A novel hypovirulence-associated Hadaka virus 1 (HadV1-LA6) in Fusarium oxysporum f. sp. cubense.

Fusarium oxysporum f. sp. cubense (Foc) poses a significant threat to banana crops as a lethal fungal pathogen. The global spread of Foc underscores the formidable challenges associated with traditional management methods in combating this pathogen. This study delves into the hypovirulence-associated mycovirus in Foc. From Foc strain LA6, we isolated and characterized a novel member of the Hadakaviridae family, named Hadaka virus 1 strain LA6 (HadV1-LA6). HadV1-LA6 comprises 10 genomic RNA segments, with RNA1 to RNA7 sharing 80.9%-95.0% amino acid sequence identity with known HadV1-7n, while RNA8 to RNA10 display significantly lower identity. HadV1-LA6 demonstrates horizontal transmission capabilities in an all-or-none fashion between different Foc strains via coculturing. Phenotypic comparisons highlight that HadV1-LA6 significantly reduces the growth rates of its host fungus under cell wall stress and oxidative stress conditions. Importantly, HadV1-LA6 attenuates Foc's virulence in detached leaves and banana plants. This study represents the first introduction of a novel hypovirulence-associated Hadaka virus 1 in Foc.IMPORTANCEFusarium wilt of banana (FWB) is a severe fungal disease caused by soil-borne Fusarium oxysporum f. sp. cubense (Foc). Among various strategies, biocontrol emerges as a safe, ecologically friendly, and cost-effective approach to managing FWB. In this study, we focus on exploring the potential of a novel hypovirulent member of hadakavirid, HadV1-LA6. Previous reports suggest that HadV1 shows no apparent effect on the host. However, through phenotypic assessments, we demonstrate that HadV1-LA6 significantly impedes the growth rates of its host fungus under stress conditions. More importantly, HadV1-LA6 exhibits a remarkable capacity to attenuate Foc's virulence in detached leaves and banana plants. Furthermore, HadV1-LA6 could be horizontally transmitted between different Foc strains, presenting a promising resource for revealing the molecular mechanism of the interaction between Hadaka virus 1 and its host.

Host Barriers Limit Viral Spread in a Spillover Host: A Study of Deformed Wing Virus in the Bumblebee Bombus terrestris.

The transmission of pathogens from reservoir to recipient host species, termed pathogen spillover, can profoundly impact plant, animal, and public health. However, why some pathogens lead to disease emergence in a novel species while others fail to establish or do not elicit disease is often poorly understood. There is strong evidence that deformed wing virus (DWV), an (+)ssRNA virus, spills over from its reservoir host, the honeybee Apis mellifera, into the bumblebee Bombus terrestris. However, the low impact of DWV on B. terrestris in laboratory experiments suggests host barriers to virus spread in this recipient host. To investigate potential host barriers, we followed the spread of DWV genotype B (DWV-B) through a host's body using RT-PCR after experimental transmission to bumblebees in comparison to honeybees. Inoculation was per os, mimicking food-borne transmission, or by injection into the bee's haemocoel, mimicking vector-based transmission. In honeybees, DWV-B was present in both honeybee faeces and haemolymph within 3 days of inoculation per os or by injection. In contrast, DWV-B was not detected in B. terrestris haemolymph after inoculation per os, suggesting a gut barrier that hinders DWV-B's spread through the body of a B. terrestris. DWV-B was, however, detected in B. terrestris faeces after injection and feeding, albeit at a lower abundance than that observed for A. mellifera, suggesting that B. terrestris sheds less DWV-B than A. mellifera in faeces when infected. Barriers to viral spread in B. terrestris following oral infection may limit DWV's impact on this spillover host and reduce its contribution to the community epidemiology of DWV.

Exploring the shared pathogenic strategies of independently evolved effectors across distinct plant viruses.

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.

Metal-binding proteins and proteases in RNA viruses: unravelling functional diversity and expanding therapeutic horizons.

IMPORTANCE: Metal-binding proteins are pivotal components with diverse functions in organisms, including viruses. Despite their significance, many metalloproteins in viruses remain uncharacterized, posing challenges to understanding viral systems. This study addresses this knowledge gap by identifying and analyzing metal-binding proteins and proteases in RNA viruses. The findings emphasize the prevalence of these proteins as essential functional classes within viruses and shed light on the role of metal ions and metalloproteins in viral replication and pathogenesis. Moreover, this research serves as a crucial foundation for further investigations in this field, offering the potential for developing innovative antiviral strategies. Additionally, the study enhances our understanding of the distribution and evolutionary patterns of metal-binding proteases in major human viruses. Continually exploring metal-binding proteomes across diverse viruses will deepen our knowledge of metal-dependent biological processes and provide valuable insights for combating viral infections, including respiratory viruses and other life-threatening diseases.

