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Virology
Persistent damaged bases in DNA allow mutagenic break repair in Escherichia coli
Jul 20, 2017   PLoS Genetics
Moore JM, Correa R, Rosenberg SM, Hastings PJ
Persistent damaged bases in DNA allow mutagenic break repair in Escherichia coli
Jul 20, 2017
PLoS Genetics
Bacteria, yeast and human cancer cells possess mechanisms of mutagenesis upregulated by stress responses. Stress-inducible mutagenesis potentially accelerates adaptation, and may provide important models for mutagenesis that drives cancers, host pathogen interactions, antibiotic resistance and possibly much of evolution generally. In Escherichia coli repair of double-strand breaks (DSBs) becomes mutagenic, using low-fidelity DNA polymerases under the control of the SOS DNA-damage response and RpoS general stress response, which upregulate and allow the action of error-prone DNA polymerases IV (DinB), II and V to make mutations during repair. Pol IV is implied to compete with and replace high-fidelity DNA polymerases at the DSB-repair replisome, causing mutagenesis. We report that up-regulated Pol IV is not sufficient for mutagenic break repair (MBR); damaged bases in the DNA are also required, and that in starvation-stressed cells, these are caused by reactive-oxygen species (ROS). First, MBR is reduced by either ROS-scavenging agents or constitutive activation of oxidative-damage responses, both of which reduce cellular ROS levels. The ROS promote MBR other than by causing DSBs, saturating mismatch repair, oxidizing proteins, or inducing the SOS response or the general stress response. We find that ROS drive MBR through oxidized guanines (8-oxo-dG) in DNA, in that overproduction of a glycosylase that removes 8-oxo-dG from DNA prevents MBR. Further, other damaged DNA bases can substitute for 8-oxo-dG because ROS-scavenged cells resume MBR if either DNA pyrimidine dimers or alkylated bases are induced. We hypothesize that damaged bases in DNA pause the replisome and allow the critical switch from high fidelity to error-prone DNA polymerases in the DSB-repair replisome, thus allowing MBR. The data imply that in addition to the indirect stress-response controlled switch to MBR, a direct cis-acting switch to MBR occurs independently of DNA breakage, caused by ROS oxidation of DNA potentially regulated by ROS regulators.
Evolutionary dynamics of recent peste des petits ruminants virus epidemic in China during 2013-2014
Jul 22, 2017   Virology
Bao J, Wang Q, Li L, Liu C, Zhang Z, Li J, Wang S, Wu X, Wang Z
Evolutionary dynamics of recent peste des petits ruminants virus epidemic in China during 2013-2014
Jul 22, 2017
Virology
Peste des petits ruminants virus (PPRV) causes a highly contagious disease, peste des petits ruminants (PPR), in sheep and goats which has been considered as a serious threat to the local economy in Africa and Asia. However, the in-depth evolutionary dynamics of PPRV during an epidemic is not well understood. We conducted phylogenetic analysis on genomic sequences of 25 PPRV strains from China 2013-2014 outbreaks. All these strains clustered into a novel clade in lineage 4. An evolutionary rate of 2.61 × 10-6 nucleotide substitutions per site per day was estimated, dating the most recent common ancestor of PPRV China 2013-2014 strains to early August 2013. Transmission network analysis revealed that all the virus sequences could be grouped into five clusters of infection, suggesting long-distance animal transmission play an important role in the spread of PPRV in China. These results expanded our knowledge for PPRV evolution to achieve effective control measures. Copyright © 2017 Elsevier Inc. All rights reserved.
