• Acute liver failure
• Hepatitis A
• Hepatitis B
• Hepatitis C
• Hepatology
• Liver disease
• Viral hepatitis

• CRM1
• G2/M checkpoint
• apoptosis
• canine parvovirus
• cyclin B1
• nuclear egress of capsids

• 2A protein
• apoptosis
• crucial amino acids
• mitochondrial pathway
• porcine sapelovirus

Fetal nuchal edema, a subcutaneous accumulation of extracellular fluid in the fetal neck, is detected as increased nuchal translucency (NT) by ultrasonography in the first trimester of pregnancy. It has been demonstrated that increased NT is associated with chromosomal anomalies and genetic syndromes accompanied with fetal malformations such as defective lymphatic vascular development, cardiac anomalies, anemia, and a wide range of other fetal anomalies. However, in many clinical cases of increased NT, causative genes, pathogenesis and prognosis have not been elucidated in humans. On the other hand, a large number of gene mutations have been reported to induce fetal nuchal edema in mouse models. Here, we review the relationship between the gene mutants causing fetal nuchal edema with defective lymphatic vascular development, cardiac anomalies, anemia and blood vascular endothelial barrier anomalies in mice. Moreover, we discuss how studies using gene mutant mouse models will be useful in developing diagnostic method and predicting prognosis.

Since the outbreak of short beak and dwarfish syndrome (SBDS) in Cherry Valley Pekin ducks in China, novel goose parvovirus (NGPV) has been isolated. Till now, little is known about the NGPV pathogenesis toward Cherry Valley Pekin ducks. Besides, due to detection of duck circovirus co-infection in SBDS clinical cases, whether sole NGPV infection can reproduce all the typical symptoms of SBDS remains unclear. In this study, based on the NGPV isolate SDJN19, an infectious plasmid clone pJNm containing the entire SDJN19 genome was constructed. Transfection of pJNm in embryonated duck eggs resulted in generation of the infectious virus carrying the genetic marker, named rJNm. rJNm infection of 2-day-old Cherry Valley Pekin ducks reproduced all the typical signs of SBDS, including beak atrophy, tongue protrusion, and growth retardation. rJNm can infect Cherry Valley Pekin ducks through the horizontal transmission route, and the infected ducks exhibited the characteristic SBDS symptoms. A high level of serum precipitation antibodies (above 5log₂) were induced in the surviving ducks, however, high viral loads were still detected in the duck organs, suggesting persistent NGPV infection in ducks. By incorporating the homologous Rep1 and VP1 gene from classical GPV, two chimeric viruses rJN-cVP1 and rJN-cRep1 were generated. Duck infection tests revealed that the non-structural protein Rep1 played a crucial role in the NGPV pathogenicity. The present result lays a solid foundation for further exploring how the Rep protein contributes to the NGPV pathogenesis.

• Goose parvovirus
• pathogenesis
• reproduction
• rescue
• short beak and dwarfish syndrome

• cellular senescence
• fibrosis
• normal human dermal fibroblasts
• parvovirus B19
• systemic sclerosis

• gene therapy
• molecular engineering

• Environmental
• Human cytomegalovirus
• Human herpesvirus-6
• Human parvovirus B19
• Pathogenesis
• Retroviruses
• SARS-CoV-2
• Scleroderma
• Silica
• Systemic sclerosis

• COVID-19/complications
• Cytomegalovirus
• Cytomegalovirus Infections/complications
• Herpesvirus 6, Human
• Humans
• Occupational Exposure/adverse effects
• Parvoviridae Infections/complications
• Parvovirus B19, Human
• Retroviridae
• Retroviridae Infections/complications
• Roseolovirus Infections/complications
• SARS-CoV-2
• Scleroderma, Systemic/etiology
• Scleroderma, Systemic/virology

• Parvovirus B19
• acute liver failure
• diagnostic
• liver disease
• real-time PCR

• anti-cancer agent
• apoptosis
• canine parvovirus
• nonstructural gene 1
• oncolytic virotherapy