Cell-type-specific need of Ddx3 and PACT for interferon induction by RNA viruses.

IMPORTANCE: Interferon-stimulated genes (ISGs) are induced in response to interferon expression due to viral infections. Role of these ISGs can be variable in different cells or organs. Our study highlights such cell-specific role of an ISG, Ddx3, which regulates the translation of mRNAs essential for interferon induction (PACT) and interferon signaling (STAT1) in a cell-specific manner. Our study also highlights the role of PACT in RNA virus-induced RLR signaling. Our study depicts how Ddx3 regulates innate immune signaling pathways in an indirect manner. Such cell-specific behavior of ISGs helps us to better understand viral pathogenesis and highlights the complexities of viral tropism and innate immune responses.

Effect of Leishmania RNA virus 2 on virulence factors and cytokines gene expression in a human macrophage infected with Leishmania major: A preliminary study.

Cutaneous leishmaniasis (CL) is one of the most important infectious parasitic diseases in the world caused by the Leishmania parasite. In recent decades, the presence of a virus from the Totiviridae family has been proven in some Leishmania species. Although the existence of LRV2 in the Old world Leishmania species has been confirmed, almost no studies have been done to determine the potential impact of LRV2 on the immunopathogenicity of the Leishmania parasite. In this preliminary study, we measured the expression of target genes, including Glycoprotein 63 (gp63), Heat Shock Protein 70 (hsp70), Cysteine Protease b (cpb), Interleukin 1 beta (IL-1ß), IL8 and IL-12 in LRV2 positive Leishmania major strain (LRV2+L. major) and LRV2 negative L. major strain (LRV2-L. major). We exposed THP-1, a human leukemia monocytic cell line, to promastigotes of both strains. After the initial infection, RNA was extracted at different time points, and the relative gene expression was determined using a real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Findings showed that the presence of LRV2 in L. major was able to increase the expression of gp63, hsp70, and cpb genes; also, we observed lower levels of expression in cytokine genes of IL-1ß, IL-8, IL-12 in the presence of LRV2+, which are critical factors in the host's immune response against leishmaniasis. These changes could suggest that the presence of LRV2 in L. major parasite may change the outcome of the disease and increase the probability of Leishmania survival; nevertheless, further studies are needed to confirm our results.

An evolutionarily conserved N-terminal leucine is essential for MX1 GTPase antiviral activity against different families of RNA viruses.

Myxovirus resistance protein 1 (MX1) and MX2 are homologous, dynamin-like large GTPases, induced upon interferon exposure. Human MX1 (HsMX1) is known to inhibit many viruses, including influenza A virus, by likely acting at various steps of their life cycles. Despite decades of studies, the mechanism(s) of action with which MX1 proteins manage to inhibit target viruses is not fully understood. MX1 proteins are mechano-enzymes and share a similar organization to dynamin, with a GTPase domain and a carboxy-terminal stalk domain, connected by a bundle signaling element. These three elements are known to be essential for antiviral activity. HsMX1 has two unstructured regions, the L4 loop, also essential for antiviral activity, and a short amino (N)-terminal region, which greatly varies between MX1 proteins of different species. The role of this N-terminal domain in antiviral activity is not known. Herein, using mutagenesis, imaging, and biochemical approaches, we demonstrate that the N-terminal domain of HsMX1 is essential for antiviral activity against influenza A virus, Vesicular Stomatitis Virus, and La Crosse virus. Furthermore, we pinpoint a highly conserved leucine within this region, which is absolutely crucial for human, mouse, and bat MX1 protein antiviral activity. Importantly, mutation of this leucine does not compromise GTPase activity or oligomerization capabilities but does modify MX1 protein subcellular localization. The discovery of this essential and highly conserved residue defines this region as key for antiviral activity and may reveal insights as to the mechanism(s) of action of MX1 proteins.

Human pathogenic RNA viruses establish noncompeting lineages by occupying independent niches.

