How does monkeypox replicate

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You will be subject to the destination website's privacy policy when you follow the link. CDC is not responsible for Section compliance accessibility on other federal or private website. Cancel Continue. Jynneos does not contain the viruses that cause smallpox or monkeypox.

It is made from a vaccinia virus, a virus that is closely related to, but less harmful than, variola or monkeypox viruses and can protect against both of these diseases.

Jynneos contains a modified form of the vaccinia virus called Modified Vaccinia Ankara, which does not cause disease in humans and is non-replicating, meaning it cannot reproduce in human cells. The effectiveness of Jynneos for the prevention of smallpox was determined in a clinical study comparing the immune responses in study participants who received either Jynneos or ACAM, an FDA-approved vaccine for the prevention of smallpox.

The study included approximately healthy adults, 18 through 42 years of age who had never been vaccinated for smallpox, in which half of the study participants received two doses of Jynneos administered 28 days apart, and half received one dose of ACAM The group vaccinated with Jynneos had an immune response that was not inferior to immune responses to ACAM Vaccine effectiveness for the prevention of smallpox was also inferred from supportive animal studies that showed prior vaccination with Jynneos protected non-human primates who were exposed to viruses related to the smallpox virus.

The effectiveness of Jynneos for the prevention of monkeypox disease is inferred from the antibody responses in the smallpox clinical study participants and from studies in non-human primates that showed protection of animals vaccinated with Jynneos who were exposed to the monkeypox virus. First enhanced replication can be observed in the first four rounds of replication after UV irradiation of viral templates.

The second major finding is that the relaxed circular intermediate model proposed for the replication of UV-damaged templates in untreated cells appears valid for replication of UV-damaged templates in carcinogen-treated cells.

Possible mechanisms and the supporting evidence are discussed and future experiments outlined. Other known broad-spectrum inhibitors of RNA virus replication such as the nucleoside analog 2'-C-methylcytidine resulted only in a moderate antiviral activity. MicroRNA regulation of human protease genes essential for influenza virus replication. Full Text Available Influenza A virus causes seasonal epidemics and periodic pandemics threatening the health of millions of people each year.

Vaccination is an effective strategy for reducing morbidity and mortality, and in the absence of drug resistance, the efficacy of chemoprophylaxis is comparable to that of vaccines. However, the rapid emergence of drug resistance has emphasized the need for new drug targets.

Knowledge of the host cell components required for influenza replication has been an area targeted for disease intervention. In this study, the human protease genes required for influenza virus replication were determined and validated using RNA interference approaches.

Analyses of host microRNAs predicted to govern expression of these genes showed that eight miRNAs regulated gene expression during virus replication.

These findings identify unique host genes and microRNAs important for influenza replication providing potential new targets for disease intervention strategies. Influenza A virus causes seasonal epidemics and periodic pandemics threatening the health of millions of people each year. Inhibition of herpesvirus and influenza virus replication by blocking polymerase subunit interactions.

Protein-protein interactions PPIs play a key role in many biological processes, including virus replication in the host cell. Since most of the PPIs are functionally essential, a possible strategy to inhibit virus replication is based on the disruption of viral protein complexes by peptides or small molecules that interfere with subunit interactions.

In particular, an attractive target for antiviral drugs is the binding between the subunits of essential viral enzymes. This review describes the development of new antiviral compounds that inhibit herpesvirus and influenza virus replication by blocking interactions between subunit proteins of their polymerase complexes. Recently, a production system for infectious particles of hepatitis C virus HCV utilizing the genotype 2a JFH1 strain has been developed.

This strain has a high capacity for replication in the cells. We observe that the presence of viral structural proteins does not influence the anti-HCV activity of CsA. Among HCV strains, the replication of genotype 1b replicons was strongly suppressed by treatment with CsA. These findings provide an insight into the mechanisms of diversity governing virus -cell interactions and in the sensitivity of these strains to antiviral agents. Definition of herpes simplex virus type 1 helper activities for adeno-associated virus early replication events.

The present study was conducted to integrate these observations and to further explore the requirement of other HSV-1 proteins during early AAV replication steps, i. Conversely, ICP27 displayed an inhibitory effect. Altogether, this work represents the first comprehensive study recapitulating the series of early events taking place during HSVinduced AAV replication.