Eomesodermin promotes the development of type 1 regulatory T (TR1) cells
Jul 24, 2017   Science Immunology
Zhang P, Lee JS, Gartlan KH, Schuster IS, Comerford I,   . . . . . .   , Engwerda CR, Degli-Esposti MA, Kallies A, Tey SK, Hill GR
Eomesodermin promotes the development of type 1 regulatory T (TR1) cells
Jul 24, 2017
Science Immunology
Type 1 regulatory T (TR1) cells are Foxp3- interleukin-10 (IL-10)-producing CD4+ T cells with potent immunosuppressive properties, but their requirements for lineage development have remained elusive. We show that TR1 cells constitute the most abundant regulatory population after allogeneic bone marrow transplantation (BMT), express the transcription factor Eomesodermin (Eomes), and are critical for the prevention of graft-versus-host disease. We demonstrate that Eomes is required for TR1 cell differentiation, during which it acts in concert with the transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) by transcriptionally activating IL-10 expression and repressing differentiation into other T helper cell lineages. We further show that Eomes induction in TR1 cells requires T-bet and donor macrophage-derived IL-27. Thus, we define the cellular and transcriptional control of TR1 cell differentiation during BMT, opening new avenues to therapeutic manipulation. Copyright © 2017, American Association for the Advancement of Science.
Combination of RT-PCR and proteomics for the identification of Crimean-Congo hemorrhagic fever virus in ticks
Jul 24, 2017   Heliyon
Fernández de Mera IG, Chaligiannis I, Hernández-Jarguín A, Villar M, Mateos-Hernández L, Papa A, Sotiraki S, Ruiz-Fons F, Cabezas-Cruz A, Gortázar C, de la Fuente J
Combination of RT-PCR and proteomics for the identification of Crimean-Congo hemorrhagic fever virus in ticks
Jul 24, 2017
Heliyon
Crimean-Congo hemorrhagic fever (CCHF) is an emerging tick-borne zoonotic disease caused by the CCHF virus (CCHFV). In this study, an experimental approach combining RT-PCR and proteomics was used for the identification and characterization of CCHFV in 106 ticks from 7 species that were collected from small ruminants in Greece. The methodological approach included an initial screening for CCHFV by RT-PCR followed by proteomics analysis of positive and control negative tick samples. This novel approach allowed the identification of CCHFV-positive ticks and provided additional information to corroborate the RT-PCR findings using a different approach. Two ticks, Dermacentor marginatus and Haemaphysalis parva collected from a goat and a sheep, respectively were positive for CCHFV. The sequences for CCHFV RNA segments S and L were characterized by RT-PCR and proteomics analysis of tick samples, respectively. These results showed the possibility of combining analyses at the RNA and protein levels using RT-PCR and proteomics for the characterization of CCHFV in ticks. The results supported that the CCHFV identified in ticks are genetic variants of the AP92 strain. Although the AP92-like strains probably do not represent a high risk of CCHF to the population, the circulation of genetically diverse CCHFV strains could potentially result in the appearance of novel viral genotypes with increased pathogenicity and fitness.
Replication of the Zika virus in different iPSC-derived neuronal cells and implications to assess efficacy of antivirals
Jul 24, 2017   Antiviral Research
Lanko K, Eggermont K, Patel A, Kaptein S, Delang L, Verfaillie CM, Neyts J
Replication of the Zika virus in different iPSC-derived neuronal cells and implications to assess efficacy of antivirals
Jul 24, 2017
Antiviral Research
Infections with the Zika virus (ZIKV) are responsible for congenital abnormalities and neurological disorders. We here demonstrate that ZIKV productively infects three types of human iPSC (induced pluripotent stem cells)-derived cells from the neural lineage, i.e. cortical and motor neurons as well as astrocytes. ZIKV infection results in all three cell types in the production of infectious virus particles and induces cytopathic effects (CPE). In cortical and motor neurons, an Asian isolate (PRVABC59) produced roughly 10-fold more virus than the prototypic African strain (MR766 strain). Viral replication and CPE is efficiently inhibited by the nucleoside polymerase inhibitor 7-deaza-2'-C-methyladenosine (7DMA). However, ribavirin and favipiravir, two molecules that inhibit ZIKV replication in Vero cells, did not inhibit ZIKV replication in the neuronal cells. These results highlight the need to assess the potential antiviral activity of novel ZIKV inhibitors in stem cell derived neuronal cultures. Copyright © 2017. Published by Elsevier B.V.
Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer
Jul 24, 2017   Molecular Cell
Luna JM, Barajas JM, Teng KY, Sun HL, Moore MJ, Rice CM, Darnell RB, Ghoshal K
Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer
Jul 24, 2017
Molecular Cell
MicroRNA-122, an abundant and conserved liver-specific miRNA, regulates hepatic metabolism and functions as a tumor suppressor, yet systematic and direct biochemical elucidation of the miR-122 target network remains incomplete. To this end, we performed Argonaute crosslinking immunoprecipitation (Argonaute [Ago]-CLIP) sequencing in miR-122 knockout and control mouse livers, as well as in matched human hepatocellular carcinoma (HCC) and benign liver tissue to identify miRNA target sites transcriptome-wide in two species. We observed a majority of miR-122 binding on 3' UTRs and coding exons followed by extensive binding to other genic and non-genic sites. Motif analysis of miR-122-dependent binding revealed a G-bulged motif in addition to canonical motifs. A large number of miR-122 targets were found to be species specific. Upregulation of several common mouse and human targets, most notably BCL9, predicted survival in HCC patients. These results broadly define the molecular consequences of miR-122 downregulation in hepatocellular carcinoma. Copyright © 2017 Elsevier Inc. All rights reserved.
Impact of carbon quantum dots on dynamic properties of BSA and BSA/DPPC adsorption layers
Jul 23, 2017   Journal Of Colloid And Interface Science
Lai L, Wei XQ, Huang WH, Mei P, Ren ZH, Liu Y
Impact of carbon quantum dots on dynamic properties of BSA and BSA/DPPC adsorption layers
Jul 23, 2017
Journal Of Colloid And Interface Science
The effects of carbon quantum dots (CQDs) on the dynamic properties of bovine serum albumin (BSA) were investigated using pendant drop profile analysis method. Moreover, the effects of CQDs on the competitive adsorption of BSA and dipalmitoyl phosphatidylcholine (DPPC) were examined. CQDs reduce the fluorescence intensity of BSA and cause a red shift in fluorescence emission. The quenching constant at pH 4.3 is almost twice as large as that of the value obtained at pH 6.0. A small amount of CQDs does not influence the dynamic surface adsorption properties of BSA molecules. As the CQD concentration increases, a gradual increase in adsorption rate of BSA molecules is observed. Moreover, the addition of CQDs results in a significant transition of kinetic dependencies of surface elasticity of BSA solution when the CQD concentration exceeds a critical value. The appearance of the maximum surface elasticity value is probably attributed to the formation of tails and loops. When the dynamic surface properties are dominated by BSA molecules, the effects of CQDs on the surface properties of BSA/DPPC mixture are similar to those of BSA alone. However, when the surface film mainly consists of DPPC, CQDs can obviously change the interfacial properties of DPPC monolayer. Copyright © 2017 Elsevier Inc. All rights reserved.
The C-terminal region of the Turnip mosaic virus P3 protein is essential for viral infection via targeting P3 to the viral replication complex
Jul 23, 2017   Virology
Cui X, Yaghmaiean H, Wu G, Wu X, Chen X, Thorn G, Wang A
The C-terminal region of the Turnip mosaic virus P3 protein is essential for viral infection via targeting P3 to the viral replication complex
Jul 23, 2017
Virology
Like other positive-strand RNA viruses, plant potyviruses assemble viral replication complexes (VRCs) on modified cellular membranes. Potyviruses encode two membrane proteins, 6K2 and P3. The former is known to play pivotal roles in the formation of membrane-associated VRCs. However, P3 remains to be one of the least characterized potyviral proteins. The P3 cistron codes for P3 as well as P3N-PIPO which results from RNA polymerase slippage. In this study, we show that the P3N-PIPO of Turnip mosaic virus (TuMV) is required for viral cell-to-cell movement but not for viral replication. We demonstrate that the C-terminal region of P3 (P3C) is indispensable for P3 to form cytoplasmic punctate inclusions and target VRCs. We reveal that TuMV mutants that lack P3C are replication-defective. Taken together, these data suggest that the P3 cistron has two distinct functions: P3N-PIPO as a dedicated movement protein and P3 as an essential component of the VRC. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.