Many pathogenic viruses are endemic among human populations and can cause a broad variety of diseases, some potentially leading to devastating pandemics. How virus populations maintain diversity and what selective pressures drive population turnover is not thoroughly understood. We conducted a large-scale phylodynamic analysis of 27 human pathogenic RNA viruses spanning diverse life history traits, in search of unifying trends that shape virus evolution. For most virus species, we identify multiple, cocirculating lineages with low turnover rates. These lineages appear to be largely noncompeting and likely occupy semiindependent epidemiological niches that are not regionally or seasonally defined. Typically, intralineage mutational signatures are similar to interlineage signatures. The principal exception are members of the family Picornaviridae, for which mutations in capsid protein genes are primarily lineage defining. Interlineage turnover is slower than expected under a neutral model, whereas intralineage turnover is faster than the neutral expectation, further supporting the existence of independent niches. The persistence of virus lineages appears to stem from limited outbreaks within small communities, so that only a small fraction of the global susceptible population is infected at any time. As disparate communities become increasingly connected through globalization, interaction and competition between lineages might increase as well, which could result in changing selective pressures and increased diversification and/or pathogenicity. Thus, in addition to zoonotic events, ongoing surveillance of familiar, endemic viruses appears to merit global attention with respect to the prevention or mitigation of future pandemics.

Metagenome-Assembled Viral Genomes Analysis Reveals Diversity and Infectivity of the RNA Virome of Gerbillinae Species.

Rodents are a known reservoir for extensive zoonotic viruses, and also possess a propensity to roost in human habitation. Therefore, it is necessary to identify and catalogue the potentially emerging zoonotic viruses that are carried by rodents. Here, viral metagenomic sequencing was used for zoonotic virus detection and virome characterization on 32 Great gerbils of Rhombomys opimus, Meriones meridianus, and Meiiones Unguiculataus species in Xinjiang, Northwest China. In total, 1848 viral genomes that are potentially pathogenic to rodents and humans, as well as to other wildlife, were identified namely Retro-, Flavi-, Pneumo-, Picobirna-, Nairo-, Arena-, Hepe-, Phenui-, Rhabdo-, Calici-, Reo-, Corona-, Orthomyxo-, Peribunya-, and Picornaviridae families. In addition, a new genotype of rodent Hepacivirus was identified in heart and lung homogenates of seven viscera pools and phylogenetic analysis revealed the closest relationship to rodent Hepacivirus isolate RtMm-HCV/IM2014 that was previously reported to infect rodents from Inner Mongolia, China. Moreover, nine new genotype viral sequences that corresponded to Picobirnaviruses (PBVs), which have a bi-segmented genome and belong to the family Picobirnaviridae, comprising of three segment I and six segment II sequences, were identified in intestines and liver of seven viscera pools. In the two phylogenetic trees that were constructed using ORF1 and ORF2 of segment I, the three segment I sequences were clustered into distinct clades. Additionally, phylogenetic analysis showed that PBV sequences were distributed in the whole tree that was constructed using the RNA-dependent RNA polymerase (RdRp) gene of segment II with high diversity, sharing 68.42-82.67% nucleotide identities with other genogroup I and genogroup II PBV strains based on the partial RdRp gene. By RNA sequencing, we found a high degree of biodiversity of Retro-, Flavi-, Pneumo-, and Picobirnaridae families and other zoonotic viruses in gerbils, indicating that zoonotic viruses are a common presence in gerbils from Xinjiang, China. Therefore, further research is needed to determine the zoonotic potential of these viruses that are carried by other rodent species from different ecosystems and wildlife in general.

Honey bees and climate explain viral prevalence in wild bee communities on a continental scale.

Viruses are omnipresent, yet the knowledge on drivers of viral prevalence in wild host populations is often limited. Biotic factors, such as sympatric managed host species, as well as abiotic factors, such as climatic variables, are likely to impact viral prevalence. Managed and wild bees, which harbor several multi-host viruses with a mostly fecal-oral between-species transmission route, provide an excellent system with which to test for the impact of biotic and abiotic factors on viral prevalence in wild host populations. Here we show on a continental scale that the prevalence of three broad host viruses: the AKI-complex (Acute bee paralysis virus, Kashmir bee virus and Israeli acute paralysis virus), Deformed wing virus, and Slow bee paralysis virus in wild bee populations (bumble bees and solitary bees) is positively related to viral prevalence of sympatric honey bees as well as being impacted by climatic variables. The former highlights the need for good beekeeping practices, including Varroa destructor management to reduce honey bee viral infection and hive placement. Furthermore, we found that viral prevalence in wild bees is at its lowest at the extreme ends of both temperature and precipitation ranges. Under predicted climate change, the frequency of extremes in precipitation and temperature will continue to increase and may hence impact viral prevalence in wild bee communities.