In addition, emetine treatment also resulted in decreased synthesis of viral proteins. In a cell free endogenous viral polymerase assay, emetine was found to significantly inhibit replication of NDV, but not BPXV genome, suggesting that besides directly inhibiting specific viral polymerases, emetine may also target other factors essentially required for efficient replication of the viral genome.

Moreover, emetine was found to significantly inhibit BPXV-induced pock lesions on chorioallantoic membrane CAM along with associated mortality of embryonated chicken eggs.

At a lethal dose 50 LD 50 of Emetine was also found to significantly delay NDV-induced mortality in chicken embryos associated with reduced viral titers. Collectively, we have extended the effective antiviral activity of emetine against diverse groups of DNA and RNA viruses and propose that emetine could provide significant therapeutic value against some of these viruses without inducing an antiviral drug-resistant phenotype.

The low-pH stability discovered in neuraminidase of pandemic influenza A virus enhances virus replication. Full Text Available The "Spanish" pandemic influenza A virus , which killed more than 20 million worldwide in , is one of the serious pathogens in recorded history.

Characterization of the pandemic virus reconstructed by reverse genetics showed that PB1, hemagglutinin HA, and neuraminidase NA genes contributed to the viral replication and virulence of the pandemic influenza virus. However, the function of the NA gene has remained unknown. Here we show that the avian-like low-pH stability of sialidase activity discovered in the pandemic virus NA contributes to the viral replication efficiency.

We found that deletion of Thr at position or deletion of Gly at position in the pandemic virus NA was related to the low-pH stability of the sialidase activity in the pandemic virus NA by comparison with the sequences of other human N1 NAs and sialidase activity of chimeric constructs.

Both amino acids were located in or near the amino acid resides that were important for stabilization of the native tetramer structure in a low-pH condition like the N2 NAs of pandemic viruses that emerged in and The mutant virus that included "Spanish Flu"-like low-pH-stable NA showed remarkable replication in comparison with the mutant virus that included low-pH-unstable N1 NA.

Our results suggest that the avian-like low-pH stability of sialidase activity in the pandemic virus NA contributes to the viral replication efficiency.

Identification of rep-associated factors in herpes simplex virus type 1-induced adeno-associated virus type 2 replication compartments. Adeno-associated virus AAV is a human parvovirus that replicates only in cells coinfected with a helper virus , such as adenovirus or herpes simplex virus type 1 HSV This study resulted in the identification of approximately 60 cellular proteins, among which factors involved in DNA and RNA metabolism represented the largest functional categories.

We demonstrated for the first time that this protein plays a role during AAV replication by enhancing the resolution of AAV replicative forms and AAV particle production. Altogether, these analyses provide the basis to understand how AAV adapts its replication strategy to the nuclear environment induced by the helper virus.

Full Text Available Monkeypox is a smallpox-like illness that can be accompanied by a range of significant medical complications. To date there are no standard or optimized guidelines for the clinical management of monkeypox MPX patients, particularly in low-resource settings. Consequently, patients can experience protracted illness and poor outcomes.

Improving care necessitates developing a better understanding of the range of clinical manifestations—including complications and sequelae—as well as of features of illness that may be predictive of illness severity and poor outcomes. Experimental and natural infection of non-human primates with monkeypox virus can inform the approach to improving patient care, and may suggest options for pharmaceutical intervention.

These studies have traditionally been performed to address the threat of smallpox bioterrorism and were designed with the intent of using MPX as a disease surrogate for smallpox.

In many cases this necessitated employing high-dose, inhalational or intravenous challenge to recapitulate the severe manifestations of illness seen with smallpox. Overall, these data—and data from biomedical research involving burns, superficial wounds, herpes, eczema vaccinatum, and so forth—suggest that MPX patients could benefit from clinical support to mitigate the consequences of compromised skin and mucosa.

This should include prevention and treatment of secondary bacterial infections and other complications, ensuring adequate hydration and nutrition, and protecting vulnerable anatomical locations such as the eyes and genitals.