C-Reactive Protein Mediating Immunopathological Lesions: A Potential Treatment Option for Severe Influenza A Diseases
Jul 23, 2017   EBioMedicine
Gao R, Wang L, Bai T, Zhang Y, Bo H, Shu Y
C-Reactive Protein Mediating Immunopathological Lesions: A Potential Treatment Option for Severe Influenza A Diseases
Jul 23, 2017
EBioMedicine
Severe influenza diseases with high mortality have been frequently reported, especially in those patients infected with avian influenza A (H5N1, H7N9 or H10N8) or during a pandemic. Respiratory distress, which is attributed to alveolar damage associated with immunopathological lesions, is the most common cause of death. There is a wealth of information on pathogenesis or treatment options. In this study, we showed that high levels of C-reactive protein (CRP) were induced and correlated with complement activation in patients infected with severe influenza A (H5N1, H7N9 or H10N8), and higher levels were induced in fatal patients than in survivors. CRP treatment enhanced the phagocytosis of monocytes THP-1 to H5N1 virus as well as the expression of proinflammatory cytokines or apoptosis-associated genes in THP-1 cells or pneumocytes A-549 respectively. CRP may link to proinflammatory mediators contributing to activation of complement and boosting inflammatory response in severe influenza infections. Compound 1,6-bis(phosphocholine)-hexane improved the severity and mortality of mice infected with lethal influenza virus significantly. These observations showed that CRP is involved in deterioration of severe influenza diseases, and indicated a substantial candidate molecule for immunotherapy of severe influenza diseases. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
Response to letter of Singh K 'Role of silver nitrate in the efficacy of hydrogen peroxide aerial decontamination systems' regarding S Ali et al. 'Efficacy of two hydrogen peroxide vapour aerial decontamination systems for enhanced disinfection of methicillin-resistant Staphylococcus aureus, Klebsiella pneumoniae and Clostridium difficile in single isolation rooms.'
Jul 23, 2017   The Journal Of Hospital Infection
Ali S, Yui S, Muzslay M, Wilson APR
Epidemiology, Evolution, and Pathogenesis of H7N9 Influenza Viruses in Five Epidemic Waves since 2013 in China
Jul 23, 2017   Trends In Microbiology
Su S, Gu M, Liu D, Cui J, Gao GF, Zhou J, Liu X
Epidemiology, Evolution, and Pathogenesis of H7N9 Influenza Viruses in Five Epidemic Waves since 2013 in China
Jul 23, 2017
Trends In Microbiology
H7N9 influenza viruses were first isolated in 2013 and continue to cause human infections. H7N9 infections represent an ongoing public health threat that has resulted in 1344 cases with 511 deaths as of April 9, 2017. This highlights the continued threat posed by the current poultry trade and live poultry market system in China. Until now, there have been five H7N9 influenza epidemic waves in China; however, the steep increase in the number of humans infected with H7N9 viruses observed in the fifth wave, beginning in October 2016, the spread into western provinces, and the emergence of highly pathogenic (HP) H7N9 influenza outbreaks in chickens and infection in humans have caused domestic and international concern. In this review, we summarize and compare the different waves of H7N9 regarding their epidemiology, pathogenesis, evolution, and characteristic features, and speculate on factors behind the recent increase in the number of human cases and sudden outbreaks in chickens. The continuous evolution of the virus poses a long-term threat to public health and the poultry industry, and thus it is imperative to strengthen prevention and control strategies. Copyright © 2017. Published by Elsevier Ltd.
The Global State of Helminth Control and Elimination in Children
Jul 23, 2017   Pediatric Clinics Of North America
Weatherhead JE, Hotez PJ, Mejia R
The Global State of Helminth Control and Elimination in Children
Jul 23, 2017
Pediatric Clinics Of North America
Helminth infections, including soil-transmitted helminths and schistosomiasis, remain one of the most common infections in the world with over 1 billion people infected. These infections cause significant morbidity, particularly in young children, that may last a lifetime, including growth and cognitive stunting. There is an urgent need for the control and elimination of helminth infections from areas of poverty to reduce morbidity in children. Mass drug administration programs were adopted by the World Health Assembly in 2001 and have evolved to provide coverage with multiple anthelmintic medications in a single rapid impact package and more extensive coverage within a community. Copyright © 2017 Elsevier Inc. All rights reserved.
