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Telomere length (TL) is increasingly recognized as a molecular marker that reflects how reproductive aging affects intergenerational transmissions. Here, we investigated the effects of parental age on offspring survival and the regulation of TL by examining the telomere-elongating activity of telomerase in the Pacific oyster. We assessed the classical hallmarks of aging in parents at three age classes (young, middle-aged, and old) and crossbred them using a split-brood design to examine the consequences of the nine maternal-by-paternal age combinations on their offspring. Reproductive aging leads to increased larval mortality and accelerated telomere shortening in spats, rendering them more susceptible to infection by the Ostreid herpesvirus. Viral exposure stimulates telomerase activity, a response that we identified as adaptive, but weakened by parental aging. While telomerase lengthens a spat's telomere, paradoxically, longer individual TL predicts higher mortality in adults. The telomerase-telomere complex appeared as a conservative biomarker for distinguishing survivors and losers upon exposure to polymicrobial diseases.

Background: Emerging evidence suggests that viral infections may contribute to Alzheimer's disease (AD) onset and/or progression. However, the extent of their involvement and the mechanisms through which specific viruses increase AD susceptibility risk remain elusive., Methods: We used an integrative systems bioinformatics approach to identify viral-mediated pathogenic mechanisms, by which Herpes Simplex Virus 1 (HSV-1), Human Cytomegalovirus (HCMV), Epstein-Barr virus (EBV), Kaposi Sarcoma-associated Herpesvirus (KSHV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Influenza A Virus (IAV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) could facilitate AD pathogenesis via virus-host protein-protein interactions (PPIs). We also explored potential synergistic pathogenic effects resulting from herpesvirus reactivation (HSV-1, HCMV, and EBV) during acute SARS-CoV-2 infection, potentially increasing AD susceptibility., Results: Herpesviridae members (HSV-1, EBV, KSHV, HCMV) impact AD-related processes like amyloid-β (Aβ) formation, neuronal death, and autophagy. Hepatitis viruses (HBV, HCV) influence processes crucial for cellular homeostasis and dysfunction, they also affect microglia activation via virus-host PPIs. Reactivation of HCMV during SARS-CoV-2 infection could potentially foster a lethal interplay of neurodegeneration, via synergistic pathogenic effects on AD-related processes like response to unfolded protein, regulation of autophagy, response to oxidative stress, and Aβ formation., Conclusions: These findings underscore the complex link between viral infections and AD development. Viruses impact AD-related processes through shared and distinct mechanisms, potentially influencing variations in AD susceptibility., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Herpesviruses are DNA viruses and the cause of diseases ranging from mild skin conditions to severe brain diseases. Mammalian antiviral host defense comprises an array of mechanisms, including restriction factors (RFs), which block specific steps in viral replication cycles. In recent years, knowledge of RFs that contribute to controlling herpesvirus infections has expanded significantly, along with a new understanding of viral evasion mechanisms and disease pathogenesis. By integrating findings from human genetics, murine models, and cellular studies, this review provides a current view of RF control of herpesvirus infections. We also explore the regulation of RF expression, discuss the roles of RFs in diseases, and point towards their growing potential as candidate therapeutic targets., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Viruses are exemplary molecular biologists and have been integral to scientific discovery for generations. It is therefore no surprise that nuclear replicating viruses have evolved to systematically take over host cell function through astoundingly specific nuclear and chromatin hijacking. In this review, we focus on nuclear replicating DNA viruses-herpesviruses and adenoviruses-as key examples of viral invasion in the nucleus. We concentrate on critical features of nuclear architecture, such as chromatin and the nucleolus, to illustrate the complexity of the virus-host battle for resources in the nucleus. We conclude with a discussion of the technological advances that have enabled the discoveries we describe and upcoming steps in this burgeoning field.

The ability to impact the immune response of the host has been recognized as essential for the success of a virus during infection. A few groups of viruses can combine these immunomodulatory mechanisms with specific patterns of their own transcriptional and replication regulation to achieve persistence within the host long term. The Herpesvirales order is one of those groups and the resultant state is known as latency. Throughout the years, latency has been studied in many host-herpesvirus models to attempt to understand the complex and profound effects of this state on the host's systems, and in the hopes of deciphering a way to eliminate the latent state from survivors of the primary infection. Most studies of herpesvirus latency have been conducted on mammalian host species, but this review summarizes the data available regarding herpesviruses in fish species and their latent state. As the field of aquatic animal health research continues to advance, the elucidation of these complex mechanisms will be crucial for disease control, prevention, and treatment., (© 2024 The Author(s). Journal of Fish Diseases published by John Wiley & Sons Ltd.)

Oncogenic viruses play a pivotal role in oncology due to their unique role in unraveling the complexities of cancer development. Understanding the role viruses play in specific cancers is important to provide basic insights into the transformation process, which will help identify potential cellular targets for treatment. This review discusses the diverse role of animal herpesviruses in initiating and promoting various forms of cancer. We will summarize the mechanisms that underlie the development of animal herpesvirus-induced cancer that may provide a basis for developing potential therapeutic interventions or preventative strategies in the future., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The viral nuclear egress complex (NEC) allows herpesvirus capsids to escape from the nucleus without compromising the nuclear envelope integrity. The NEC lattice assembles on the inner nuclear membrane and mediates the budding of nascent nucleocapsids into the perinuclear space and their subsequent release into the cytosol. Its essential role makes it a potent antiviral target, necessitating structural information in the context of a cellular infection. Here we determined structures of NEC-capsid interfaces in situ using electron cryo-tomography, showing a substantial structural heterogeneity. In addition, while the capsid is associated with budding initiation, it is not required for curvature formation. By determining the NEC structure in several conformations, we show that curvature arises from an asymmetric assembly of disordered and hexagonally ordered lattice domains independent of pUL25 or other viral capsid vertex components. Our results advance our understanding of the mechanism of nuclear egress in the context of a living cell., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

HnRNP A/B belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family and plays an important role in regulating viral protein translation and genome replication. Here, we found that overexpression of hnRNP A/B promoted spring viremia of carp virus (SVCV) and cyprinid herpesvirus 3 (CyHV3) replication. Further, hnRNP A/B was shown to act as a negative regulator of type I interferon (IFN) response. Mechanistically, hnRNP A/B interacted with MITA, TBK1 and IRF3 to initiate their degradation. In addition, hnRNP A/B bound to the kinase domain of TBK1, the C terminal domain of MITA and IAD domain of IRF3, and the RRM1 domain of hnRNP A/B bound to TBK1, RRM2 domain bound to IRF3 and MITA. Our study provides novel insights into the functions of hnRNP A/B in regulating host antiviral response., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Viruses exploit the host cell machinery to enable infection and propagation. This review discusses the complex landscape of DNA virus-host interactions, focusing primarily on herpesviruses and adenoviruses, which replicate in the nucleus of infected cells, and vaccinia virus, which replicates in the cytoplasm. We discuss experimental approaches used to discover and validate interactions of host proteins with viral genomes and how these interactions impact processes that occur during infection, including the host DNA damage response and viral genome replication, repair, and transcription. We highlight the current state of knowledge regarding virus-host protein interactions and also outline emerging areas and future directions for research.