A standard of care that considers these factors should be developed and assessed in different settings, using clinical metrics specific for MPX alongside consideration of antiviral therapies. Recombinant viruses carrying these mutations in both sites and one with a deletion of the whole oriS were constructed. NB protein does not affect influenza B virus replication in vitro and is not required for replication in or transmission between ferrets. Elderfield, Ruth A.

The influenza B virus encodes a unique protein, NB, a membrane protein whose function in the replication cycle is not, as yet, understood. Replication of the virus lacking NB was not different to wild-type virus with full-length NB in clonal immortalized or complex primary cell cultures. In ferrets infected with a mixture of viruses that did or did not express NB, there was no fitness advantage for the virus that retained NB.

Moreover, virus lacking NB protein was transmitted following respiratory droplet exposure of sentinel animals. These data suggest no role for NB in supporting replication or transmission in vivo in this animal model. The role of NB and the nature of selection to retain it in all natural influenza B viruses remain unclear. Adeno-associated virus type 2 enhances goose parvovirus replication in embryonated goose eggs. The autonomous goose parvovirus GPV and the human helper-dependent adeno-associated virus type 2 AAV2 share a high degree of homology.

To determine if this evolutionary relationship has a biological impact, we studied viral replication in human cells and in embryonated goose eggs coinfected with both viruses. Similar experiments were performed with the minute virus of mice MVM , an autonomous murine parvovirus with less homology to AAV2. To our knowledge, this is the first report that a human helper-dependent member of the Parvoviridae can provide helper activity for an autonomous parvovirus in a natural host.

So far how hepatitis C virus HCV replication modulates subsequent virus growth and propagation still remains largely unknown. We first engineered a full-length, HCV genotype 2a JFH1 genome containing a blasticidin-resistant cassette inserted at amino acid residue of in nonstructural NS protein 5A, which allowed selection of human hepatoma Huh7 cells stably-expressing HCV.

Short-term establishment of HCV stable cells attained a highly- replicating status, judged by higher expressions of viral RNA and protein as well as higher titer of viral infectivity as opposed to cells harboring the same genome without selection. The decreased CD81 cell surface expression occurred through reduced total expression and cytoplasmic retention of CD81 within an endoplasmic reticulum -associated compartment. Moreover, productive viral RNA replication in cells harboring a JFH1 subgenomic replicon containing a similar blasticidin resistance gene cassette in NS5A and in cells robustly replicating full-length infectious genome also reduced permissiveness to HCVpp infection through decreasing the surface expression of CD The downregulation of CD81 surface level in HCV RNA highly- replicating cells thus interfered with reinfection and led to attenuated viral amplification.

Full Text Available So far how hepatitis C virus HCV replication modulates subsequent virus growth and propagation still remains largely unknown. A replication -deficient rabies virus vaccine expressing Ebola virus glycoprotein is highly attenuated for neurovirulence.

Papaneri, Amy B. We are developing inactivated and live-attenuated rabies virus RABV vaccines expressing Ebola virus EBOV glycoprotein for use in humans and endangered wildlife, respectively. Recently, rapid progress in three-dimensional 3D imaging technologies, such as electron tomography ET and focused ion beam-scanning electron microscopy FIB-SEM, has enabled researchers to visualize the novel membrane structures induced by viruses at high resolution.

These 3D imaging technologies provide new mechanistic insights into the viral infection cycle. In this review, we summarize the latest reports on the cellular remodeling that occurs during plant virus infection; in particular, we focus on studies that provide 3D architectural information on viral replication factories.

We also outline the mechanisms underlying the formation of these membranous structures and discuss possible future research directions. Inhibition of Zika Virus Replication by Silvestrol. Full Text Available The Zika virus ZIKV outbreak in in South America with specific pathogenic outcomes highlighted the need for new antiviral substances with broad-spectrum activities to react quickly to unexpected outbreaks of emerging viral pathogens.

Therefore, we investigated the effects of silvestrol on ZIKV replication in A cells and primary human hepatocytes. Two different ZIKV strains were used. In both infected A cells and primary human hepatocytes, silvestrol has the potential to exert a significant inhibition of ZIKV replication for both analyzed strains, even though the ancestor strain from Uganda is less sensitive to silvestrol.

