Mitochondria are key cellular organelles responsible for many essential functions, including ATP production, ion homeostasis and apoptosis induction. Recent studies indicate their significant role ...during viral infection. In the present study, we examined the effects of equine herpesvirus type 1 (EHV-1) infection on the morphology and mitochondrial function in primary murine neurons in vitro. We used three EHV-1 strains: two non-neuropathogenic (Jan-E and Rac-H) and one neuropathogenic (EHV-1 26). The organization of the mitochondrial network during EHV-1 infection was assessed by immunofluorescence. To access mitochondrial function, we analyzed reactive oxygen species (ROS) production, mitophagy, mitochondrial inner-membrane potential, mitochondrial mass, and mitochondrial genes' expression. Changes in mitochondria morphology during infection suggested importance of their perinuclear localization for EHV-1 replication. Despite these changes, mitochondrial functions were preserved. For all tested EHV-1 strains, the similarities in the increased fold expression were detected only for COX18, Sod2, and Tspo. For non-neuropathogenic strains (Jan-E and Rac-H), we detected mainly changes in the expression of genes related to mitochondrial morphology and transport. The results indicate that mitochondria play an important role during EHV-1 replication in cultured neurons and undergo specific morphological and functional modifications.
Kaposi's sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV8)) is the infectious cause ...of this neoplasm. In this Review we describe the epidemiology of KS and KSHV, and the insights into the remarkable mechanisms through which KSHV can induce KS that have been gained in the past 16 years. KSHV latent transcripts, such as latency-associated nuclear antigen (LANA), viral cyclin, viral FLIP and viral-encoded microRNAs, drive cell proliferation and prevent apoptosis, whereas KSHV lytic proteins, such as viral G protein-coupled receptor, K1 and virally encoded cytokines (viral interleukin-6 and viral chemokines) further contribute to the unique angioproliferative and inflammatory KS lesions through a mechanism called paracrine neoplasia.
Feline herpesvirus type 1 (FHV-1) is an enveloped dsDNA virus belonging to the
family and is considered one of the two primary viral etiological factors of feline upper respiratory tract disease. In ...this study, we investigated the entry of FHV-1 into host cells using two models: the AK-D cell line and primary feline skin fibroblasts (FSFs). We employed confocal microscopy, siRNA silencing, and selective inhibitors of various entry pathways. Our observations revealed that the virus enters cells via pH and dynamin-dependent endocytosis, as the infection was significantly inhibited by NH
Cl, bafilomycin A1, dynasore, and mitmab. Additionally, genistein, nystatin, and filipin treatments, siRNA knock-down of caveolin-1, as well as FHV-1 and caveolin-1 colocalization suggest the involvement of caveolin-mediated endocytosis during the entry process. siRNA knock-down of clathrin heavy chain and analysis of virus particle colocalization with clathrin indicated that clathrin-mediated endocytosis also takes part in the primary cells. This is the first study to systematically examine FHV-1 entry into host cells, and for the first time, we describe FHV-1 replication in AK-D and FSFs. IMPORTANCE Feline herpesvirus 1 (FHV-1) is one of the most prevalent viruses in cats, causing feline viral rhinotracheitis, which is responsible for over half of viral upper respiratory diseases in cats and can lead to ocular lesions resulting in loss of sight. Although the available vaccine reduces the severity of the disease, it does not prevent infection or limit virus shedding. Despite the clinical relevance, the entry mechanisms of FHV-1 have not been thoroughly studied. Considering the limitations of commonly used models based on immortalized cells, we sought to verify our findings using primary feline skin fibroblasts, the natural target for infection in cats.
Bovine alphaherpesvirus-1 (BoAHV-1) infection is common in cattle worldwide. However, information on the spread of BoAHV-1-circulating strains in Italy remains limited. In this study, we investigated ...an outbreak characterized by severe respiratory symptoms in a cattle herd (n = 30) located in Central Italy. BoAHV-1 was isolated from three cattle in a cell culture, which confirmed viral infection. Next, we characterized one (16453/07 TN) of the three isolates of BoAHV-1 using whole-genome sequencing. BLASTn and phylogenetic analysis revealed a nucleotide identity >99% with all BoAHV-1 strains belonging to subtype 1.1, highlighting the genetic stability of the virus. This study reports the first full genomic characterization of a BoAHV-1 isolate in Italy, enriching our understanding of the genetic characteristics of the circulating BoAHV-1 strain in Italy.
The aim of this review was to provide an updated overview of drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS). Several new insights have ...been made, particularly with regards to the diagnosis, pathogenesis and care of some important complications and sequelae. The indication of herpesvirus reactivations in diagnosis in the assessment of disease severity is now better specified. Nevertheless, because fatal complications and autoimmune sequelae have been under-recognized, there is a clear need to identify effective parameters for assessing disease severity and predicting prognosis of the disease in the early phase. In this regard, we have established a scoring system that can be used to monitor severity, predict prognosis and stratify the risk of developing severe complications including fatal cytomegalovirus (CMV) disease. Regulatory T cells are likely to be central to the mechanism and would represent potential targets for therapeutic approaches that can ameliorate inflammatory responses occurring at the acute phase while preventing the subsequent development of harmful outcomes, such as CMV disease and autoimmune diseases.