Alzheimer's disease (AD) is a real and current scientific and societal challenge. Alzheimer's disease is characterised by a neurodegenerative neuroinflammatory process, but the etiopathogenetic mechanisms are still unclear. The possible infectious aetiology and potential involvement of Herpes viruses as triggers for the formation of extracellular deposits of amyloid beta (Aβ) peptide (amyloid plaques) and intraneuronal aggregates of hyperphosphorylated and misfold could be a possible explanation. In fact, the possible genetic interference of Herpes viruses with the genome of the host neuronal cell or the stimulation of the infection to a continuous immune response with a consequent chronic inflammation could constitute those mechanisms underlying the development of AD, with possible implications in the understanding and management of the disease. Herpes viruses could be significantly involved in the pathogenesis of AD and in particular, their ability to reactivate in particular conditions such as immunocompromise and immunosenescence, could explain the neurological damage characteristic of AD. Our review aims to evaluate the state of the art of knowledge and perspectives regarding the potential relationship between Herpes viruses and AD, in order to be able to identify the possible etiopathogenetic mechanisms and the possible therapeutic implications., (© 2024 John Wiley & Sons Ltd.)

Understanding the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that a herpesvirus infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment-symptoms consistent with ME/CFS and Long COVID. This paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within the ECs of ME/CFS patients. This review offers conceptual advances by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research toward potentially unexplored avenues in understanding and treating this complex syndrome.

Apoptosis is a physiological cell death phenomenon, representing one of the fundamental physiological mechanisms for maintaining homeostasis in living organisms. Previous studies have observed typical apoptotic features in Carassius auratus gibelio caudal fin cell (GiCF) infected with Cyprinid herpesvirus 2 (CyHV-2), and found a significant up-regulation of ccBAX expression in these infected cells. However, the specific apoptotic mechanism involved remains unclear. In this study, we utilized the GiCF cell line to investigate the apoptotic mechanism during CyHV-2 infection. Immunofluorescence staining revealed translocation of ccBAX into mitochondria upon CyHV-2 infection. Flow cytometry analysis demonstrated that overexpression of ccBAX expedited virus-induced apoptosis, characterized by heightened mitochondrial depolarization, increased transcriptional levels of Cytochrome c (Cyto c) in both the cytoplasm and mitochondria, and augmented Caspase 3/7 enzyme activity. Bax inhibitor peptide V5 (BIP-V5), an inhibitor interfering with the function of Bax proteins, inhibited Bax-mediated apoptotic events through the mitochondrial pathway and attenuated apoptosis induced by CyHV-2. In this study, it was identified for the first time that CyHV-2 induces apoptosis via the mitochondrial pathway in GiCF cells, bridging an important gap in our understanding regarding cell death mechanisms induced by herpesvirus infections in fish species. These findings provide a theoretical basis for comprehending viral apoptotic regulation mechanisms and the prevention and control of cellular pathologies caused by CyHV-2 infection., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The transporter associated with antigen processing (TAP) is a key player in the major histocompatibility class I-restricted antigen presentation and an attractive target for immune evasion by viruses. Bovine herpesvirus 1 impairs TAP-dependent antigenic peptide transport through a two-pronged mechanism in which binding of the UL49.5 gene product to TAP both inhibits peptide transport and triggers its proteasomal degradation. How UL49.5 promotes TAP degradation has, so far, remained unknown. Here, we use high-content siRNA and genome-wide CRISPR-Cas9 screening to identify CLR2 KLHDC3 as the E3 ligase responsible for UL49.5-triggered TAP disposal. We propose that the C terminus of UL49.5 mimics a C-end rule degron that recruits the E3 to TAP and engages the cullin-RING E3 ligase in endoplasmic reticulum-associated degradation., Competing Interests: Competing interests statement:The authors declare no competing interest.

Localized juvenile (aggressive) periodontitis starts at puberty in otherwise healthy individuals and involves the proximal surfaces of permanent incisors and first molars. The disease destroys a sizeable amount of periodontal bone within a few months despite minimal dental plaque and gingival tissue inflammation. Cytomegalovirus and Epstein-Barr virus, as well as the two main periodontopathic bacteria Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, are linked to juvenile periodontitis. Juvenile periodontitis-affected teeth show cementum hypoplasia. We hypothesize that an active herpesvirus infection, at the time of root formation, hampers cementum formation and, at puberty, herpesvirus reactivation triggers an upgrowth of bacterial pathogens which produce rapid periodontal destruction on teeth with a defective periodontium. A pathogenic interaction between active herpesviruses and bacterial pathogens can potentially explain the etiology and incisor-first molar destructive pattern of juvenile periodontitis. Effective treatment of juvenile periodontitis may target the herpesvirus-bacteria co-infection., (© 2023 The Authors. Periodontology 2000 published by John Wiley & Sons Ltd.)

The herpesviruses are the most common infectious agents associated with both primary and secondary cytokine storm syndromes (CSS). While Epstein-Barr Virus (EBV) is most frequently reported in association with CSS, cytomegalovirus (CMV) and many other herpesviruses (e.g., herpes simplex virus, varicella zoster virus, and human herpesviruses 6 and 8) are clearly associated with CSS in children and adults. Immunocompromised hosts, whether due to primary immunodeficiency or secondary immune compromise (e.g., solid organ or stem cell transplantation), appear to be at particularly increased risk of herpesvirus-associated CSS. In this chapter, the association of the non-EBV herpesviruses with CSS will be discussed, including predisposing factors and treatment considerations., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The human herpesviruses (HHVs) are classified into the following three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. These HHVs have distinct pathological features, while containing a highly conserved viral replication pathway. Among HHVs, the basic viral particle structure and the sequential processes of viral replication are nearly identical. In particular, the capsid formation mechanism has been proposed to be highly similar among herpesviruses, because the viral capsid-organizing proteins are highly conserved at the structural and functional levels. Herpesviruses form capsids containing the viral genome in the nucleus of infected cells during the lytic phase, and release infectious virus (i.e., virions) to the cell exterior. In the capsid formation process, a single-unit-length viral genome is encapsidated into a preformed capsid. The single-unit-length viral genome is produced by cleavage from a viral genome precursor in which multiple unit-length viral genomes are tandemly linked. This encapsidation and cleavage is carried out by the terminase complex, which is composed of viral proteins. Since the terminase complex-mediated encapsidation and cleavage is a virus-specific mechanism that does not exist in humans, it may be an excellent inhibitory target for anti-viral drugs with high virus specificity. This review provides an overview of the functions of the terminase complexes of HHVs.

Background: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a severe adverse event (mortality of 10%). Its pathophysiology involves herpesviruses, particularly HHV-6, but the exact mechanisms are still poorly understood., Objective: To describe severe cases of DRESS and especially their association with herpesvirus reactivation., Methods: This study was a multicentre case series conducted between 2007 and 2021 at five University Hospital Centres in France. The study included patients who had severe DRESS, which was defined as death, transfer to the intensive care unit (ICU), or severe damage to internal organs. We excluded patients without blood PCR sample, without a drug formally attributed or with RegiSCAR score < 6. We collected data on severity, causative drug, associated visceral damage and results of viral blood PCRs. HHV-6 reactivation was studied in skin biopsies by detection of small non-coding transcripts (HHV-6 miR-aU14) and a late viral protein (GP82/105)., Results: Fifty-two patients were included (29 female, median age 62, interquartile range (IQR) [37;72]). Eight patients (15%) died, 13 (27%) were admitted to ICU. Most patients (n = 34; 65%) had multisystem involvement: most frequent was liver (n = 46; 88%), then renal failure (n = 24; 46%). Forty patients (77%) had at least one blood viral reactivation among HHV-6, EBV or CMV, of which 21 (53%) had at least two. Median time of blood HHV-6 reactivation was 24 days (IQR [20;35]). HHV-6 reactivation was demonstrated in 15 out of 20 skin biopsies, with a median time of 11 days [9;17]., Conclusions: We confirmed the high rate of HHV-6 reactivation in severe DRESS and demonstrated cutaneous HHV-6 reactivation using small non-coding transcripts (HHV-6 miR-aU14), which preceded viral PCR positivity in blood. These results suggest that HHV-6 reactivation during DRESS may start in skin. Furthermore, search for miR-aU14 in skin biopsy could become a useful diagnostic tool for early detection of HHV-6 reactivation., (© 2023 European Academy of Dermatology and Venereology.)

