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Volume 92,
Issue 7,
2011
Volume 92, Issue 7, 2011
- Animal
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- DNA viruses
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Virally induced changes in cellular microRNAs maintain latency of human cytomegalovirus in CD34+ progenitors
More LessOne site of latency of human cytomegalovirus (HCMV; human herpesvirus 5) is known to be CD34+ haematopoietic progenitor cells, and it is likely that carriage of latent virus has profound effects on cellular gene expression in order to optimize latency and reactivation. As microRNAs (miRNAs) play important roles in regulating stem-cell gene expression, this study asked whether latent carriage of HCMV led to changes in cellular miRNA expression. A comprehensive miRNA screen showed the differential regulation of a number of cellular miRNAs during HCMV latency in CD34+ progenitor cells. One of these, hsa-miR-92a, was robustly decreased in three independent miRNA screens. Latency-induced change in hsa-miR-92a results in an increase in expression of GATA-2 and subsequent increased expression of cellular IL-10, which aids the maintenance of latent viral genomes in CD34+ cells, probably resulting from their increased survival.
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In vivo function of the murid herpesvirus-4 ribonucleotide reductase small subunit
More LessThe difficulty of eliminating herpesvirus carriage makes host entry a key target for infection control. However, its viral requirements are poorly defined. Murid herpesvirus-4 (MuHV-4) can potentially provide insights into gammaherpesvirus host entry. Upper respiratory tract infection requires the MuHV-4 thymidine kinase (TK) and ribonucleotide reductase large subunit (RNR-L), suggesting a need for increased nucleotide production. However, both TK and RNR-L are likely to be multifunctional. We therefore tested further the importance of nucleotide production by disrupting the MuHV-4 ribonucleotide reductase small subunit (RNR-S). This caused a similar attenuation to RNR-L disruption: despite reduced intra-host spread, invasive inoculations still established infection, whereas a non-invasive upper respiratory tract inoculation did so only at high dose. Histological analysis showed that RNR-S−, RNR-L− and TK− viruses all infected cells in the olfactory neuroepithelium but unlike wild-type virus then failed to spread. Thus captured host nucleotide metabolism enzymes, up to now defined mainly as important for alphaherpesvirus reactivation in neurons, also have a key role in gammaherpesvirus host entry. This seemed to reflect a requirement for lytic replication to occur in a terminally differentiated cell before a viable pool of latent genomes could be established.
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The viral ankyrin repeat protein (ORF124L) from infectious spleen and kidney necrosis virus attenuates nuclear factor-κB activation and interacts with IκB kinase β
The ankyrin (ANK) repeat is one of the most common protein–protein interaction motifs, found predominantly in eukaryotes and bacteria, but the functions of the ANK repeat are rarely researched in animal viruses, with the exception of poxviruses. Infectious spleen and kidney necrosis virus (ISKNV) is a typical member of the genus Megalocytivirus in the family Iridoviridae and is a causative agent of epizootics in fish. The genome of ISKNV contains four putative viral ANK (vANK) repeat proteins and their functions remain largely unknown. In the present study, it was found that ORF124L, a vANK repeat protein in ISKNV, encodes a protein of 274 aa with three ANK repeats. Transcription of ORF124L was detected at 12 h post-infection (p.i.) and reached a peak at 40 h p.i. ORF124L was found to localize to both the nucleus and the cytoplasm in mandarin fish fry cells. ISKNV ORF124L interacted with the mandarin fish IκB kinase β protein (scIKKβ), and attenuated tumour necrosis factor alpha (TNF-α)- or phorbol myristate acetate (PMA)-induced activity of a nuclear factor κB (NF-κB)–luciferase reporter but did not interfere with the activity of an activator protein 1 (AP-1)–luciferase reporter. Phosphorylation of IκBα and nuclear translocation of NF-κB were also impaired by ISKNV ORF124L. In summary, ORF124L was identified as a vANK repeat protein and its role in inhibition of TNF-α-induced NF-κB signalling was investigated through interaction with the mandarin fish IKKβ. This work may help to improve our understanding of the function of fish iridovirus ANK repeat proteins.
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Characterization of immunostimulatory components of orf virus (parapoxvirus ovis)
Inactivated orf virus (ORFV, parapoxvirus ovis) induces antiviral activity in animal models of acute and chronic viral infections and exerts strong effects on human immune cells. ORFV activates antigen presenting cells (APC) via CD14 and, probably, Toll-like receptor signalling, and triggers the release of IFN-γ that has been identified as the key mediator of the antiviral activity. After delineating virus proteins as being the most likely active constituent, we aimed to characterize the ORFV proteins responsible for the therapeutic effect. By using a vaccinia virus/ORFV expression library we identified several multi-gene DNA fragments with strong immunomodulatory activity. Together these fragments contain 27 ORFs. The encoded proteins are related to virion structure and transcription but are otherwise unrelated. Two proteins were separately expressed and purified, and demonstrated immunostimulatory activity. Gene expression profiles induced by ORFV and the identified fragments were investigated by microarray analysis. Interestingly, all active fragments induced a similar gene-expression pattern, differing only in quantitative aspects. Obviously, several proteins of ORFV activate similar cellular pathways, modulating APC to generate a strong T-helper 1-dominated immune response. This was balanced by additional induction of immune dampening mechanisms, suggesting regulatory differences compared to single cytokine therapies. We conclude that ORFV may have the potential to enrich the armamentarium of antiviral therapies.