Suppression of HBV replication by the expression of nickase- and nuclease dead-Cas9
Jul 22, 2017   Scientific Reports
Kurihara T, Fukuhara T, Ono C, Yamamoto S, Uemura K, Okamoto T, Sugiyama M, Motooka D, Nakamura S, Ikawa M, Mizokami M, Maehara Y, Matsuura Y
Suppression of HBV replication by the expression of nickase- and nuclease dead-Cas9
Jul 22, 2017
Scientific Reports
Complete removal of hepatitis B virus (HBV) DNA from nuclei is difficult by the current therapies. Recent reports have shown that a novel genome-editing tool using Cas9 with a single-guide RNA (sgRNA) system can cleave the HBV genome in vitro and in vivo. However, induction of a double-strand break (DSB) on the targeted genome by Cas9 risks undesirable off-target cleavage on the host genome. Nickase-Cas9 cleaves a single strand of DNA, and thereby two sgRNAs are required for inducing DSBs. To avoid Cas9-induced off-target mutagenesis, we examined the effects of the expressions of nickase-Cas9 and nuclease dead Cas9 (d-Cas9) with sgRNAs on HBV replication. The expression of nickase-Cas9 with a pair of sgRNAs cleaved the target HBV genome and suppressed the viral-protein expression and HBV replication in vitro. Moreover, nickase-Cas9 with the sgRNA pair cleaved the targeted HBV genome in mouse liver. Interestingly, d-Cas9 expression with the sgRNAs also suppressed HBV replication in vitro without cleaving the HBV genome. These results suggest the possible use of nickase-Cas9 and d-Cas9 with a pair of sgRNAs for eliminating HBV DNA from the livers of chronic hepatitis B patients with low risk of undesirable off-target mutation on the host genome.
Multiplex polymerase chain reaction for pathogen detection in donor/recipient corneal transplant tissue and donor storage solution
Jul 21, 2017   Scientific Reports
Hariya T, Maruyama K, Sugita S, Takahashi M, Yokokura S, Sato K, Tomaru Y, Shimizu N, Nakazawa T
Multiplex polymerase chain reaction for pathogen detection in donor/recipient corneal transplant tissue and donor storage solution
Jul 21, 2017
Scientific Reports
Corneal transplantation is a safe, reliable method of restoring visual acuity in patients with corneal disorders. Although it has a very high success rate, rejection can still occur, especially if the site is infected. Therefore, seeking to find better ways to manage infection risk, this study investigated a new technique, based on multiplex polymerase chain reaction (mPCR), to identify pathogens, including viruses, bacteria, and fungi, in corneal transplantation recipient sites, donor corneas and the donor cornea storage solution. The subjects comprised 50 patients who underwent corneal transplantation at Tohoku University Hospital between July 2014 and April 2015. We obtained extracted (recipient) cornea samples in 37 cases, donor cornea samples in 50 cases, and corneal storage solution samples in 50 cases (18 of these 50 samples contained DNA). Herpes simplex virus type 1 DNA was detected in four recipient corneas, Parvovirus B19 DNA was detected in two recipient corneas, Human herpes virus type 6 was detected in two donor corneas, and Aspergillus DNA was detected in one corneal storage solution sample. Thus, mPCR successfully identified pathogenic DNA in corneal tissues and storage solution, suggesting that evaluation with mPCR may improve the ability to predict the risk of infection after corneal transplantation.