• SADS-CoV
• apoptosis
• apoptosis-inducing factor
• pathogenesis

• Alphacoronavirus/physiology
• Animals
• Apoptosis
• Caspases/metabolism
• Chlorocebus aethiops
• Coronavirus Infections/metabolism
• Coronavirus Infections/virology
• Peptidyl-Prolyl Isomerase F/genetics
• Peptidyl-Prolyl Isomerase F/metabolism
• Swine
• Vero Cells
• Virus Replication

• B19V
• SLE
• anti-dsDNA antibody
• apoptotic bodies
• glomerulonephritis

• Animals
• Antibodies, Antinuclear/blood
• Antibodies, Antinuclear/metabolism
• Apoptosis/drug effects
• Autoimmunity
• Brain/pathology
• DNA/immunology
• Enzyme Inhibitors/pharmacology
• Extracellular Vesicles/immunology
• Female
• Glomerulonephritis/immunology
• Glomerulonephritis/pathology
• Immunosuppressive Agents/pharmacology
• Kidney Glomerulus/metabolism
• Kidney Glomerulus/pathology
• Liver/pathology
• Mice
• Myocardium/pathology
• Parvovirus B19, Human
• Staurosporine/pharmacology
• Terpenes/pharmacology
• Viral Nonstructural Proteins/metabolism

Parvovirus B19 (B19V) is pathogenic to humans and causes bone marrow failure diseases and various other inflammatory disorders. B19V infection exhibits high tropism for human erythroid progenitor cells (EPCs) in the bone marrow and fetal liver. The exclusive restriction of B19V replication to erythroid lineage cells is partly due to the expression of receptor and co-receptor(s) on the cell surface of human EPCs and partly depends on the intracellular factors essential for virus replication. We first summarize the latest developments in the viral entry process and the host cellular factors or pathways critical for B19V replication. We discuss the role of hypoxia, erythropoietin signaling and STAT5 activation in the virus replication. The B19V infection-induced DNA damage response (DDR) and cell cycle arrest at late S-phase are two key events that promote B19V replication. Lately, the virus infection causes G2 arrest, followed by the extensive cell death of EPCs that leads to anemia. We provide the current understanding of how B19V exploits the cellular resources and manipulate pathways for efficient virus replication. B19V encodes a single precursor mRNA (pre-mRNA), which undergoes alternate splicing and alternative polyadenylation to generate at least 12 different species of mRNA transcripts. The post-transcriptional processing of B19V pre-mRNA is tightly regulated through cis-acting elements and trans-acting factors flanking the splice donor or acceptor sites. Overall, in this review, we focus on the recent advances in the molecular virology and pathogenesis of B19V infection.

• DNA replication
• RNA processing
• erythroid precursor cells
• human
• infection
• parvovirus B19

Human parvovirus (HPV) B19 is linked to a variety of clinical manifestations, such as erythema infectiosum, nonimmune hydrops fetalis, and transient aplastic anemia. Although a few cases have shown HPVB19 infection as a possible causative agent for hepatitis-associated aplastic anemia (HAAA) in immunocompetent patients, most reported cases of HAAA following transient hepatitis did not have delayed remission. Here we report a rare case of severe aplastic anemia following acute hepatitis with prolonged jaundice due to HPVB19 infection in a previously healthy young male. Clinical laboratory examination assessed marked liver injury and jaundice as well as peripheral pancytopenia, and bone marrow biopsy revealed severe hypoplasia and fatty replacement. HPVB19 infection was diagnosed by enzyme immunoassay with high titer of anti-HPVB19 immunoglobulin M antibodies. Immunosuppressive therapy was initiated 2 months after the onset of acute hepatitis when liver injury and jaundice were improved. Cyclosporine provided partial remission after 2 months of medication without bone marrow transplantation. Our case suggests that HPVB19 should be considered as a hepatotropic virus and a cause of acquired aplastic anemia, including HAAA.