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Genomic characterization of ten novel cutaneous human papillomaviruses from keratotic lesions of immunosuppressed patients
Viral warts from immunosuppressed organ transplant recipients (OTR) persist over years and may progress into non-melanoma skin cancer. The types of human papillomaviruses (HPV) in such lesions are different from that seen in the general population. A subset of these lesions is not infected with the classical wart-associated HPV types. In order to gain a better understanding of the HPV types in those lesions, we isolated ten novel HPVs from persisting keratotic lesions of immunosuppressed OTRs by rolling circle amplification and subsequent long-template PCR. Additionally, we sequenced and characterized the whole genome of the ten novel HPV types. Phylogenetic analyses revealed that nine HPV types belonged to the genus Gammapapillomavirus (γ-PV) and one to the genus Betapapillomavirus. In a phylogenetic analysis using L1 fragments of human and non-human PV types, primate papillomaviruses and our novel HPV types nested within the genus γ-PV in a highly polyphyletic pattern. This study significantly broadens the knowledge concerning the diversity and evolution of the poorly known γ-PV types.
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- Plant
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A discovery 70 years in the making: characterization of the Rose rosette virus
More LessRose rosette was first described in the early 1940s and it has emerged as one of the most devastating diseases of roses. Although it has been 70 years since the disease description, the rosette agent is yet to be characterized. In this communication, we identify and characterize the putative causal agent of the disease, a negative-sense RNA virus and new member of the genus Emaravirus. The virus was detected in 84/84 rose rosette-affected plants collected from the eastern half of the USA, but not in any of 30 symptomless plants tested. The strong correlation between virus and disease is a good indication that the virus, provisionally named Rose rosette virus, is the causal agent of the disease. Diversity studies using two virus proteins, p3 and p4, demonstrated that the virus has low diversity between isolates as they share nucleotide identities ranging from 97 to 99%.
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- Other Agents
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Characterization of the effect of heat on agent strains of the transmissible spongiform encephalopathies
More LessThe causal agents of the transmissible spongiform encephalopathy (TSE) diseases, sometimes called prion diseases, are characterized by high resistance to inactivation with heat. Results from thermal inactivation experiments on nine TSE strains, seven passaged in two PrP genotypes, showed differences in sensitivity to heat inactivation ranging over 17 °C. In addition, the rate of inactivation with increasing temperature varied between TSE models. In some cases passage in an alternative PrP genotype had little effect on the resulting inactivation properties, but for others the infectious agent was inactivated at lower temperatures. No strain with higher thermostability properties was selected. The effect of mixing two TSE strains, to see whether their properties were affected through interaction with each other, was also examined. The results showed that both strains behaved as expected from the behaviour of the unmixed controls, and that the strain responsible for inducing TSE disease could be identified. There was no evidence of a direct effect on intrinsic strain properties. Overall, the results illustrate the diversity in properties of TSE strains. They require intrinsic molecular properties of TSE agents to accommodate high resistance to inactivation and a mechanism, independent of the host, to directly encode these differences. These findings are more readily reconciled with models of TSE agents with two separate components, one of which is independent of the host and comprises a TSE-specific nucleic acid, than with models based solely on conformational changes to a host protein.
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- Phage
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Identification, sequencing and molecular analysis of Chp4, a novel chlamydiaphage of Chlamydophila abortus belonging to the family Microviridae
Members of the family Microviridae have been identified in a number of chlamydial species infecting humans (phage CPAR39 in Chlamydophila pneumoniae), other mammals (φCPG1 in Chlamydophila caviae, Chp2 in Chlamydophila abortus and Chp3 in Chlamydophila pecorum) and birds (Chp1 in Chlamydophila psittaci). This study describes the identification and genome sequencing of Chp4, an icosahedral, 4530 bp, ssDNA phage in C. abortus. Chp4 is predicted to contain eight ORFs, six of which could be assigned putative functions based on sequence similarity to characterized bacteriophage. Gene order and content were highly conserved amongst chlamydiaphage, with the highest sequence variability occurring in the IN5 and INS variable regions of the VP1 major coat protein, which has been associated with host cell recognition and binding. Phylogenetic analysis of VP1 indicated that Chp4 is a member of the Chlamydiamicrovirus, and is most closely related to phage φCPG1 and CPAR39.
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Volumes and issues
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Volume 104 (2023)
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