Our data might contribute to identify host factors involved in the control of ZIKV infection and help to develop antiviral concepts that can be used to treat a variety of viral infections without the risk of resistances because a host protein is targeted. Phospholipase D PLD is a phosphatidylcholine- and phosphatidylethanolamine-hydrolyzing enzyme that catalyzes the production of phosphatidic acid PA, a lipid second messenger that modulates diverse intracellular signaling in various organisms.

Consistent with this, exogenous application of PA enhanced viral RNA replication in plant cells and plant-derived cell-free extracts. Several clones of simian virus 40 SV40 -transformed hamster kidney cells, which are heterogeneous for induction of infectious SV40, have been studied.

In order to clarify the mechanism s by which virus is produced in induced cells, we analyzed the replication of viral DNA and production of virion V antigen and infectious virus after induction in various clones as well as in lytically infected permissive cells.

Cells replicating SV40 DNA or synthesizing V antigen were visualized by in situ hybridization and immunofluorescence techniques, respectively.

Only some cells in induced cultures were found to produce SV40 and those which did were less efficient than lytically infected monkey cells. A greater proportion of cells could be induced to replicate SV40 DNA than to synthesize V antigen in all induced clones studied. These findings indicate that one of the effects of induction treatments on SVtransformed hamster cells is an enhancement of the cells' capacity to support SV40 replication. The V protein of canine distemper virus is required for virus replication in human epithelial cells.

Full Text Available Canine distemper virus CDV becomes able to use human receptors through a single amino acid substitution in the H protein. In addition, CDV strains possessing an intact C protein replicate well in human epithelial H cells. The present study showed that CDV strain Lm, which was isolated from lymph node tissue of a dog with distemper, failed to replicate in H cells, although it possessed an intact C protein.

Sequence analyses suggested that a cysteine-to-tyrosine substitution at position of the V protein caused this growth defect.

Analyses using H cells constitutively expressing the CDV V protein showed that the V protein with a cysteine, but not that with a tyrosine, at this position effectively blocked the interferon-stimulated signal transduction pathway, and supported virus replication of Lm in H cells. Thus, the V protein as well as the C protein appears to be functional and essential for CDV replication in human epithelial cells.

Mosquito-transmitted viruses are spread globally and present a great risk to human health. Among the many approaches investigated to limit the diseases caused by these viruses are attempts to make mosquitos resistant to virus infection. Investigation of the stages of the ZIKV life cycle inhibited by w Stri identified two distinct blocks in viral replication.

This was partially rescued by the addition of a cholesterol-lipid supplement. Independent of entry, transfected viral genome was unable to replicate in Wolbachia -infected cells. This study's findings increase the potential for application of w Stri to block additional arboviruses and also identify specific blocks in viral infection caused by Wolbachia coinfection.

Existing programs that seek to contain these diseases through elimination of the mosquito population have so. Full Text Available Wild birds are the reservoir for low-pathogenic avian influenza viruses , which are frequently transmitted to domestic birds and occasionally to mammals. In , an H10N7 virus caused severe mortality in harbor seals in northeastern Europe. Although the hemagglutinin HA of this virus was closely related to H10 of avian H10N4 virus , it possessed unique nonsynonymous mutations, particularly in the HA1 subunit in or adjacent to the receptor binding domain and proteolytic cleavage site.

Here, the impact of these mutations on virus replication was studied in vitro. Using reverse genetics, an avian H10N4 virus was cloned, and nine recombinant viruses carrying one of eight unique mutations or the complete HA from the seal virus were rescued. Receptor binding affinity, replication in avian and mammalian cell cultures, cell-to-cell spread, and HA cleavability of these recombinant viruses were studied.

Results show that wild-type recombinant H10N4 virus has high affinity to avian-type sialic acid receptors and no affinity to mammalian-type receptors. The H10N7 virus exhibits dual receptor binding affinity. Interestingly, QL H10 numbering in the rim of the receptor binding pocket increased the affinity of the H10N4 virus to mammal-type receptors and completely abolished the affinity to avian-type receptors. No remarkable differences in cell-to-cell spread or HA cleavability were observed.