Cyprinid herpesvirus type 3 (CyHV-3), also called Koi herpesvirus (KHV), which leads to mass cyprinid mortality and enormous economic losses. To establish an infection, CyHV-3 needs to counteract host antiviral responses. CD81 belongs to the evolutionary conserved tetraspanin family of proteins. Several studies have shown that different members of the tetraspanin superfamily modulates different virus infectious processes. Here we aimed at analysing the role of CD81 in CyHV-3 infection. In this study, we cloned and characterized the CD81 of Common Carp, the open reading frame of CcCD81 gene was 702 bp, which encoded 234 amino acids with four transmembrane domains (TM1 to TM4), a small extracellular loop (SEL), and a large extracellular loop (LEL). Tissue distribution analysis showed that CcCD81 was widely expressed in all the tested tissues with the highest expression in head kidney, followed by a high expression in brain. Subsequently, expression levels of CcCD81 were significantly increased in CCB cells within the first 3h after infection, meanwhile, the expression of viral gene VP136 was reduced after CcCD81 knockdown in CCB cells post CyHV-3 infection. Furthermore, CcCD81 knockdown can significantly reduce the autophagy process and increase the promoter activity of ISRE and IFN-1 in the CCB cells after viral infection, as well as other genes involved in the IFN signaling pathway, including RIG-1、MDA5、MAVS、TBK1 and IRF3. Taking the data together, we revealed that CcCD81 mediates autophagy and blocks RIG-1-mediated antiviral signaling and negatively regulates the promoter activity of type I interferon (IFN) promoting virus replication. These results reveal a new link between autophagy and four-transmembrane-domain protein superfamily and contribute to elucidate the mechanism of CyHV-3 infection., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cyprinid herpesvirus 3 (CyHV-3) can induce up to 100% mortality among carp populations. To date, there has been no safe method to prevent the consequences of the activity of CyHV-3. Thyme is widely used in cooking due to its flavour. Both thyme and thyme essential oil (TEO) are used in traditional herbal medicine, mainly to treat respiratory system disorders. In this study, TEO containing predominantly cymene and thymol was applied to explore its antiviral effect. The toxicity of TEO was examined in MTT and crystal violet assays. The anti-CyHV-3 activity of TEO in the intracellular and extracellular stages of the viral replication cycle was explored in a plaque assay and TaqMan qPCR. TEO interfered with the intracellular stages of the CyHV-3 replication cycle with selectivity indexes (SI) of around 5. It also displayed virucidal activity in a dose- and time-dependent manner. Two-hour preincubation of CyHV-3 with TEO generated SI, ranging from 13.37 to 18.47 depending on cell line and method of examination. Preincubation of cells with TEO at a safe concentration did not decrease the intracellular viral DNA copy number, which suggests that TEO does not disturb the attachment of the virus to the cells. Further research regarding the antiviral activity of compounds of TEO is required in order to indicate the most potent molecules that could be considered candidates for application in aquaculture., (© 2023 John Wiley & Sons Ltd.)

Genome duplication supplies raw genetic materials and has been thought to be essential for evolutionary innovation and ecological adaptation. Here, we select Kelch-like ( klhl ) genes to study the evolution of the duplicated genes in the polyploid Carassius complex, including amphidiploid C. auratus and amphitriploid C. gibelio . Phylogenetic, chromosomal location and read coverage analyses indicate that most of Carassius klhl genes exhibit a 2:1 relationship with zebrafish orthologs and confirm two rounds of polyploidy, an allotetraploidy followed by an autotriploidy, occurred during Carassius evolution. The lineage-specific expansion and biased retention/loss of klhl genes are also found in Carassius . Transcriptome analyses across eight adult tissues and seven embryogenesis stages reveal varied expression dominance and divergence between the two species. The expression of klhls in response to Carassius herpesvirus 2 infection shows different expression changes corresponding to distinct herpesvirus resistances in three C. gibelio gynogenetic clones. Finally, we find that most C. gibelio klhl genes possess three alleles except eight genes that have lost one or two alleles due to genome rearrangement. The allele expression bias is prosperous for Cgklhl genes and varies during embryogenesis owning to the sequential expression manner of the alleles. The current study provides global insights into the genomic and transcriptional evolution of duplicated genes in a given superfamily resulting from multiple rounds of polyploidization.

Infectious diseases are a major constraint to the expansion of shellfish production worldwide. Pacific oyster mortality syndrome (POMS), a polymicrobial disease triggered by the Ostreid herpesvirus-1 (OsHV-1), has devastated the global Pacific oyster ( Crassostrea gigas ) aquaculture industry. Recent ground-breaking research revealed that C. gigas possess an immune memory, capable of adaption, which improves the immune response upon a second exposure to a pathogen. This paradigm shift opens the door for developing 'vaccines' to improve shellfish survival during disease outbreaks. In the present study, we developed an in-vitro assay using hemocytes - the main effectors of the C. gigas immune system - collected from juvenile oysters susceptible to OsHV-1. The potency of multiple antigen preparations (e.g., chemically and physically inactivated OsHV-1, viral DNA, and protein extracts) to stimulate an immune response in hemocytes was evaluated using flow cytometry and droplet digital PCR to measure immune-related subcellular functions and gene expression, respectively. The immune response to the different antigens was benchmarked against that of hemocytes treated with Poly (I:C). We identified 10 antigen preparations capable of inducing immune stimulation in hemocytes (ROS production and positively expressed immune- related genes) after 1 h of exposure, without causing cytotoxicity. These findings are significant, as they evidence the potential for priming the innate immunity of oysters using viral antigens, which may enable cost-effective therapeutic treatment to mitigate OsHV-1/POMS. Further testing of these antigen preparations using an in-vivo infection model is essential to validate promising candidate pseudo-vaccines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Delisle, Rolton and Vignier.)

Liquid-liquid phase separation (LLPS) has emerged as a fundamental mechanism to compartmentalize biomolecules into membraneless organelles. In this issue, Zhou et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202201088), report that MHV-68 ORF52 undergoes LLPS to form cytoplasmic virion assembly compartments, regulating the spatiotemporal compartmentalization of viral components., (© 2022 Chung et al.)