• B19 virus
• human bocavirus
• parvovirus

• Gene Expression Regulation, Viral
• Genome, Viral
• Human bocavirus/genetics
• Humans
• Parvoviridae Infections/epidemiology
• Parvoviridae Infections/immunology
• Parvovirus B19, Human/genetics
• Prevalence
• Viral Vaccines/therapeutic use

• P30 GM103326 NIGMS NIH HHS
• R01 AI070723 NIAID NIH HHS
• R21 AI105543 NIAID NIH HHS
• R21 AI112803 NIAID NIH HHS

This study was conducted to analyse the course and the outcome of the liver disease in the co-infected animals in order to evaluate a possible synergic effect of human parvovirus B19 (B19V) and hepatitis A virus (HAV) co-infection. Nine adult cynomolgus monkeys were inoculated with serum obtained from a fatal case of B19V infection and/or a faecal suspension of acute HAV. The presence of specific antibodies to HAV and B19V, liver enzyme levels, viraemia, haematological changes, and necroinflammatory liver lesions were used for monitoring the infections. Seroconversion was confirmed in all infected groups. A similar pattern of B19V infection to human disease was observed, which was characterised by high and persistent viraemia in association with reticulocytopenia and mild to moderate anaemia during the period of investigation (59 days). Additionally, the intranuclear inclusion bodies were observed in pro-erythroblast cell from an infected cynomolgus and B19V Ag in hepatocytes. The erythroid hypoplasia and decrease in lymphocyte counts were more evident in the co-infected group. The present results demonstrated, for the first time, the susceptibility of cynomolgus to B19V infection, but it did not show a worsening of liver histopathology in the co-infected group.

• Anti-tumor immune response
• Apoptosis
• Breast cancer
• Cancer vaccine adjuvant
• NS1
• Poly (I:C)
• TLR3

• apoptosis
• anticancer genes
• cancer
• gene therapy
• chicken infectious anemia
• apoptin
• vp3
• parvovirus
• ns1
• adenovirus
• e4orf4
• b19pv
• mvm
• h-1pv
• cpv

• Adenoviridae/genetics
• Animals
• Apoptosis
• Capsid Proteins/analysis
• Capsid Proteins/genetics
• Chicken anemia virus/genetics
• Genes, Viral
• Humans
• Neoplasms/therapy
• Oncolytic Virotherapy/methods
• Oncolytic Viruses/genetics
• Parvovirus/genetics

• Animals
• Calcium/metabolism
• Cats
• Cell Line
• Dogs
• Enzyme Activation
• Extracellular Signal-Regulated MAP Kinases/metabolism
• MAP Kinase Signaling System
• Membrane Potential, Mitochondrial
• Mitochondria/metabolism
• Mitochondria/pathology
• Mitochondria/ultrastructure
• Mitochondrial Membranes/metabolism
• Mitochondrial Membranes/ultrastructure
• Mitochondrial Membranes/virology
• Parvoviridae Infections/pathology
• Parvoviridae Infections/virology
• Parvovirus, Canine/physiology
• Reactive Oxygen Species/metabolism

Erythema infectiosum is the most common clinical manifestation of Parvovirus B19 infection although it has also been associated with rheumatologic diseases and various types of systemic vasculitides. Acute hepatitis and benign myositis however are rarely reported in association with Parvovirus B19 infection.

Here we report a 14-year old male, who developed acute hepatitis and benign myositis associated with erythema infectiosum following Parvovirus B19 infection.

Parvovirus B19 infection has rarely been associated with acute hepatitis and exceptionally rarely with benign myositis. Parvovirus B19 should be considered in the differential diagnosis of acute non-A to E hepatitis and in the case of acute benign myositis presenting with a rash especially in children.

