressed NtRBP45 was able to enhance local post‐transcriptional gene silencing (PTGS), facilitate siRNA accumulation, and compromise the RNA silencing suppression mediated by Tomato aspermy virus 2b protein. Deletion mutagenesis showed that both the N‐ and C‐terminal regions of NtRBP45 were necessary for enhancing PTGS. The data overall indicated a novel RNA silencing factor that might participate in antiviral defense. [ABSTRACT FROM AUTHOR]

The reciprocal interaction between influenza virus and host microRNAs (miRNAs) has been implicated in the regulation of viral replication and host tropism. However, the global roles of the cellular miRNA repertoire and the mechanisms of miRNA-mediated antiviral defense await further elucidation. In this study, we systematically screened 297 cellular miRNAs from human and mouse epithelial cells and identified five inhibitory miRNAs that efficiently inhibited influenza virus replication in vitro and in vivo. Among these miRNAs, hsa-mir-127-3p, hsa-mir-486-5p, hsa-mir-593-5p, and mmu-mir-487b-5p were found to target at least one viral gene segment of both the human seasonal influenza H3N2 and the attenuated PR8 (H1N1) virus, whereas hsa-miR-1-3p inhibited viral replication by targeting the supportive host factor ATP6V1A. Moreover, the number of miRNA binding sites in viral RNA segments was positively associated with the activity of host miRNA-induced antiviral defense. Treatment with a combination of the five miRNAs through agomir delivery pronouncedly suppressed viral replication and effectively improved protection against lethal challenge with PR8 in mice. These data suggest that the highly expressed miRNAs in respiratory epithelial cells elicit effective antiviral defenses against influenza A viruses and will be useful for designing miRNA-based therapies against viral infection.

RNA silencing is a major mechanism of constitutive antiviral defense in plants, mediated by a number of proteins, including the Dicer-like (DCL) and Argonaute (AGO) endoribonucleases. Both DCL and AGO protein families comprise multiple members. In particular, the AGO protein family has expanded considerably in different plant lineages, with different family members having specialized functions. Although the general mode of action of AGO proteins is well established, the properties that make different AGO proteins more or less efficient at targeting viruses are less well understood. In this report, we review methodologies used to study AGO antiviral activity and current knowledge about which AGO family members are involved in antiviral defense. In addition, we discuss what is known about the different properties of AGO proteins thought to be associated with this function. [ABSTRACT FROM AUTHOR]

• STING plays a key role in type I interferon production for antimicrobial defense. • STING is tightly regulated to prevent autoinflammation and type I interferonopathies. • Common and rare polymorphisms in STING alter innate immune responses. • Viruses exploit STING-defective cell types as a niche. • DNA and RNA viruses evade STING-mediated innate immunity. Rapid detection of microbes is crucial for eliciting an effective immune response. Innate immune receptors survey the intracellular and extracellular environment for signs of a microbial infection. When they detect a pathogen-associated molecular pattern (PAMP), such as viral DNA, they alarm the cell about the ongoing infection. The central signaling hub in sensing of viral DNA is the stimulator of interferon genes (STING). Upon activation, STING induces downstream signaling events that ultimately result in the production of type I interferons (IFN I), important cytokines in antimicrobial defense, in particular towards viruses. In this review, we describe the molecular features of STING, including its upstream sensors and ligands, its sequence and structural conservation, common polymorphisms, and its localization. We further highlight how STING activation requires a careful balance: its activity is essential for antiviral defense, but unwanted activation through mutations or accidental recognition of self-derived DNA causes autoinflammatory diseases. Several mechanisms, such as post-translational modifications, ensure this balance by fine-tuning STING activation. Finally, we discuss how viruses evade detection of their genomes by either exploiting cells that lack a functional DNA sensing pathway as a niche or by interfering with STING activation through viral evasion molecules. Insight into STING's exact mechanisms in health and disease will guide the development of novel clinical interventions for microbial infections, autoinflammatory diseases, and beyond. [ABSTRACT FROM AUTHOR]