Cyprinid herpesvirus-2 (CyHV-2) is an important virus that causes herpesviral hematopoietic necrosis disease (HVHND) leading to huge economic losses in goldfish (Carassius auratus). However, until now no proper prophylactic measure or treatment is available for CyHV-2 infection in goldfish. Hence, in this experiment, we developed a heat-inactivated CyHV-2 vaccine and evaluated its performance in goldfish. Initially, CyHV-2 was propagated in the fantail goldfish fin (FtGF) cell line and the titer of the viral inoculum was 10 7.8 TCID 50 /ml. Subsequently, various temperatures (40 °C, 50 °C, 60 °C, 70 °C, and 80 °C) were evaluated to achieve the complete inactivation of CyHV-2. Only the viral inoculum inactivated at 80 °C for 1 h did not show any cytopathic effect in the FtGF cell line after five blind passages. Hence the heat-inactivated CyHV-2 vaccine developed at 80 °C was further used for immunization trials in goldfish. The experimental goldfish were intraperitoneally immunized with 300 μL of the heat-inactivated CyHV-2 vaccine. Subsequently, the kidney and spleen tissues were sampled at various time points post-vaccination (6th hr, 2nd day, 4th day, 6th day, 10th day, 16th day, and 30th day) to evaluate the expression of immune genes (IL-12, IL-10, IFN-γ, CD8, and CD4). A significant upregulation of immune genes was observed at various time points in the kidney and spleen tissue of the vaccinated goldfish. Furthermore, in order to study the efficacy of the vaccine, the experimental fish were challenged with CyHV-2 (10 7.8 TCID 50 /ml) after the 30th day post-vaccination. The survival of the fish in the vaccine group (86.7%) was significantly higher compared to the non-vaccinated group (20%). Moreover, the relative percentage survival of the vaccinated group was 83.34%. In spite of the single dose, the heat-killed vaccine developed in the present study elicited the immune response and offered better protection in goldfish against CyHV-2. However, further large-scale field performance evaluation studies are necessary to develop this vaccine on a commercial scale., Competing Interests: Conflict of interest disclosure The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Several factors influence the susceptibility of cell lines to infection by different viruses. These can be related to tissue specificity of the viruses, physiological status of the cells, their differentiation level and their capacity to mount immune responses to combat viral infection. To study the influence of cell characteristics and immune responses on their susceptibility on virus infection, newly developed cell lines from common carp brain (CCAbre), fins (CCApin), gills (CCAgill), and heart (CCAcar) and the established common carp brain (CCB) cells were exposed to the carp infecting viruses cyprinid herpesvirus 3 (CyHV-3), carp oedema virus (CEV), and the yet not fully characterized common carp paramyxovirus (CCPV). The susceptibility of these cells to viral infection was measured by formation of a cytopathic effect (CPE), estimation of viral particles produced by the cells and presence of viral mRNA in the cells. Viral susceptibility of the cells was compared to cell characteristics, measured by mRNA expression of the epithelial cell markers cadherin 1, occludin, and cytokeratin 15 and the mesenchymal cell marker vimentin, as well as to the level of type I interferon (IFN) responses. All cell lines were susceptible to CyHV-3 and CCPV but not to CEV infection. The cell lines had different levels of type I IFN responses towards the viruses. Typically, CyHV-3 did not induce high type I IFN responses, while CCPV induced high responses in CCAbre, CCAcar, CCApin cells but no response in CCAgill cells. Consequently, the type I IFN response modulated cell susceptibility to CCPV but not to CyHV-3. Interestingly, when the three different passage levels of CCB cells were examined, the susceptibility of one passage was significantly lower for CyHV-3 and higher for CCPV infection. This coincided with a loss of epithelial markers and lower type I IFN responses. This study confirms an influence of cell characteristics and immune responses on the susceptibility of carp cell lines for virus infection. Depending on the vulnerability of the virus to type I IFN responses, cells with a lower IFN-response can be superior for replication of some viruses. Batches of CCB cells can differentiate and thus may have significantly different levels of susceptibility to certain viruses., (© 2022 The Authors. Journal of Fish Diseases published by John Wiley & Sons Ltd.)

Economic importance of common carp (Cyprinus carpio L.) increases every year. Viral diseases are major threat for carp aquaculture and cause significant economic losses. Koi herpesvirus (KHV) is one of the most serious carp diseases. Current study is focused on confirmation of possible differences in early immune response to KHV depending on level of resistance. Class I interferon signalling, complement cascade and cell-mediated cytotoxicity are hypothesized as major mechanisms of early innate immune response against KHV. Different breeds of common carp show distinct level of resistance to KHV. Two breeds of common carp with completely different susceptibility to KHV were chosen for current research: amur wild carp (AS) as highly resistant and koi carp (KOI) as very susceptible breed. KHV infection caused no mortalities, but the viral load in selected tissues increased during infection. Levels of expressions of chosen genes was examined using qRT-PCR and overall change in protein expression profiles was analysed by mass spectrometry. Significant differences in immune response between AS and KOI were detected mostly at the level of protein expression. Although cell-mediated cytotoxicity showed minimal influence during KHV infection, many immune response parameters related to class I interferon signalling pathway and complement cascade were increased earlier during KHV infection in AS comparing to KOI., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Herpesviruses have been reported to be able to encode and express functional viral microRNAs that target both viral and cellular transcripts. In our previous studies, we found a new miRNA miR-KT-635 encoded by Cyprinid herpesvirus 2, which is predicted to target viral genes and cellular genes involved in innate immune signalling pathway and apoptosis. However, the function and target gene of miR-KT-635 are not proved. In this study, the regulating target gene of miR-KT-635 was proved as the viral gene ORF23 directly, the target point sequence on gene was verified and miR-KT-635 was identified to regulate the expression of ORF23 protein. According to the bioinformatics analysis, the tRNA domain and ribosome domain in the protein sequence of ORF23 were found to share high homology with R2i and P53R2i, which are related to the ribonucleotide reductase small subunit in the host (transform NTP to dNTP). Within expectations, silencing of viral ORF23 or transfecting miR-KT-635 mimics in Carassius auratus gibelio caudal fin cell line (GiCF) could suppress viral propagation significantly., (© 2022 John Wiley & Sons Ltd.)

Most viruses undergo a maturation process from a weakly self-assembled, noninfectious particle to a stable, infectious virion. For herpesviruses, this maturation process resolves several conflicting requirements: (i) assembly must be driven by weak, reversible interactions between viral particle subunits to reduce errors and minimize the energy of self-assembly, and (ii) the viral particle must be stable enough to withstand tens of atmospheres of DNA pressure resulting from its strong confinement in the capsid. With herpes simplex virus 1 (HSV-1) as a prototype of human herpesviruses, we demonstrated that this mechanical capsid maturation is mainly facilitated through capsid binding auxiliary protein UL25, orthologs of which are present in all herpesviruses. Through genetic manipulation of UL25 mutants of HSV-1 combined with the interrogation of capsid mechanics with atomic force microscopy nano-indentation, we suggested the mechanism of stepwise binding of distinct UL25 domains correlated with capsid maturation and DNA packaging. These findings demonstrate another paradigm of viruses as elegantly programmed nano-machines where an intimate relationship between mechanical and genetic information is preserved in UL25 architecture. IMPORTANCE The minor capsid protein UL25 plays a critical role in the mechanical maturation of the HSV-1 capsid during virus assembly and is required for stable DNA packaging. We modulated the UL25 capsid interactions by genetically deleting different UL25 regions and quantifying the effect on mechanical capsid stability using an atomic force microscopy (AFM) nanoindentation approach. This approach revealed how UL25 regions reinforced the herpesvirus capsid to stably package and retain pressurized DNA. Our data suggest a mechanism of stepwise binding of two main UL25 domains timed with DNA packaging.