All viruses , including the wild-type H10N7 virus , replicated at higher levels in chicken cells than in human cells. These results indicate that H10N7 acquired adaptive mutations e. Wild birds are the reservoir for low-pathogenic avian influenza viruses , which are frequently transmitted to domestic birds and occasionally to mammals. Full Text Available Unlike stereotypical neurotropic viruses , influenza A viruses have been detected in the brain tissues of human and animal models.

To investigate the interaction between neurons and influenza A viruses , mouse cortical neurons were isolated, infected with human H1N1 influenza virus , and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication.

The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication -induced cytopathy. Differential association with cellular substructures of pseudorabies virus DNA during early and late phases of replication. Pseudorabies virus DNA synthesis can be divided into two phases, early and late, which can be distinguished from each other on the basis of the structures of the replicating DNA.

The two types of replicating virus DNA can also be distinguished from each other on the basis of the cellular substructures with which each is associated. Analysis by electron microscopic autoradiography showed that during the first round of replication , nascent virus DNA was found in the vicinity of the nuclear membrane; during later rounds of replication the nascent virus DNA was located centrally within the nucleus.

The degree of association of virus DNA synthesized at early and late phases with the nuclear matrix fractions also differed; a larger proportion of late than of early nascent virus DNA was associated with this fraction. However, no retention of specific virus proteins in this fraction was observed. The large proportion of virus DNA associated with the nuclear fraction indicated that virus DNA may be intimately associated with some proteins.

Classical swine fever CSF , caused by classical swine fever virus CSFV , is one of the most devastating epizootic diseases of pigs in many countries. Viruses are small intracellular parasites and thus rely on the cellular factors for replication.

Fundamental aspects of CSFV-host interactions have been well described, such as factors contributing to viral attachment, modulation of genomic replication and translation, antagonism of innate immunity, and inhibition of cell apoptosis.

However, those host factors that participate in the viral entry, assembly, and release largely remain to be elucidated. In this review, we summarize recent progress in the virus -host interactions involved in the life cycle of CSFV and analyze the potential mechanisms of viral entry, assembly, and release. We conclude with future perspectives and highlight areas that require further understanding. Replication of M40 in cell culture is virtually indistinguishable from that of control viruses.

However, the presence of the Ebola PTAP motif in the M40 recombinant enabled this virus to interact with and recruit host Tsg, which was packaged into M40 virions. In this brief report, we compared replication and the pathogenic profiles of M40 and the parental virus M51R in mice to determine whether the presence of the Ebola L-domains and flanking residues altered in vivo characteristics of the virus. Overall, the in vivo characteristics of M40 were similar to those of the parental M51R virus , indicating that the Ebola sequences did not alter pathogenesis of VSV in this small animal model of infection.

The two nonstructural proteins encoded by RNA3 were dispensable for replication , but sequences in the 3'-terminal 58 nucleotides were required.

Brome mosaic virus BMV replicates in vesicular invaginations of the endoplasmic reticulum membrane. BMV has served as a productive model system to study processes like virus -host interactions, RNA replication and recombination.

Here we present multiple lines of evidence showing that the structure of the viral RNA replication compartments plays a fundamental role and that recruitment of parental RNAs to a common replication compartment is a limiting step in intermolecular RNA recombination. We show that a previously defined requirement for an RNA recruitment element on both parental RNAs is not to function as a preferred crossover site, but in order for individual RNAs to be recruited into the replication compartments.

Moreover, modulating the form of the replication compartments from spherular vesicles spherules to more expansive membrane layers increased intermolecular RNA recombination frequency by to fold. We propose that intermolecular RNA recombination requires parental RNAs to be recruited into replication compartments as monomers, and that recruitment of multiple RNAs into a contiguous space is much more common for layers than for spherules.

These results could explain differences in recombination frequencies between viruses that replicate in association with smaller spherules versus larger double-membrane vesicles and convoluted membranes. EBOV encodes one viral surface glycoprotein GP , which is essential for replication , a determinant of pathogenicity and an important immunogen. GP mediates viral entry through interaction with cellular surface molecules, which results in the uptake of virus particles via macropinocytosis.