Parvovirus B19 infection can present with myriads of clinical diseases and syndromes; liver manifestations and hepatitis are examples of them. Parvovirus B19 hepatitis associated aplastic anemia and its coinfection with other hepatotropic viruses are relatively underrecognized, and there is sufficient evidence in the literature suggesting that B19 infections can cause a spectrum of liver diseases from elevation of transaminases to acute hepatitis to fulminant liver failure and even chronic hepatitis. It can also cause fatal macrophage activation syndrome and fibrosing cholestatic hepatitis. Parvovirus B19 is an erythrovirus that can only be replicate in pronormoblasts and hepatocytes, and other cells which have globosides and glycosphingolipids in their membrane can also be affected by direct virus injury due to nonstructural protein 1 persistence and indirectly by immune mediated injury. The virus infection is suspected in bone marrow aspiration in cases with sudden drop of hemoglobin and onset of transient aplastic anemia in immunosuppressed or immunocompetent patients and is confirmed either by IgM and IgG positive serology, PCR analysis, and in situ hybridization in biopsy specimens or by application of both. There is no specific treatment for parvovirus B19 related liver diseases, but triple therapy regimen may be effective consisting of immunoglobulin, dehydrohydrocortisone, and cyclosporine.

Human parvovirus B19 (B19V) is the causative agent of erythema infectiosum in humans. B19 infection also causes severe disease manifestations, such as chronic anemia in immunocompromised patients, aplastic crisis in patients with a high turnover rate of red blood cells, and hydrops fetalis in pregnant women. Although a secreted phospholipase A2 (PLA2) motif has been identified in the unique region of the B19V minor capsid protein VP1(VP1u), the determinants for its enzyme activity and its influences on host cells are not well understood. The purpose of this study was to investigate the contribution of the PLA2 motif and other regions of the VP1u to the PLA2 activity, to determine the cellular localization of the VP1u protein, and to examine the effects of VP1u on cellular cytokines. We found that in addition to the critical conserved and non-conserved amino acids within the VP1u PLA2 motif, amino acid residues outside the VP1u PLA2 motif are also important for the PLA2 activity. VP1u and various mutants all revealed a nucleo-cytoplasmic distribution. UT7-Epo cells treated with prokaryotic expressed VP1u or mutant proteins with PLA2 activity released a large amount of free fatty acid (FFA), and the cell morphological change occurred dramatically. However, neither free fatty acid nor cell morphology change occurred for cells treated with the mutants without PLA2 activity. The wild type and the VP1u mutants with the PLA2 activity also activated TNF-α promoter and upregulated the transcription activity of NF-κB in transfected cells. In addition, we found that the amino acids outside the PLA2 domain are critical for the viral PLA2 activity, and that these tested VP1u mutants did not affect the localization of the VP1u protein.

• DNA damage response
• adeno-associated virus
• bocavirus
• minute virus of canines
• minute virus of mice
• parvovirus
• parvovirus B19
• parvovirus H-1

• Animals
• Antigen-Presenting Cells/metabolism
• Apoptosis/immunology
• Autoantigens/metabolism
• Autoimmunity/immunology
• Flow Cytometry
• Hep G2 Cells
• Humans
• Immune Tolerance/immunology
• Microscopy, Electron, Scanning
• Parvoviridae Infections/immunology
• Parvovirus B19, Human/immunology
• Phagocytosis/physiology
• Sf9 Cells
• Spodoptera
• Viral Nonstructural Proteins/metabolism

The non-structural proteins (NS) of the parvovirus family are highly conserved multi-functional molecules that have been extensively characterized and shown to be integral to viral replication. Along with NTP-dependent helicase activity, these proteins carry within their sequences domains that allow them to bind DNA and act as nucleases in order to resolve the concatameric intermediates developed during viral replication. The parvovirus B19 NS1 protein contains sequence domains highly similar to those previously implicated in the above-described functions of NS proteins from adeno-associated virus (AAV), minute virus of mice (MVM) and other non-human parvoviruses. Previous studies have shown that transient transfection of B19 NS1 into human liver carcinoma (HepG2) cells initiates the intrinsic apoptotic cascade, ultimately resulting in cell death. In an effort to elucidate the mechanism of mammalian cell demise in the presence of B19 NS1, we undertook a mutagenesis analysis of the protein's endonuclease domain. Our studies have shown that, unlike wild-type NS1, which induces an accumulation of DNA damage, S phase arrest and apoptosis in HepG2 cells, disruptions in the metal coordination motif of the B19 NS1 protein reduce its ability to induce DNA damage and to trigger S phase arrest and subsequent apoptosis. These studies support our hypothesis that, in the absence of replicating B19 genomes, NS1-induced host cell DNA damage is responsible for apoptotic cell death observed in parvoviral infection of non-permissive mammalian cells.