Multiple sclerosis (MS) is a debilitating disease that arises from immune system attacks to the protective myelin sheath that covers nerve fibers and ensures optimal communication between brain and body. Although the cause of MS is unknown, a number of factors, which include viruses, have been identified as increasing the risk of displaying MS symptoms. Specifically, the ubiquitous and highly prevalent Epstein-Barr virus, human herpesvirus 6, cytomegalovirus, varicella-zoster virus, and other viruses have been identified as potential triggering agents. In this review, we examine the specific role of proline-rich proteins encoded by these viruses and their potential role in MS at a molecular level.

Haemorrhagic disease associated with elephant endotheliotropic herpesvirus (Elephantid herpesvirus, EEHV) infections is the leading cause of death for Asian elephant ( Elephas maximus ) calves. This study assessed the effect of captive herd management on EEHV shedding, as evidence of latent infection reactivation, focusing on: (1) the influence of social change on the odds of recrudescence; (2) the respective effects of between and within herd moves; and (3) characteristics of recrudescent viral shedding. Trunk and conjunctival swabs ( n = 165) were obtained from six elephants at an EAZA-accredited zoo, collected during a period of social stability, and at times of social change. Longitudinal sampling took place at times of moving two bulls out of the collection and one new bull into an adjacent enclosure to the cow herd (between herd moves), and during a period of mixing this new bull with the cow herd to facilitate mating (within herd moves). Quantitative PCR was employed to detect EEHV 1a/b, 4a/b, and EF-1-α (housekeeping gene). Generalised estimating equations determined EEHV recrudescence odds ratios (OR) and relative viral DNA load. Sixteen EEHV 1a/b shedding events occurred, but no EEHV 4a/b was detected. All management-derived social changes promoted recrudescence (social change OR = 3.27, 95% CI = 0.412-26, p = 0.262; and between herd moves OR = 1.6, 95% CI = 0.178-14.4, p = 0.675), though within herd movements posed the most significant increase of EEHV reactivation odds (OR = 6.86, 95% CI = 0.823-57.1, p = 0.075) and demonstrated the strongest relative influence (post hoc Tukey test p = 0.0425). Shedding onset and magnitude ranged from six to 54 days and from 3.59 to 11.09 ΔCts. Differing challenges are associated with between and within herd movements, which can promote recrudescence and should be considered an exposure risk to naïve elephants.

Clostridium perfringens is an important food-borne zoonotic pathogen and a member of the commensal gut microbiome of many mammals. Predisposing factors such as coinfection with other pathogens or diet change can, however, cause overgrowth and subsequent disease development. Here we investigated the occurrence of C. perfringens in a free-ranging badger population with up to 100% prevalence of herpesvirus infection. Herpesvirus reactivation is known to be associated with increased susceptibility bacterial infections. PCR screening of rectal swabs from 69 free-ranging badgers revealed 15.9% (11/69, 95% CI = 9.1-26.3%) prevalence of detectable C. perfringens (Type A) DNA in the digestive tracts of assymptomatic animals. The results of Fisher's exact test revealed C. perfringens detection was not biased by age, sex and seasons. However, badgers with genital tract gammaherpesvirus (MusGHV-1) reactivation (p = 0.007) and infection with a specific MusGHV-1 genotype (p = 0.019) were more prone to of C. perfringens proliferation, indicating coinfection biased dynamics of intestinal C. perfringens. An inclusion pattern analysis further indicated that, causally, MusGHV-1 reactivation potentiated C. perfringens detection. Whether or not specific MusGHV-1 genotype infection or reactivation plays a role in C. perfringens overgrowth or disease development in badgers will require further investigation. Nevertheless, a postmortem examination of a single badger that died of fatal disease, likely associated with C. perfringens, revealed MusGHV-1 detection in the small intestine., (© 2021. The Author(s).)

Herpesvirus capsids are assembled in the nucleus and undergo a two-step process to cross the nuclear envelope. Capsids bud into the inner nuclear membrane (INM) aided by the nuclear egress complex (NEC) proteins UL31/34. At that stage of egress, enveloped virions are found for a short time in the perinuclear space. In the second step of nuclear egress, perinuclear enveloped virions (PEVs) fuse with the outer nuclear membrane (ONM) delivering capsids into the cytoplasm. Once in the cytoplasm, capsids undergo re-envelopment in the Golgi/trans-Golgi apparatus producing mature virions. This second step of nuclear egress is known as de-envelopment and is the focus of this review. Compared with herpesvirus envelopment at the INM, much less is known about de-envelopment. We propose a model in which de-envelopment involves two phases: (i) fusion of the PEV membrane with the ONM and (ii) expansion of the fusion pore leading to release of the viral capsid into the cytoplasm. The first phase of de-envelopment, membrane fusion, involves four herpes simplex virus (HSV) proteins: gB, gH/gL, gK and UL20. gB is the viral fusion protein and appears to act to perturb membranes and promote fusion. gH/gL may also have similar properties and appears to be able to act in de-envelopment without gB. gK and UL20 negatively regulate these fusion proteins. In the second phase of de-envelopment (pore expansion and capsid release), an alpha-herpesvirus protein kinase, US3, acts to phosphorylate NEC proteins, which normally produce membrane curvature during envelopment. Phosphorylation of NEC proteins reverses tight membrane curvature, causing expansion of the membrane fusion pore and promoting release of capsids into the cytoplasm.

Herpesvirus genomes show abundant evidence of past recombination. Its functional importance is unknown. A key question is whether recombinant viruses can outpace the immunity induced by their parents to reach higher loads. We tested this by coinfecting mice with attenuated mutants of murid herpesvirus 4 (MuHV-4). Infection by the natural olfactory route routinely allowed mutant viruses to reconstitute wild-type genotypes and reach normal viral loads. Lung coinfections rescued much less well. Attenuated murine cytomegalovirus mutants similarly showed recombinational rescue via the nose but not the lungs. These infections spread similarly, so route-specific rescue implied that recombination occurred close to the olfactory entry site. Rescue of replication-deficient MuHV-4 confirmed this, showing that coinfection occurred in the first encountered olfactory cells. This worked even with asynchronous inoculation, implying that a defective virus can wait here for later rescue. Virions entering the nose get caught on respiratory mucus, which the respiratory epithelial cilia push back toward the olfactory surface. Early infection was correspondingly focused on the anterior olfactory edge. Thus, by concentrating incoming infection into a small area, olfactory entry seems to promote functionally significant recombination. IMPORTANCE All organisms depend on genetic diversity to cope with environmental change. Small viruses rely on frequent point mutations. This is harder for herpesviruses because they have larger genomes. Recombination provides another means of genetic optimization. Human herpesviruses often coinfect, and they show evidence of past recombination, but whether this is rare and incidental or functionally important is unknown. We showed that herpesviruses entering mice via the natural olfactory route meet reliably enough for recombination routinely to repair crippling mutations and restore normal viral loads. It appeared to occur in the first encountered olfactory cells and reflected a concentration of infection at the anterior olfactory edge. Thus, natural host entry incorporates a significant capacity for herpesvirus recombination.