Later in this pathway endosomal acidification activates the cysteine proteases Cathepsin B and L CatB, CatL , which have been shown to cleave ZEBOV-GP leading to subsequent exposure of the putative receptor-binding and fusion domain and productive infection. Furthermore, EBOV glycoprotein cleavage seems to be mediated by an array of proteases making targeted therapeutic approaches difficult.

EBOV encodes one viral surface glycoprotein GP, which is essential for replication , a determinant of pathogenicity and an important immunogen. Later in this pathway endosomal acidification activates the cysteine proteases Cathepsin B and L CatB, CatL, which have been shown to cleave ZEBOV-GP leading to subsequent exposure of the putative receptor-binding and fusion domain and productive infection.

Inhibition of herpes simplex virus replication by tobacco extracts. Herpes simplex virus type 1 HSV-1 has been associated with the genesis of leukoplakias, epithelial atypia, and oral cancer. Tobacco habits, such as snuff dipping, are also definitely correlated with this type of lesion.

The normal cytolytic HSV-1 infection can, after in vitro inactivation, transform cells. Extracts of snuff were prepared and assayed for their ability to inhibit HSV-1 replication. Plaque formation assays of HSV-1 in the presence of snuff extract showed that a reduced number of plaques was formed.

Different batches of one brand of snuff were tested for inhibition of herpes simplex virus HSV production. In agreement, the attachment of the virus to the host cell and penetration of the virus to the cell nuclei were found to be inhibited as was the synthesis of viral DNA.

Nicotine had an inhibitory effect, while aromatic additions to snuff were found to have no major inhibitory effect on HSV replication.

Snuff extracts were prepared from different brands of snuff reported to contain high and low quantities of tobacco-specific N-nitrosamines.

The number of genes regulated at 7 hpi increased to 10 genes, resembling The observed suppression of ATM results in weaker signaling of the pathway and consequently reduces response to DNA damage and routine DNA repair, additionally, it disables a major apoptosis activation process. Cluster analysis of expression profile for genes of ataxia telangiectasia mutated ATM pathway. Columns of the heat-map represent expression of genes transcripts at 3 and 7 hpi time points in a triplicate A, B, C.

Chance for random association of listed genes at 3 or 7 hpi with this pathway is 1. A significant proportion of the genes in data sets 3 and 7 hpi were enriched in three major cell cycle regulation pathways. Out of the 36 molecules found in cell-cycle regulation by BTG family pathway, seven molecules were found in each of the 3 and 7 hpi data sets with P-values of 8.

Essential genes to pathway signaling and G1 arrest were severely suppressed Figure. Retinoblastoma 1 Rb and B-cell translocation gene-1 BTG1 were downregulated in both time points and reached Furthermore, cyclin D1 and cyclin E exhibited 4. The products of these two genes function as regulators that inactivate the growth suppression activity of Rb indirectly by promoting CDK kinases [ 46 — 48 ].

Phosphorylation of Rb by CDK kinase inactivates its function, leading to the release of E2F and cell cycle progression [ 49 , 50 ]. The net outcome of this pattern of gene expression in this pathway is cell cycle release from potential arrest in G1 phase and block of BTG1-induced apoptosis. The pathway consists of 59 molecules from which eight molecules or The calculated P-values for random implication of this pathway were 2.

Cluster analysis of differentially- expressed genes involved in cell cycle regulation. Heat-map of gene expression levels at 3 and 7 hpi in triplicate A, B, C. Folds of change in gene expression represented as a gradient of green and red color for low- and high-expression intensity, respectively. Time point 7 hpi showed regulation of Progression of cell cycle into mitosis requires the activation of cell-division cycle-2 Cdc2 by the rapid dephosphorylation of its tyrosine 15 Tyr via action of Cdc25 and subsequent binding to cyclin B [ 60 , 61 ].

The latter kinase inhibits Cdc25B and Cdc25C which function as a phosphorylase that activate Cdc2 before binding to cyclin B and entry into mitosis [ 67 ]. The observed regulation of these genes would intensify this checkpoint signaling leading to a further delay in entry into mitosis Fig. Apoptosis is a natural controlled cell death mechanism triggered by diverse stimuli to maintain tissue homeostasis and eliminate abnormal or infected cells [ 68 ]. Because apoptosis represents an important part of antiviral host response, poxviruses developed numerous ways to target it and disrupt its function [ 69 ].