Role of HDAC9-FoxO1 Axis in the Transcriptional Program Associated with Hepatic Gluconeogenesis
Jul 22, 2017   Scientific Reports
Chen J, Zhang Z, Wang N, Guo M, Chi X, Pan Y, Jiang J, Niu J, Ksimu S, Li JZ, Chen X, Wang Q
Role of HDAC9-FoxO1 Axis in the Transcriptional Program Associated with Hepatic Gluconeogenesis
Jul 22, 2017
Scientific Reports
Histone deacetylase 9 (HDAC9) regulates hepatic gluconeogenesis by deacetylating Forkhead box O 1 (FoxO1). HDAC9 upregulation is involved in hepatitis C virus (HCV)-associated exaggerated gluconeogenesis. Herein, we found in addition to FoxO1, HDAC9 also regulates other gluconeogenic transcription factors, including peroxisomeproliferator-activated receptor-γ coactivator-1α (PGC-1α), cyclic AMP-responsive element-binding protein (CREB), and glucocorticoid receptor (GR). Unlike FoxO1, which is regulated by post-translational modification responses to HDAC9, HDAC9 regulates PGC-1α, CREB and GR by altering gene expression. Similar to PGC-1α, CREB and GR were found to be novel regulatory targets of FoxO1 by examination of the FoxO1 binding site in their promoter. PGC-1α, CREB and GR were upregulated in response to HDAC9 via FoxO1 deacetylation. These findings indicate that HDAC9-FoxO1 signalling contributes to gluconeogenesis by modulating the expression of gluconeogenic transcription factors. In particular, metabolic profiling demonstrated a clear shift towards gluconeogenesis metabolism, and HDAC9-FoxO1 signalling can be strongly induced to upregulate gluconeogenic transcription factors following HCV infection. The positive correlation between HDAC9 and gluconeogenic transcription factor expression levels in the livers of both HCV-infected patients and normal individuals further emphasizes the clinical relevance of these results. Thus, HDAC9-FoxO1 signalling axis is involved in regulating gluconeogenic transcription factors, gluconeogenesis, and HCV-induced type 2 diabetes.
Selective silencing of hippocampal parvalbumin interneurons induces development of recurrent spontaneous limbic seizures in mice
Jul 22, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Drexel M, Romanov RA, Wood J, Weger S, Heilbronn R, Wulff P, Tasan RO, Harkany T, Sperk G
Selective silencing of hippocampal parvalbumin interneurons induces development of recurrent spontaneous limbic seizures in mice
Jul 22, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWD, 40.0 ± 9.07 per month) and 64% showed spontaneous recurrent seizures (SRS, 5.3 ± 0.83 per month). Mice injected with a control vector neither presented C-SWD nor SRS. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented only C-SWD but no SRS, developed SRS upon injection of a sub-convulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRS declined by about 30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV containing neurons transiently reduced the seizure-threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons suggesting that their sustained silencing could be causally involved in the development of TLE.SIGNIFICANCE STATEMENT. Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyper-excitability and spontaneous recurrent seizures in mice. Like in patients with non-lesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE. Copyright © 2017 the authors.
A heterologous prime-boost Ebola virus vaccine regimen induces durable neutralizing antibody response and prevents Ebola virus-like particle entry in mice
Jul 22, 2017   Antiviral Research
Chen T, Li D, Song Y, Yang X, Liu Q, Jin X, Zhou D, Huang Z
A heterologous prime-boost Ebola virus vaccine regimen induces durable neutralizing antibody response and prevents Ebola virus-like particle entry in mice
Jul 22, 2017
Antiviral Research
Ebola virus (EBOV) is one of the most virulent pathogens known to humans. Neutralizing antibodies play a major role in the protection against EBOV infections. Thus, an EBOV vaccine capable of inducing a long-lasting neutralizing antibody response is highly desirable. We report here that a heterologous prime-boost vaccine regimen can elicit durable EBOV-neutralizing antibody response in mice. A chimpanzee serotype 7 adenovirus expressing EBOV GP (denoted AdC7-GP) was generated and used for priming. A truncated version of EBOV GP1 protein (denoted GP1t) was produced at high levels in Drosophila S2 cells and used for boosting. Mouse immunization studies showed that the AdC7-GP prime/GP1t boost vaccine regimen was more potent in eliciting neutralizing antibodies than either the AdC7-GP or GP1t alone. Neutralizing antibodies induced by the heterologous prime-boost regimen sustained at high titers for at least 18 weeks after immunization. Significantly, in vivo challenge studies revealed that the entry of reporter EBOV-like particles was efficiently blocked in mice receiving the heterologous prime-boost regimen even at 18 weeks after the final dose of immunization. These results suggest that this novel AdC7-GP prime/GP1t boost regimen represents an EBOV vaccine approach capable of establishing long-term protection, and therefore warrants further development. Copyright © 2017. Published by Elsevier B.V.