Inferring Protein Function in an Emerging Virus: Detection of the Nucleoprotein in Tilapia Lake Virus.

Emerging viruses impose global threats to animal and human populations and may bear novel genes with limited homology to known sequences, necessitating the development of novel approaches to infer and test protein functions. This challenge is dramatically evident in tilapia lake virus (TiLV), an emerging "orthomyxo-like" virus that threatens the global tilapia aquaculture and food security of millions of people. The majority of TiLV proteins have no homology to known sequences, impeding functionality assessments. Using a novel bioinformatics approach, we predicted that TiLV's Protein 4 encodes the nucleoprotein, a factor essential for viral RNA replication. Multiple methodologies revealed the expected properties of orthomyxoviral nucleoproteins. A modified yeast three-hybrid assay detected Protein 4-RNA interactions, which were independent of the RNA sequence, and identified specific positively charged residues involved. Protein 4-RNA interactions were uncovered by R-DeeP and XRNAX methodologies. Immunoelectron microscopy found that multiple Protein 4 copies localized along enriched ribonucleoproteins. TiLV RNA from cells and virions coimmunoprecipitated with Protein 4. Immunofluorescence microscopy detected Protein 4 in the cytoplasm and nuclei, and nuclear Protein 4 increased upon CRM1 inhibition, suggesting CRM1-dependent nuclear export of TiLV RNA. Together, these data reveal TiLV's nucleoprotein and highlight the ability to infer protein functionality, including novel RNA-binding proteins, in emerging pathogens. These are important in light of the expected discovery of many unknown viruses and the zoonotic potential of such pathogens. IMPORTANCE Tilapia is an important source of dietary protein, especially in developing countries. Massive losses of tilapia were identified worldwide, risking the food security of millions of people. Tilapia lake virus (TiLV) is an emerging pathogen responsible for these disease outbreaks. TiLV's genome encodes 10 major proteins, 9 of which show no homology to other known viral or cellular proteins, hindering functionality assessment of these proteins. Here, we describe a novel bioinformatics approach to infer the functionality of TiLV proteins, which predicted Protein 4 as the nucleoprotein, a factor essential for viral RNA replication. We provided experimental support for this prediction by applying multiple molecular, biochemical, and imaging approaches. Overall, we illustrate a strategy for functional analyses in viral discovery. The strategy is important in light of the expected discovery of many unknown viruses and the zoonotic potential of such pathogens.

The transcription factor ZIP-1 promotes resistance to intracellular infection in Caenorhabditis elegans.

Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts; specifically, the transcription factors that induce defense against intracellular intestinal infection in the model nematode Caenorhabditis elegans remain understudied. Two different types of intracellular pathogens that naturally infect the C. elegans intestine are the Orsay virus, which is an RNA virus, and microsporidia, which comprise a phylum of fungal pathogens. Despite their molecular differences, these pathogens induce a common host transcriptional response called the intracellular pathogen response (IPR). Here we show that zip-1 is an IPR regulator that functions downstream of all known IPR-activating and regulatory pathways. zip-1 encodes a putative bZIP transcription factor, and we show that zip-1 controls induction of a subset of genes upon IPR activation. ZIP-1 protein is expressed in the nuclei of intestinal cells, and is at least partially required in the intestine to upregulate IPR gene expression. Importantly, zip-1 promotes resistance to infection by the Orsay virus and by microsporidia in intestinal cells. Altogether, our results indicate that zip-1 represents a central hub for triggers of the IPR, and that this transcription factor has a protective function against intracellular pathogen infection in C. elegans.

Phytosterol metabolism in plant positive-strand RNA virus replication.

The genome of most plant viruses consists of a single positive-strand of RNA (+ ssRNA). Successful replication of these viruses is fully dependent on the endomembrane system of the infected cells, which experiences a massive proliferation and a profound reshaping that enables assembly of the macromolecular complexes where virus genome replication occurs. Assembly of these viral replicase complexes (VRCs) requires a highly orchestrated interplay of multiple virus and co-opted host cell factors to create an optimal microenvironment for efficient assembly and functioning of the virus genome replication machinery. It is now widely accepted that VRC formation involves the recruitment of high levels of sterols, but the specific role of these essential components of cell membranes and the precise molecular mechanisms underlying sterol enrichment at VRCs are still poorly known. In this review, we intend to summarize the most relevant knowledge on the role of sterols in ( +)ssRNA virus replication and discuss the potential of manipulating the plant sterol pathway to help plants fight these infectious agents.