Diverse anti-apoptotic viral strategies are identified in different poxviruses, e. MC gene encodes a protein with glutathione peroxidase-like function to convert oxygen-reactive species to neutral molecules, hence preventing apoptosis triggered by increased oxidative stress associated with infection [ 71 ]. Little is known about apoptosis in cells infected with MPV, but related orthopoxviruses exhibit clear anti-apoptotic functions.

Cowpox virus for instance expresses a protein that can block apoptosis in multiple ways. One of the most potent anti-apoptotic proteins is the cytokine response modifier A CrmA which inhibits caspase-8, caspase, and blocks garnzyme B-mediated apoptosis [ 72 , 73 ].

Similarly, Vaccinia viruses use SPI-2 family protein member of serine protease inhibitors serpins encoded by B13R gene to block apoptosis induced by death receptors [ 74 ]. The presence of many viral proteins that block apoptosis at multiple points suggests that apoptosis is detrimental to viral survival. Although many pathogens and viruses other than poxviruses are reported to promote apoptosis [ 77 ], it is unlikely that MPV will differ from other poxviruses in their common anti-apoptotic trend, and the observed divergence between the regulation of apoptosis-specific genes in MPV-infected cells and overall anti-apoptotic outcome seen in other poxvirus-infected cells suggests an anti-apoptotic viral mechanism that functions downstream of apoptosis induction in the host.

MPV genes involved in blocking apoptosis remain unknown, but our data suggests the presence of an ortholog s of Vaccinia virus F1L gene in MPV, which acts directly on the mitochondria in Bcl-2 like manner. Double-stranded DNA mammalian viruses have large genomes reaching Kbp or few hundreds of micrometers in length as in the case of fowlpox virus [ 78 ].

Compacting the genome is an indispensible biological task due to the rich negative charge and large size of DNA molecules. In eukaryotes, this was solved by wrapping DNA around a heterooctameric molecule composed of four dimerized, positively charged core histones to form nucleosomes. Further stability is brought about by linker histones that bind DNA laterally. Nucleosomes, in a nucleofilaments form or in a form of higher-order-structure assemblies, chromatin, play an essential role in the regulation of gene expression and chromatin remodeling via acetylation and deacetylation of the N-terminal histone tails protruding from nucleosomes.

Viruses exhibit similar architecture in their DNA compaction. Staining vaccinia-infected cells with osmium ammine-SO 2 revealed areas with concentrated viral DNA in two predominant DNA configurations varying depending on the level of viral synthetic activities.

Encapsidated genomes exhibited a nucleosome structure like those observed in resting eukaryotes, which was in agreement with biochemical data showing the supercoiled organization of nucleoproteins extracted from Vaccinia viruses [ 79 ].

On the other hand, like active cellular chromatin, non-encapsidated viral genomes exhibited extended DNA features [ 80 ]. Similar variation in DNA density was observed in Herpes simplex viruses HSV , another double stranded DNA virus, with two well described configurations of euchromatin or heterochromatin that correlated strongly with lytic or latent HSV infection stages, respectively. Generally, little is known about chromatin potential in poxviruses as an antiviral mechanism.

Our results showed an interesting downregulation of five essential histone expression regulation factors and five enzymes regulating chromatin dynamics in MPV-infected cells. It is unclear if these results are part of the host response, which include chromatin-mediated silencing of the viral genome and activation of DNA damage [ 81 ], or part of the viral strategies to take over its host.

However, our observation predicts an important role for histone expression, histone posttranslational modification, and dynamic exchanges of chromatin in host-poxvirus interactions.

Recent work suggested a role for the viral A32L gene of Vaccinia virus in DNA packaging based on sequence similarities with the product of gene I of filamentous single-stranded DNA bacteriophages and the Iva2 gene of adenoviruses. Additional Vaccinia genes that map to I6 or I1 telomere-binding proteins are believed to play roles in DNA packaging, because mutants of VACV in either of these two genes fail to exhibit normal DNA packaging at different morphogenesis stages.