The infection of mammalian cells by enveloped viruses is triggered by the interaction of viral envelope glycoproteins with the glycosaminoglycan, heparan sulfate. By mimicking this carbohydrate, some anionic polysaccharides can block this interaction and inhibit viral entry and infection. As heparan sulfate carries both carboxyl and sulfate groups, this work focused on the derivatization of a (1→3)(1→6)-β-D-glucan, botryosphaeran, with these negatively-charged groups in an attempt to improve its antiviral activity. Carboxyl and sulfonate groups were introduced by carboxymethylation and sulfonylation reactions, respectively. Three derivatives with the same degree of carboxymethylation (0.9) and different degrees of sulfonation (0.1; 0.2; 0.4) were obtained. All derivatives were chemically characterized and evaluated for their antiviral activity against herpes (HSV-1, strains KOS and AR) and dengue (DENV-2) viruses. Carboxymethylated botryosphaeran did not inhibit the viruses, while all sulfonated-carboxymethylated derivatives were able to inhibit HSV-1. DENV-2 was inhibited only by one of these derivatives with an intermediate degree of sulfonation (0.2), demonstrating that the dengue virus is more resistant to anionic β-D-glucans than the Herpes simplex virus. By comparison with a previous study on the antiviral activity of sulfonated botryosphaerans, we conclude that the presence of carboxymethyl groups might have a detrimental effect on antiviral activity.

Members of the family Herpesviridae have enveloped, spherical virions with characteristic complex structures consisting of symmetrical and non-symmetrical components. The linear, double-stranded DNA genomes of 125-241 kbp contain 70-170 genes, of which 43 have been inherited from an ancestral herpesvirus. In general, herpesviruses have coevolved with and are highly adapted to their hosts, which comprise many mammalian, avian and reptilian species. Following primary infection, they are able to establish lifelong latent infection, during which there is limited viral gene expression. Severe disease is usually observed only in the foetus, the very young, the immunocompromised or following infection of an alternative host. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Herpesviridae , which is available at ictv.global/report/herpesviridae.

Cell-cell fusion is a fundamental and complex process that occurs during reproduction, organ and tissue growth, cancer metastasis, immune response, and infection. All enveloped viruses express one or more proteins that drive the fusion of the viral envelope with cellular membranes. The same proteins can mediate the fusion of the plasma membranes of adjacent cells, leading to the formation of multinucleated syncytia. While cell-cell fusion triggered by alpha- and gammaherpesviruses is well-studied, much less is known about the fusogenic potential of betaherpesviruses such as human cytomegalovirus (HCMV) and human herpesviruses 6 and 7 (HHV-6 and HHV-7). These are slow-growing viruses that are highly prevalent in the human population and associated with several diseases, particularly in individuals with an immature or impaired immune system such as fetuses and transplant recipients. While HHV-6 and HHV-7 are strictly lymphotropic, HCMV infects a very broad range of cell types including epithelial, endothelial, mesenchymal, and myeloid cells. Syncytia have been observed occasionally for all three betaherpesviruses, both during in vitro and in vivo infection. Since cell-cell fusion may allow efficient spread to neighboring cells without exposure to neutralizing antibodies and other host immune factors, viral-induced syncytia may be important for viral dissemination, long-term persistence, and pathogenicity. In this review, we provide an overview of the viral and cellular factors and mechanisms identified so far in the process of cell-cell fusion induced by betaherpesviruses and discuss the possible consequences for cellular dysfunction and pathogenesis.

Human herpesviruses, classified into three subfamilies, are double-stranded DNA viruses that establish lifelong latent infections within most of the world's population and can cause severe disease, especially in immunocompromised people. There is no cure, and current preventative and therapeutic options are limited. Therefore, understanding the biology of these viruses is essential for finding new ways to stop them. Capsids play a central role in herpesvirus biology. They are sophisticated vehicles that shelter the pressurized double-stranded-DNA genomes while ensuring their delivery to defined cellular destinations on the way in and out of the host cell. Moreover, the importance of capsids for multiple key steps in the replication cycle makes their assembly an attractive therapeutic target. Recent cryo-electron microscopy reconstructions of capsids from all three subfamilies of human herpesviruses revealed not only conserved features but also remarkable structural differences. Furthermore, capsid assembly studies have suggested subfamily-specific roles of viral capsid protein homologs. In this review, we compare capsid structures, assembly mechanisms, and capsid protein functions across human herpesvirus subfamilies, highlighting the differences.

In aquaculture, disease management and pathogen control are key for a successful fish farming industry. In past years, European catfish farming has been flourishing. However, devastating fish pathogens including limiting fish viruses are considered a big threat to further expanding of the industry. Even though mainly the ranavirus ( Iridoviridea ) and circovirus ( Circoviridea ) infections are considered well- described in European catfish, more other agents including herpes-, rhabdo or papillomaviruses are also observed in the tissues of catfish with or without any symptoms. The etiological role of these viruses has been unclear until now. Hence, there is a requisite for more detailed information about the latter and the development of preventive and therapeutic approaches to complete them. In this review, we summarize recent knowledge about viruses that affect the European catfish and describe their origin, distribution, molecular characterisation, and phylogenetic classification. We also highlight the knowledge gaps, which need more in-depth investigations in the future.

An evolutionary arms race occurs between viruses and hosts. Hosts have developed an array of antiviral mechanisms aimed at inhibiting replication and spread of viruses, reducing their fitness, and ultimately minimising pathogenic effects. In turn, viruses have evolved sophisticated counter-measures that mediate evasion of host defence mechanisms. A key aspect of host defences is the ability to differentiate between self and non-self. Previous studies have demonstrated significant suppression of CpG and UpA dinucleotide frequencies in the coding regions of RNA and small DNA viruses. Artificially increasing these dinucleotide frequencies results in a substantial attenuation of virus replication, suggesting dinucleotide bias could facilitate recognition of non-self RNA. The interferon-inducible gene, zinc finger antiviral protein (ZAP) is the host factor responsible for sensing CpG dinucleotides in viral RNA and restricting RNA viruses through direct binding and degradation of the target RNA. Herpesviruses are large DNA viruses that comprise three subfamilies, alpha, beta and gamma, which display divergent CpG dinucleotide patterns within their genomes. ZAP has recently been shown to act as a host restriction factor against human cytomegalovirus (HCMV), a beta-herpesvirus, which in turn evades ZAP detection by suppressing CpG levels in the major immediate-early transcript IE1, one of the first genes expressed by the virus. While suppression of CpG dinucleotides allows evasion of ZAP targeting, synonymous changes in nucleotide composition that cause genome biases, such as low GC content, can cause inefficient gene expression, especially in unspliced transcripts. To maintain compact genomes, the majority of herpesvirus transcripts are unspliced. Here we discuss how the conflicting pressures of ZAP evasion, the need to maintain compact genomes through the use of unspliced transcripts and maintaining efficient gene expression may have shaped the evolution of herpesvirus genomes, leading to characteristic CpG dinucleotide patterns.

Various intrinsic and extrinsic factors can interfere with the process of protein folding, resulting in protein aggregates. Usually, cells prevent the formation of aggregates or degrade them to prevent the cytotoxic effects they may cause. However, during viral infection, the formation of aggregates may serve as a cellular defense mechanism. On the other hand, some viruses are able to exploit the process of aggregate formation and removal to promote their replication or evade the immune response. This review article summarizes the process of cellular protein aggregation and gives examples of how different viruses exploit it. Particular emphasis is placed on the ribonucleotide reductases of herpesviruses and how their additional non-canonical functions in viral immune evasion are closely linked to protein aggregation.