A vertically transmitted amalgavirus is present in certain accessions of the bryophyte Physcomitrium patens.

In the last few years, next-generation sequencing techniques have started to be used to identify new viruses infecting plants. This has allowed to rapidly increase our knowledge on viruses other than those causing symptoms in economically important crops. Here we used this approach to identify a virus infecting Physcomitrium patens that has the typical structure of the double-stranded RNA endogenous viruses of the Amalgaviridae family, which we named Physcomitrium patens amalgavirus 1, or PHPAV1. PHPAV1 is present only in certain accessions of P. patens, where its RNA can be detected throughout the cell cycle of the plant. Our analysis demonstrates that PHPAV1 can be vertically transmitted through both paternal and maternal germlines, in crosses between accessions that contain the virus with accessions that do not contain it. This work suggests that PHPAV1 can replicate in genomic backgrounds different from those that actually contain the virus and opens the door for future studies on virus-host coevolution.

Special Issue "Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses".

Numerous species of RNA viruses pathogenic for humans are present worldwide [...].

SARS-CoV-2: lessons from both the history of medicine and from the biological behavior of other well-known viruses.

SARS-CoV-2 is the etiological agent of the current pandemic worldwide and its associated disease COVID-19. In this review, we have analyzed SARS-CoV-2 characteristics and those ones of other well-known RNA viruses viz. HIV, HCV and Influenza viruses, collecting their historical data, clinical manifestations and pathogenetic mechanisms. The aim of the work is obtaining useful insights and lessons for a better understanding of SARS-CoV-2. These pathogens present a distinct mode of transmission, as SARS-CoV-2 and Influenza viruses are airborne, whereas HIV and HCV are bloodborne. However, these viruses exhibit some potential similar clinical manifestations and pathogenetic mechanisms and their understanding may contribute to establishing preventive measures and new therapies against SARS-CoV-2.

Thermodynamic effect of RNA virus infection on the human cardiovascular system.

In this work, analysis of cardiovascular system under the influence of RNA virus infection has been performed from a thermodynamic perspective. An exergetic efficiency of the system has been defined for this purpose. Results show that except for asymptomatic case, the exergetic efficiency reduces as the viral load goes up. Dynamics of viral growth along with change in efficiency is examined under different parameters such as virus production rate, infectivity rate and cell death rate. Results show that the drop in the exergetic efficiency of cardiovascular system under viral infection can be up to about 20%. Under infection, the exergy requirement of the lungs increases significantly as the work rate required by lungs increase by up to 240%.

Hidden Viral Sequences in Public Sequencing Data and Warning for Future Emerging Diseases.

RNA viruses cause numerous emerging diseases, mostly due to transmission from mammalian and avian reservoirs. Large-scale surveillance of RNA viral infections in these animals is a fundamental step for controlling viral infectious diseases. Metagenomic analysis is a powerful method for virus identification with low bias and has contributed substantially to the discovery of novel viruses. Deep-sequencing data have been collected from diverse animals and accumulated in public databases, which can be valuable resources for identifying unknown viral sequences. Here, we screened for infections of 33 RNA viral families in publicly available mammalian and avian sequencing data and found approximately 900 hidden viral infections. We also discovered six nearly complete viral genomes in livestock, wild, and experimental animals: hepatovirus in a goat, hepeviruses in blind mole-rats and a galago, astrovirus in macaque monkeys, parechovirus in a cow, and pegivirus in tree shrews. Some of these viruses were phylogenetically close to human-pathogenic viruses, suggesting the potential risk of causing disease in humans upon infection. Furthermore, infections of five novel viruses were identified in several different individuals, indicating that their infections may have already spread in the natural host population. Our findings demonstrate the reusability of public sequencing data for surveying viral infections and identifying novel viral sequences, presenting a warning about a new threat of viral infectious disease to public health. IMPORTANCE Monitoring the spread of viral infections and identifying novel viruses capable of infecting humans through animal reservoirs are necessary to control emerging viral diseases. Massive amounts of sequencing data collected from various animals are publicly available, and these data may contain sequences originating from a wide variety of viruses. Here, we analyzed more than 46,000 public sequencing data and identified approximately 900 hidden RNA viral infections in mammalian and avian samples. Some viruses discovered in this study were genetically similar to pathogens that cause hepatitis, diarrhea, or encephalitis in humans, suggesting the presence of new threats to public health. Our study demonstrates the effectiveness of reusing public sequencing data to identify known and unknown viral infections, indicating that future continuous monitoring of public sequencing data by metagenomic analyses would help prepare and mitigate future viral pandemics.