The sharp upregulation we observed in three out the four core histones, and the striking similarities in DNA compaction architecture observed in eukaryotes and some viruses, with absence of known poxvirus proteins that exhibit histone-like properties makes it tempting to hypothesize a role of host cell histones in viral DNA compaction and nucleosome formation, especially that similar involvement was described recently in simian virus 40 SV40 DNA compaction [ 82 ].

Our analysis identified ephrin receptor pathway ERP as a major influenced pathway in infected cells. This might be due to either increased cell to cell communication by signaling through this receptor tyrosine kinases RTK family in response to infection, or to the presence of many pleiotropic genes that are found in ERP, and simultaneously have essential roles in cytoskeleton reorganization or actin polymerization.

Intracellular viral motility and morphogenesis of Vaccinia virus into a cell-associated enveloped virion CEV and extracellular enveloped virions EEV forms are shown to be driven by interactions of host microtubules and Vaccinia A27L, A17L and A14L genes. Actin polymerization produces microvilli at cell surface that lift CEV and project it on adjacent cells to finally deliver the virus with minimal exposure to host immune system. Our results confirm regulation of many principal signaling components involved in actin cytoskeletal dynamics, and introduce additional infection regulated genes with functions related to microtubules signaling.

This includes intersectin 1 SH3 domain protein gene, which encodes a cytoplasmic membrane-associated protein that indirectly coordinates endocytic membrane traffic with the actin assembly machinery, Rho-effector ROCK1 serve a number of key cellular functions, such as morphological differentiation and cell motility which are closely associated with changes in cytoskeletal dynamics [ 83 ]. Additionally, RAS p21 protein activator GTPase activating protein [ 84 ], v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [ 85 ] and SOS2 [ 86 ] are crucial genes in polymerization of actin filaments and cytoskeleton reorganization.

Ion channels represent an intriguing and novel class of genes that were impacted by MPV infection. We identified 10 genes encoding nine ion channels and a transporter that underwent increasing suppression during infection. Most of these channels localize to cell membrane, and collectively contribute to transport of all essential ions involved in maintenance of cell membrane potential and osmolarity homeostasis.

While mechanisms of transport modulation have been described previously, as in the indirect consequences of Ras, Rho, and Rab small GTPases regulation [ 87 ], its effect on viral infections and global cell biology remain unclear except for a recent report describing the interaction of myxoma poxvirus protein M11L with mitochondrial permeability transition pore and its role in delaying apoptosis in host cells [ 88 ].

The downregulation trend of channel expression identified here pose many intriguing questions, especially in the light of evolving evidence in support of ion channels role in virus release [ 89 ] and infected cells rupture [ 90 ].

Progression of the cell cycle is tightly regulated process with many redundant checkpoints that ensure proper transition across cell cycle phases. The impact of this mode of cell cycle regulation on viral infection remains unknown.

However, cell arrest in G2 phase was described in other viral infections including human immunodeficiency virus HIV and was found to be mainly mediated by viral protein R Vpr [ 91 — 93 ].

Recently, evidence supporting a role for PP2A in Vpr-induced arrest has emerged, and was substantiated further by other studies in support of PP2A being a common target during infection with other viruses, including simian virus 40 SV40 , polyoma virus, human T lymphotrophic retrovirus and adenovirus [ 95 ]. Because genetically diverse viruses seem to induce the same G2 arrest response in different infected cells, it is likely that this response has an important function and might be part of antiviral host defenses.

In this study we combined microarray with data mining and statistical analysis to identify important interfaces of host-pathogen interaction. Our results aligned nicely with previous reports carried out using viruses from the same or different genus, and provided new set of genes that play important roles in MPV infection.

Further work is warranted to validate and examine the potential of these genes in antiviral therapies. Using microarrays, we studied MPV-induced changes in gene expression of Macaca mulatta kidney epithelial cells to identify major host-virus interaction interfaces.

The majority of genes While downregulated genes exhibited a steady trend during the study, upregulated genes showed more time-dependent regulation intensity.

Further data analysis showed that regulated genes cluster into distinctive functional classes, canonical pathways and networks that can be linked to established viral biogenesis.

Our results introduce a set of host genes and novel pathways for further evaluation as targets for potential use in developing new antiviral therapies. Bull World Health Organ , J Gen Virol ,