The MX dynamin GTPases inhibit diverse viruses at early post-entry phases. While MXA acts antiviral against influenza viruses, the anti HIV-1 activity of MXB was discovered recently. Here, we have ...studied the antiviral effect of MX proteins on murine cytomegalovirus (MCMV). Our data demonstrate that human MXB but not other human or murine MX proteins inhibit MCMV propagation. Evidently, the viral protein expression was delayed and the viral DNA amount in nucleus was diminished in MXB expressing cells indicating an obstruction of nuclear entry. Of note, MCMV did not deplete MX proteins. Considering the role of capsid on HIV-1 sensitivity to MXB, MXB binding to tested MCMV capsids was not detected. Moreover, MCMV restriction occurred only when MXB contained both the nuclear localization signal and a functional GTPase domain. Hence, we propose a new mode of inhibition of MCMV by MXB that is conspicuously different from that of HIV-1.
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•Human MXB but not MXA and mouse Mx proteins restricts Murine Cytomegalovirus (MCMV).•MXB blocks MCMV at an early stage of infection, presumably before nuclear entry.•Fully functional MXB is crucial for MCMV restriction, indicating a novel mechanism.•It seems MXB potentially guards against many DNA viruses relying on nuclear entry.
Human cytomegalovirus (HCMV) establishes latency in myeloid cells. Using the Kasumi-3 latency model, we previously showed that lytic gene expression is activated prior to the establishment of latency ...in these cells. The early events in infection may have a critical role in shaping the establishment of latency. Here, we have used an integrative multi-omics approach to investigate dynamic changes in host and HCMV gene expression and epigenomes at early times postinfection. Our results show dynamic changes in viral gene expression and viral chromatin. Analyses of polymerase II (Pol II), histone 3 lysine 27 acetylation (H3K27Ac), and histone 3 lysine 27 trimethylation (H3K27me3) occupancy of the viral genome showed that (i) Pol II occupancy was highest at the major IE promoter (MIEP) at 4 h postinfection. However, it was observed throughout the genome. (ii) At 24 h, H3K27Ac was localized to the major immediate early promoter/enhancer and to a possible second enhancer in the origin of replication oriLyt; (iii) viral chromatin was broadly accessible at 24 hpi. In addition, although HCMV infection activated expression of some host genes, we observed an overall loss of de novo transcription. This was associated with loss of promoter-proximal Pol II and H3K27Ac but not with changes in chromatin accessibility or a switch in modification of H3K27. IMPORTANCE Human cytomegalovirus (HCMV) is an important human pathogen in immunocompromised hosts and developing fetuses. Current antiviral therapies are limited by toxicity and emergence of resistant strains. Our studies highlight emerging concepts that challenge current paradigms of regulation of HCMV gene expression in myeloid cells. In addition, our studies show that HCMV has a profound effect on de novo transcription and the cellular epigenome. These results may have implications for mechanisms of viral pathogenesis.
Herpesviruses are ubiquitous, and infection by some, like Epstein-Barr virus (EBV), is nearly universal. To persist, EBV must periodically switch from a latent to a replicative/lytic phase. This ...productive phase is responsible for most herpesvirus-associated diseases. EBV encodes a latency-to-lytic switch protein which, upon activation, sets off a vectorially constrained cascade of gene expression that results in production of infectious virus. While triggering expression of the switch protein ZEBRA is essential to lytic cycle entry, sustaining its expression is equally important to avoid premature termination of the lytic cascade. We report that the viral protein kinase (vPK), encoded by a gene that is kinetically downstream of the lytic switch, sustains expression of ZEBRA, amplifies the lytic cascade, increasing virus production, and, importantly, prevents the abortive lytic cycle. We find that vPK, through a noncanonical site phosphorylation, activates the cellular phosphatidylinositol 3-kinase-related kinase ATM to cause phosphorylation of the heterochromatin enforcer KAP1/TRIM28 even in the absence of EBV genomes or other EBV proteins. Phosphorylation of KAP1 renders it unable to restrain ZEBRA, thereby further derepressing and sustaining its expression to culminate in virus production. This partnership with a host kinase and a transcriptional corepressor enables retrograde regulation by vPK of ZEBRA, an observation that is counter to the unidirectional regulation of gene expression reminiscent of most DNA viruses.
Herpesviruses infect nearly all humans and persist quiescently for the life of the host. These viruses intermittently activate into the lytic phase to produce infectious virus, thereby causing disease. To ensure that lytic activation is not prematurely terminated, expression of the virally encoded lytic switch protein needs to be sustained. In studying Epstein-Barr virus, one of the most prevalent human herpesviruses that also causes cancer, we have discovered that a viral kinase activated by the viral lytic switch protein partners with a cellular kinase to deactivate a silencer of the lytic switch protein, thereby providing a positive feedback loop to ensure successful completion of the viral productive phase. Our findings highlight key nodes of interaction between the host and virus that could be exploited to treat lytic phase-associated diseases by terminating the lytic phase or kill cancer cells harboring herpesviruses by accelerating the completion of the lytic cascade.
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