• apoptotic cell death
• host cell DNA damage
• parvoviral infection

• DNA damage and repair
• Parvovirus B19
• apoptosis
• autoantibody
• fulminant liver failure
• systemic lupus erythematosus

Viruses have great potential as nanotools in medicine for gene transfer, targeted gene delivery, and oncolytic cancer virotherapy. Here we have studied cell death mechanisms of canine parvovirus (CPV) to increase the knowledge on the CPV life cycle in order to facilitate the development of better parvovirus vectors. Morphological studies of CPV-infected Norden laboratory feline kidney (NLFK) cells and canine fibroma cells (A72) displayed characteristic apoptotic events. Apoptosis was further confirmed by activation of caspases and cellular DNA damage. However, results from annexin V-propidium iodide (PI) labeling and membrane polarization assays indicated disruption of the plasma membrane uncommon to apoptosis. These results provide evidence that secondary necrosis followed apoptosis. In addition, two human cancer cell lines were found to be infected by CPV. This necrotic event over apoptotic cell death and infection in human cells provide insightful information when developing CPV as a nanotool for cancer treatments.

• apoptosis
• canine parvovirus
• nanoparticle
• necrosis
• virotherapy

Human parvovirus B19 (B19) is known to induce apoptosis that has been associated with a variety of autoimmune disorders. Although we have previously reported that B19 non-structural protein (NS1) induces mitochondrial-dependent apoptosis in COS-7 cells, the precise mechanism of B19-NS1 in developing autoimmunity is still obscure.

To further examine the effect of B19-NS1 in presence of autoantigens, COS-7 cells were transfected with pEGFP, pEGFP-B19-NS1 and pEGFP-NS1K334E, a mutant form of B19-NS1, and detected the expressions of autoantigens by various autoantibodies against Sm, U1 small nuclear ribonucleoprotein (U1-snRNP), SSA/Ro, SSB/La, Scl-70, Jo-1, Ku, and centromere protein (CENP) A/B by using Immunoblotting.

Significantly increased apoptosis was detected in COS-7 cells transfected with pEGFP-B19-NS1 compared to those transfected with pEGFP. Meanwhile, the apoptotic 70 kDa U1-snRNP protein in COS-7 cells transfected with pEGFP-B19-NS1 is cleaved by caspase-3 and converted into a specific 40 kDa product, which were recognized by anti-U1-snRNP autoantibody. In contrast, significantly decreased apoptosis and cleaved 40 kDa product were observed in COS-7 cells transfected with pEGFP-NS1K334E compared to those transfected with pEGFP-B19-NS1.

These findings suggested crucial association of B19-NS1 in development of autoimmunity by inducing apoptosis and specific cleavage of 70 kDa U1-snRNP.

• Apoptosis
• B19
• Cytotoxicity
• Fulminant Liver Failure
• Parvovirus

AIM: To evaluate the synergistic targeting and killing of human hepatocellular carcinoma (HCC) cells lacking p53 by the oncolytic autonomous parvovirus (PV) H-1 and chemotherapeutic agents and its dependence on functional promyelocytic leukemia protein (PML).

METHODS: The role of p53 and PML in regulating cytotoxicity and gene transfer mediated by wild-type (wt) PV H-1 were explored in two pairs of isogenic human hepatoma cell lines with different p53 status. Furthermore, H-1 PV infection was combined with cytostatic drug treatment.