Koi herpesvirus (KHV) is a highly contagious virus that causes KHV disease (KHVD) inducing high mortality in carp and koi (Cyprinus carpio L.). In the late stage, latency occurs with very low, often non-detectable virus concentrations, which represents a challenge for virus detection. After validation according to OIE recommendations, an antibody ELISA was established to recognize antibodies of C. carpio against KHV infection. In this study, the ELISA was modified to detect anti-KHV antibodies from a non-cyprinid fish. Experimentally infected rainbow trout (Oncorhynchus mykiss) were able to transmit KHV to naïve carp at two different temperatures, demonstrating their potential as a reservoir host. At 20°C, KHVD was induced in carp but not at 15°C. Unexpectedly, rainbow trout developed humoral response against KHV at both temperatures. In contrast to carp, at 15°C trout produced neutralizing antibodies but not at 20°C. While antibodies obtained from infected carp sera reacted in a similar way against all KHV, antibodies from rainbow trout sera reacted differently to the same isolates by ELISA. The data show that even when non-cyprinid fish species are infected with KHV, they can produce antibodies that differ from those observed in carp., (© 2021 John Wiley & Sons Ltd.)

The Human Herpesviruses persist in the form of a latent infection in specialized cell types. During latency, the herpesvirus genomes associate with cellular histone proteins and the viral lytic genes assemble into transcriptionally repressive heterochromatin. Although there is divergence in the nature of heterochromatin on latent herpesvirus genomes, in general, the genomes assemble into forms of heterochromatin that can convert to euchromatin to permit gene expression and therefore reactivation. This reversible form of heterochromatin is known as facultative heterochromatin and is most commonly characterized by polycomb silencing. Polycomb silencing is prevalent on the cellular genome and plays a role in developmentally regulated and imprinted genes, as well as X chromosome inactivation. As herpesviruses initially enter the cell in an un-chromatinized state, they provide an optimal system to study how de novo facultative heterochromatin is targeted to regions of DNA and how it contributes to silencing. Here, we describe how polycomb-mediated silencing potentially assembles onto herpesvirus genomes, synergizing what is known about herpesvirus latency with facultative heterochromatin targeting to the cellular genome. A greater understanding of polycomb silencing of herpesviruses will inform on the mechanism of persistence and reactivation of these pathogenic human viruses and provide clues regarding how de novo facultative heterochromatin forms on the cellular genome.

Elephant endotheliotropic herpesvirus haemorrhagic disease (EEHV-HD) is widely acknowledged as the most common cause of mortality in young Asian elephants (Elephas maximus) in captivity. The objective of the current study was to perform a blinded, retrospective pathology review of European EEHV-HD fatalities, constituting the largest systematic assessment of EEHV-HD pathology to date. Findings between viral genotypes were compared with the aim to investigate if disseminated intravascular coagulation (DIC) could be substantiated as a significant complicating factor, thereby increasing the understanding of disease pathophysiology. Immunohistochemical staining confirmed endothelial cell (EC) damage and the presence of EC intranuclear inclusion bodies, demonstrating a direct viral cytopathic effect. Microthrombi were observed in 63% of cases in several organs, including lungs, which, together with widespread haemorrhage and thrombocytopenia reported in EEHV-HD case reports, supports the presence of overt DIC as a serious haemostatic complication of active EEHV infection. Death was attributed to widespread vascular damage with multi-organ dysfunction, including severe acute myocardial haemorrhage and subsequent cardiac failure. Systemic inflammation observed in the absence of bacterial infection may be caused by cytokine release syndrome. Findings reinforce the necessity to investigate cytokine responses and haemostatic status during symptomatic and asymptomatic EEHV viraemia, to potentially support the use of anti-inflammatory treatment in conjunction with anti-viral therapy and cardiovascular support.

Anti-disease breeding is becoming the most promising solution to cyprinid herpesvirus-3 (CyHV-3) infection, the major threat to common carp aquaculture. Virus challenging studies suggested that a breeding strain of common carp developed resistance to CyHV-3 infection. This study illustrates the immune mechanisms involved in both sensitivity and anti-virus ability for CyHV3 infection in fish. An integrative analysis of the protein-coding genes and long non-coding RNAs (lncRNAs) using transcriptomic data was performed. Tissues from the head kidney of common carp were extracted at days 0 (the healthy control) and 7 after CyHV-3 infection (the survivors) and used to analyze the transcriptome through both Illumina and PacBio sequencing. Following analysis of the GO terms and KEGG pathways involved, the immune-related terms and pathways were merged. To dig out details on the immune aspect, the DEGs were filtered using the current common carp immune gene library. Immune gene categories and their corresponding genes in different comparison groups were revealed. Also, the immunological Gene Ontology terms for lncRNA modulation were retained. The weighted gene co-expression network analysis was used to reveal the regulation of immune genes by lncRNA. The results demonstrated that the breeding carp strain develops a marked resistance to CyHV-3 infection through a specific innate immune mechanism. The featured biological processes were autophagy, phagocytosis, cytotoxicity, and virus blockage by lectins and MUC3. Moreover, the immune-suppressive signals, such as suppression of IL21R on STAT3, PI3K mediated inhibition of inflammation by dopamine upon infection, as well as the inhibition of NLRC3 on STING during a steady state. Possible susceptible factors for CyHV-3, such as ITGB1, TLR18, and CCL4, were also revealed from the non-breeding strain. The results of this study also suggested that Nramp and PAI regulated by LncRNA could facilitate virus infection and proliferation for infected cells respectively, while T cell leukemia homeobox 3 (TLX3), as well as galectin 3 function by lncRNA, may play a role in the resistance mechanism. Therefore, immune factors that are immunogenetically insensitive or susceptible to CyHV-3 infection have been revealed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jia, Wu, Jiang, Li, Sun, Shi, Li, Ge, Hu, Ye, Tang, Shan, Cheng, Xia and Shi.)

α-herpesviruses have been very successful, principally because they establish lifelong latency in sensory ganglia. An essential piece of the lifecycle of α-herpesviruses involves the capacity to travel from sensory neurons to epithelial tissues following virus reactivation from latency, a process known as anterograde transport. Virus particles formed in neuron cell bodies hitchhike on kinesin motors that run along microtubules, the length of axons. Herpes simplex virus (HSV) and pseudorabies virus (PRV) have been intensely studied to elucidate anterograde axonal transport. Both viruses use similar strategies for anterograde transport, although there are significant differences in the form of virus particles transported in axons, the identity of the kinesins that transport viruses, and how certain viral membrane proteins, gE/gI and US9, participate in this process. This review compares the older models for HSV and PRV anterograde transport with recent results, which are casting a new light on several aspects of this process., (Copyright © 2021. Published by Elsevier Inc.)