Antiviral Immunity and Circular RNA: No End in Sight
Jul 21, 2017   Molecular Cell
Cadena C, Hur S
Antiviral Immunity and Circular RNA: No End in Sight
Jul 21, 2017
Molecular Cell
In this issue of Molecular Cell, two papers by Chen et al. (2017) and Li et al. (2017) describe new insights into circRNA biogenesis and function, connecting circRNAs to innate immune pathways. Copyright © 2017 Elsevier Inc. All rights reserved.
Point-of-care screening for hepatitis B virus infection in pregnant women at an antenatal clinic: A South African experience
Jul 21, 2017   PloS One
Chotun N, Preiser W, van Rensburg CJ, Fernandez P, Theron GB, Glebe D, Andersson MI
Point-of-care screening for hepatitis B virus infection in pregnant women at an antenatal clinic: A South African experience
Jul 21, 2017
PloS One
Elimination of HIV and syphilis mother-to-child transmission (MTCT) has received much attention but little consideration has been given to the possibility of elimination of HBV MTCT. In sub-Saharan Africa, HBV vertical transmission continues to be reported and it remains an important public health problem. This study aimed to assess the feasibility of screening pregnant women for HBV using a point-of-care (POC) test and implementing interventions to prevent HBV MTCT. In this observational prospective cohort study, HIV-uninfected pregnant women who consented to testing were screened for HBV using a rapid POC test for HBsAg. Positive results were laboratory-confirmed and tested for HBV DNA and serological markers. Women with viral loads ≥ 20 000 IU/ml received tenofovir (TDF) treatment and all infants received birth-dose HBV vaccine. Two blood samples collected six months apart from HBV-exposed infants within their first year of life were tested for HBV DNA. Of 144 women who were approached, 134 consented to participating (93% acceptance rate of HBV POC test). Six women tested positive for HBsAg (4.5%; 95% CI 0.99%-8.01%), all confirmed by laboratory testing. Two mothers, M1 and M4, were treated with TDF during their third trimester of pregnancy. Six HBV-exposed infants received the HBV vaccine within 24 hours of birth, of whom two were lost to follow-up and four (including the two born to M1 and M4) had undetectable levels of HBV DNA when tested at the two time points. We found that HBV screening using POC testing fulfilled the criteria considered necessary for implementation. It has acceptable performance, is inexpensive, reliable, and was well accepted by the study participants. Screening pregnant women as part of the HBV MTCT prevention strategy is therefore feasible in a South African clinical setting.
Analysis of patient data from laboratories during the Ebola virus disease outbreak in Liberia, April 2014 to March 2015
Jul 21, 2017   PLoS Neglected Tropical Diseases
Furuse Y, Fallah M, Oshitani H, Kituyi L, Mahmoud N, Musa E, Gasasira A, Nyenswah T, Dahn B, Bawo L
Analysis of patient data from laboratories during the Ebola virus disease outbreak in Liberia, April 2014 to March 2015
Jul 21, 2017
PLoS Neglected Tropical Diseases
An outbreak of Ebola virus disease (EVD) in Liberia began in March 2014 and ended in January 2016. Epidemiological information on the EVD cases was collected and managed nationally; however, collection and management of the data were challenging at the time because surveillance and reporting systems malfunctioned during the outbreak. EVD diagnostic laboratories, however, were able to register basic demographic and clinical information of patients more systematically. Here we present data on 16,370 laboratory samples that were tested between April 4, 2014 and March 29, 2015. A total of 10,536 traceable individuals were identified, of whom 3,897 were confirmed cases (positive for Ebola virus RNA). There were significant differences in sex, age, and place of residence between confirmed and suspected cases that tested negative for Ebola virus RNA. Age (young children and the elderly) and place of residence (rural areas) were the risk factors for death due to the disease. The case fatality rate of confirmed cases decreased from 80% to 63% during the study period. These findings may help support future investigations and lead to a fuller understanding of the outbreak in Liberia.