RESULTS: While the HCC cells with different p53 status studied were all susceptible to H-1 PV-induced apoptosis, the cytotoxicity of H-1 PV was more pronounced in p53-negative than in p53-positive cells. Apoptosis rates in p53-negative cell lines treated by genotoxic drugs were further enhanced by a treatment with H-1 PV. In flow cytometric analyses, H-1 PV infection resulted in a reduction of the mitochondrial transmembrane potential. In addition, H-1 PV cells showed a significant increase in PML expression. Knocking down PML expression resulted in a striking reduction of the level of H-1 PV infected tumor cell death.

CONCLUSION: H-1 PV is a suitable agent to circumvent the resistance of p53-negative HCC cells to genotoxic agents, and it enhances the apoptotic process which is dependent on functional PML. Thus, H-1 PV and its oncolytic vector derivatives may be considered as therapeutic options for HCC, particularly for p53-negative tumors.

• Autonomous parvovirus
• Apoptosis
• p53
• Promyelocytic leukemia protein
• Human hepatocellular carcinoma
• Hepatocytes

AIM: To study at transcriptional level the similarities and differences of the physiological and biochemical activities between liver tumor (LT) and regenerating liver cells.

METHODS: LT-associated genes and their expression changes in LT were obtained from databases and scientific articles, and their expression profiles in rat liver regeneration (LR) were detected using Rat Genome 230 2.0 array. Subsequently their expression changes in LT and LR were compared and analyzed.

RESULTS: One hundred and twenty one LT-associated genes were found to be LR-associated. Thirty four genes were up-regulated, and 14 genes were down-regulated in both LT and regenerating liver; 20 genes up-regulated in LT were down-regulated in regenerating liver; 21 up-regulated genes and 16 down-regulated genes in LT were up-regulated at some time points and down-regulated at others during LR.

CONCLUSION: Results suggested that apoptosis activity suppressed in LT was still active in regenerating liver, and there are lots of similarities and differences between the LT and regenerating liver at the aspects of cell growth, proliferation, differentiation, migration and angiogenesis.

• Partial hepatectomy
• Rat Genome 230 2.0 Array
• Apoptosis
• Liver regeneration-associated gene
• Liver tumor-associated gene

• Animals
• Apoptosis
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Regeneration
• Oligonucleotide Array Sequence Analysis
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction

As with a number of other viruses, Porcine reproductive and respiratory syndrome virus (PRRSV) has been shown to induce apoptosis, although the mechanism(s) involved remain unknown. In this study we have characterized the apoptotic pathways activated by PRRSV infection. PRRSV-infected cells showed evidence of apoptosis including phosphatidylserine exposure, chromatin condensation, DNA fragmentation, caspase activation (including caspase-8, 9, 3), and PARP cleavage. DNA fragmentation was dependent on caspase activation but blocking apoptosis by a caspase inhibitor did not affect PRRSV replication. Upregulation of Bax expression by PRRSV infection was followed by disruption of the mitochondria transmembrane potential, resulting in cytochrome c redistridution to the cytoplasm and subsequent caspase-9 activation. A crosstalk between the extrinsic and intrinsic pathways was demonstrated by dependency of caspase-9 activation on active caspase-8 and by Bid cleavage. Furthermore, in this study we provide evidence of the possible involvement of reactive oxygen species (ROS)-mediated oxidative stress in apoptosis induced by PRRSV. Our data indicated that cell death caused by PRRSV infection involves necrosis as well as apoptosis. In summary, these findings demonstrate mechanisms by which PRRSV induces apoptosis and will contribute to an enhanced understanding of PRRSV pathogenesis.

• Animals
• Apoptosis
• Caspases/analysis
• Cell Line
• Chlorocebus aethiops
• Cytochromes c/analysis
• Cytoplasm/chemistry
• DNA Fragmentation
• Humans
• Membrane Potential, Mitochondrial
• Mitochondria/metabolism
• Necrosis
• Phosphatidylserines/analysis
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases/metabolism
• Porcine respiratory and reproductive syndrome virus/physiology
• bcl-2-Associated X Protein/biosynthesis