Elephant endotheliotropic herpesvirus-hemorrhagic disease (EEHV-HD) is an acute fatal disease in elephants. Despite the fact that the underlying pathogenesis of EEHV-HD has been proposed, it remains undetermined as to what mechanisms drive these hemorrhagic and edematous lesions. In the present study, we have investigated and explained the pathogenesis of acute EEHV-HD using blood profiles of EEHV-HD and EEHV-infected cases, hematoxylin and eosin (H&E) stain, special stains, immunohistochemistry, quantitative polymerase chain reaction (PCR) and reverse transcriptase polymerase chain reaction (RT-PCR). It was found that EEHV genomes were predominantly detected in various internal organs of EEHV-HD cases. Damage to endothelial cells, vasculitis and vascular thrombosis of the small blood vessels were also predominantly observed. Increases in platelet endothelial cell adhesion molecules-1 (PECAM-1)- and von Willebrand factor (vWF)-immunolabeling positive cells were significantly noticed in injured blood vessels. The expression of pro-inflammatory cytokine mRNA was significantly up-regulated in EEHV-HD cases when compared to EEHV-negative controls. We have hypothesized that this could be attributed to the systemic inflammation and disruption of small blood vessels, followed by the disseminated intravascular coagulopathy that enhanced hemorrhagic and edematous lesions in EEHV-HD cases. Our findings have brought attention to the potential application of effective preventive and therapeutic protocols to treat EEHV infection in Asian elephants.

Bcl2 family proteins play a critical role in cell death or survival. BAX, the death-promoting protein of bcl2 family, mediated mitochondrial pathway inducing cells' apoptosis in mammal. MiRNAs have been implicated as negative regulators down-regulating genes' expression after post-transcriptional level. At present, little is known about the regulatory mechanism of miRNA on the Bcl2 family proteins during CyHV-2 infection in silver crucian carp (Carassius auratus gibelio). In this study, the ccBAX (silver crucian carp BAX) gene was cloned and expressed, and polyclonal antibodies were raised in mouse against the purified ccBAX-GST fusion protein. The structure analysis indicated that ccBAX protein included four conserve domains (BH1, BH2, BH3 and transmembrane domains) and the expression of ccBAX protein occurred throughout the cells. Furthermore, two miRNAs (miR-124 and miRNA-29b) were identified to negatively regulate ccBAX gene expression in GiCF cell. miR-124 was found to suppress the expression of WT-ccBAX (wild type), but not the MT-ccBAX (mutant). Overall, the results demonstrated that the expression of the ccBAX gene was significantly down-regulated by miR-124 in silver crucian carp (Carassius auratus gibelio) during CyHV-2 infection., (© 2021 John Wiley & Sons Ltd.)

The importance of viral infections as a leading cause of morbidity and mortality is well documented in severely immunosuppressed patients undergoing allogeneic stem cell transplantation. By contrast, viral infections generally receive less attention in patients with malignant disorders undergoing chemotherapy, where the onset of neutropenic fever is mostly associated with bacterial or fungal infections, and screening for viral infections is not routinely performed. To address the occurrence of invasive viral infections in a clinical setting commonly associated with less pronounced immunosuppression, we have prospectively screened 237 febrile neutropenic episodes in pediatric (n = 77) and adult (n = 69) patients undergoing intensive chemotherapy, primarily for treatment of acute leukemia. Serial peripheral blood specimens were tested by RQ-PCR assays for the presence and quantity of the clinically relevant viruses CMV, EBV, HHV6 and HAdV, commonly reactivated in highly immunocompromised patients. Viremia was documented in 36 (15%) episodes investigated, including the detection of HHV6 (n = 14), EBV (n = 15), CMV (n = 6), or HAdV (n = 1). While low or intermediate levels of viremia (<10 4 virus copies/mL) were commonly associated with bacterial or fungal co-infection, viremia at higher levels (>10 4 copies/mL) was documented in patients without evidence for other infections, raising the possibility that at least in some instances the onset of fever may have been attributable to the virus detected. The observations suggest that viral infections, potentially resulting from reactivation, might also play a clinically relevant role in patients receiving chemotherapy for treatment of malignant neoplasms, and routine screening for viremia in this clinical setting might be warranted., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The success of long-term host-virus partnerships is predicated on the ability of the host to limit the destructive potential of the virus and the virus's skill in manipulating its host to persist undetected yet replicate efficiently when needed. By mastering such skills, herpesviruses persist silently in their hosts, though perturbations in this host-virus equilibrium can result in disease. The heterochromatin machinery that tightly regulates endogenous retroviral elements and pericentromeric repeats also silences invading genomes of alpha-, beta-, and gammaherpesviruses. That said, how these viruses disrupt this constitutive heterochromatin machinery to replicate and spread, particularly in response to disparate lytic triggers, is unclear. Here, we review how the cancer-causing gammaherpesvirus Epstein-Barr virus (EBV) uses the inflammasome as a security system to alert itself of threats to its cellular home as well as to flip the virus-encoded lytic switch, allowing it to replicate and escape in response to a variety of lytic triggers. EBV provides the first example of an infectious agent able to actively exploit the inflammasome to spark its replication. Revealing an unexpected link between the inflammasome and the epigenome, this further brings insights into how the heterochromatin machinery uses differential strategies to maintain the integrity of the cellular genome whilst guarding against invading pathogens. These recent insights into EBV biology and host-viral epigenetic regulation ultimately point to the NLRP3 inflammasome as an attractive target to thwart herpesvirus reactivation.

Cyprinid herpesvirus 2 (CyHV-2), a member of the genus Cyprinivirus in the family Alloherpesviridae, has attracted worldwide attention because it causes severe disease and high mortality in crucian carp and goldfish. In this study, we focus on mRNA, protein and viral miRNA expression profiles in C. auratus gibelio caudal fin (GiCF) cells infected with CyHV-2, using high-throughput sequence techniques and TMT-labelled analyses. The results revealed that 156 virus genes were differentially expressed during the infection. Among these differentially expressed genes, 7 viral genes were significantly up-regulated and 28 were significantly down-regulated at 96 hpi (hours post-infection) vs 48 hpi. Besides, a total of 78 viral proteins, including a large number of membrane proteins and capsid proteins associated with the viral assembly, were successfully detected by using proteome analysis. Furthermore, a total of 225,143,474 raw reads were generated from cDNA library of CyHV-2-infected GiCF cells using high-throughput sequencing technology. Following annotation and secondary structure prediction, 10 viral miRNAs were found as significantly modulated in CyHV-2-infected GiCF cells (2 down-regulated and 8 up-regulated). Finally, the CyHV-2 genes (orf19, orf23, orf118, orf121, orf127) targeted by the viral miRNA CyHV-2-KT-635 identified in this study, were predicted and validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and the regulation of CyHV-2-KT-635 on orf121 protein expression was verified by western blotting assay. Taken together, this study provides a valuable basis for further research on the expression of virus genes during CyHV-2 replication and the molecular mechanisms by which miRNA may regulate CyHV-2 virus., (© 2021 John Wiley & Sons Ltd.)

The aggregation of specific proteins and their amyloid deposition in affected tissue in disease has been studied for decades assuming a sole pathogenic role of amyloids. It is now clear that amyloids can also encode important cellular functions, one of which involves the interaction potential of amyloids with microbial pathogens, including viruses. Human expressed amyloids have been shown to act both as innate restriction molecules against viruses as well as promoting agents for viral infectivity. The underlying molecular driving forces of such amyloid-virus interactions are not completely understood. Starting from the well-described molecular mechanisms underlying amyloid formation, we here summarize three non-mutually exclusive hypotheses that have been proposed to drive amyloid-virus interactions. Viruses can indirectly drive amyloid depositions by affecting upstream molecular pathways or induce amyloid formation by a direct interaction with the viral surface or specific viral proteins. Finally, we highlight the potential of therapeutic interventions using the sequence specificity of amyloid interactions to drive viral interference.