Retinoic Acid-Inducible Gene I-Like Receptors Activate Snail To Limit RNA Viral Infections.

Retinoic acid-inducible gene I-like receptors (RLRs) are important cytosolic pattern recognition receptors (PRRs) that sense viral RNA before mounting a response leading to the activation of type I IFNs. Several viral infections induce epithelial-mesenchymal transition (EMT), even as its significance remains unclear. Here, we show that EMT or an EMT-like process is a general response to viral infections. Our studies identify a previously unknown mechanism of regulation of an important EMT-transcription factor (EMT-TF) Snail during RNA viral infections and describe its possible implication. RNA viral infections, poly(I·C) transfection, and ectopic expression of RLR components induced Snail levels, indicating that RLR pathway could regulate its expression. Detailed examination using mitochondrial antiviral signaling protein knockout (MAVS-KO) cells established that MAVS is essential in this regulation. We identified two interferon-stimulated response elements (ISREs) in the SNAI1 promoter region and demonstrated that they are important in its transcriptional activation by phosphorylated IRF3. Increasing the levels of Snail activated RLR pathway and dramatically limited replication of the RNA viruses dengue virus, Japanese encephalitis virus (JEV), and vesicular stomatitis virus, pointing to their antiviral functions. Knockdown of Snail resulted in a considerable increase in the JEV titer, validating its antiviral functions. Finally, transforming growth factor ß-mediated IFNB activation was dependent on Snail levels, confirming its important role in type I IFN activation. Thus, EMT-TF Snail is transcriptionally coregulated with type I IFN by RLRs and, in turn, promotes the RLR pathway, further strengthening the antiviral state in the cell. Our work identified an interesting mechanism of regulation of Snail that demonstrates potential coregulation of multiple innate antiviral pathways triggered by RLRs. Identification of antiviral functions of Snail also provides an opportunity to expand the sphere of RLR signaling. IMPORTANCE RLRs sense viral genomic RNA or the double-stranded RNA intermediates and trigger the activation of type I IFNs. Snail transcription factor, commonly associated with epithelial-mesenchymal transition (EMT), has been reported to facilitate EMT in several viral infections. Many of these reports are based on oncoviruses, leading to the speculation that EMT induced during infection is an important factor in the oncogenesis triggered by these infections. However, our studies reveal that EMT or EMT-like processes during viral infections have important functions in antiviral response. We have characterized a new mechanism of transcriptional regulation of Snail by IRF3 through interferon-stimulated response elements in their promoters, and this finding could have importance in nonviral contexts as well. We also identify that EMT-TF Snail promotes antiviral status of the infected cells through the RLR pathway. This study characterizes a new regulatory mechanism of activation of Snail and establishes its unidentified function in antiviral response.

Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection.

The nuclear pore complex is the sole gateway connecting the nucleoplasm and cytoplasm. In humans, the nuclear pore complex is one of the largest multiprotein assemblies in the cell, with a molecular mass of ∼110 MDa and consisting of 8 to 64 copies of about 34 different nuclear pore proteins, termed nucleoporins, for a total of 1000 subunits per pore. Trafficking events across the nuclear pore are mediated by nuclear transport receptors and are highly regulated. The nuclear pore complex is also used by several RNA viruses and almost all DNA viruses to access the host cell nucleoplasm for replication. Viruses hijack the nuclear pore complex, and nuclear transport receptors, to access the nucleoplasm where they replicate. In addition, the nuclear pore complex is used by the cell innate immune system, a network of signal transduction pathways that coordinates the first response to foreign invaders, including viruses and other pathogens. Several branches of this response depend on dynamic signaling events that involve the nuclear translocation of downstream signal transducers. Mounting evidence has shown that these signaling cascades, especially those steps that involve nucleocytoplasmic trafficking events, are targeted by viruses so that they can evade the innate immune system. This review summarizes how nuclear pore proteins and nuclear transport receptors contribute to the innate immune response and highlights how viruses manipulate this cellular machinery to favor infection. A comprehensive understanding of nuclear pore proteins in antiviral innate immunity will likely contribute to the development of new antiviral therapeutic strategies.