Apoptosis and anti-cancer drug discovery: the power of medicinal fungi and plants
Jul 21, 2017   Current Medicinal Chemistry
Wong JH, Cho Wing Sze S, Ng TB, Chi Fai Cheung R, Tam C,   . . . . . .   , Sha O, Li G, Tse R, Tse TF, Chan H
Apoptosis and anti-cancer drug discovery: the power of medicinal fungi and plants
Jul 21, 2017
Current Medicinal Chemistry
The purpose of this account is to review the compounds capable of eliciting mitochondria-mediated apoptosis in cancer cells produced by medicinal fungi and plants. The medicinal fungi discussed encompass Cordyceps, Ganoderma species, Coriolus versicolor and Hypsizygus marmoreus. The medicinal plants discussed comprise Astragalus complanatus , Dendrobium spp,Dioscorea spp, Glycyrrhiza spp, Panax notoginseng, Panax ginseng, and Momordica charantia. These compounds have the potential of development into anticancer drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Comparative Omics and Trait Analyses of Marine Pseudoalteromonas Phages Advance the Phage OTU Concept
Jul 21, 2017   Frontiers In Microbiology
Duhaime MB, Solonenko N, Roux S, Verberkmoes NC, Wichels A, Sullivan MB
Comparative Omics and Trait Analyses of Marine Pseudoalteromonas Phages Advance the Phage OTU Concept
Jul 21, 2017
Frontiers In Microbiology
Viruses influence the ecology and evolutionary trajectory of microbial communities. Yet our understanding of their roles in ecosystems is limited by the paucity of model systems available for hypothesis generation and testing. Further, virology is limited by the lack of a broadly accepted conceptual framework to classify viral diversity into evolutionary and ecologically cohesive units. Here, we introduce genomes, structural proteomes, and quantitative host range data for eight Pseudoalteromonas phages isolated from Helgoland (North Sea, Germany) and use these data to advance a genome-based viral operational taxonomic unit (OTU) definition. These viruses represent five new genera and inform 498 unaffiliated or unannotated protein clusters (PCs) from global virus metagenomes. In a comparison of previously sequenced Pseudoalteromonas phage isolates (n = 7) and predicted prophages (n = 31), the eight phages are unique. They share a genus with only one other isolate, Pseudoalteromonas podophage RIO-1 (East Sea, South Korea) and two Pseudoalteromonas prophages. Mass-spectrometry of purified viral particles identified 12-20 structural proteins per phage. When combined with 3-D structural predictions, these data led to the functional characterization of five previously unidentified major capsid proteins. Protein functional predictions revealed mechanisms for hijacking host metabolism and resources. Further, they uncovered a hybrid sipho-myovirus that encodes genes for Mu-like infection rarely described in ocean systems. Finally, we used these data to evaluate a recently introduced definition for virus populations that requires members of the same population to have >95% average nucleotide identity across at least 80% of their genes. Using physiological traits and genomics, we proposed a conceptual model for a viral OTU definition that captures evolutionarily cohesive and ecologically distinct units. In this trait-based framework, sensitive hosts are considered viral niches, while host ranges and infection efficiencies are tracked as viral traits. Quantitative host range assays revealed conserved traits within virus OTUs that break down between OTUs, suggesting the defined units capture niche and fitness differentiation. Together these analyses provide a foundation for model system-based hypothesis testing that will improve our understanding of marine copiotrophs, as well as phage-host interactions on the ocean particles and aggregates where Pseudoalteromonas thrive.
Sudan ebolavirus long recovered survivors produce GP-specific Abs that are of the IgG1 subclass and preferentially bind FcγRI
Jul 21, 2017   Scientific Reports
Radinsky O, Edri A, Brusilovsky M, Fedida-Metula S, Sobarzo A, Gershoni-Yahalom O, Lutwama J, Dye J, Lobel L, Porgador A
Sudan ebolavirus long recovered survivors produce GP-specific Abs that are of the IgG1 subclass and preferentially bind FcγRI
Jul 21, 2017
Scientific Reports
Ebolavirus is a highly lethal pathogen, causing a severe hemorrhagic disease with a high fatality rate. To better understand immune correlates of protection by virus specific IgG, we investigated the evolution of the Fcγ receptors (FcγRs)-activating capabilities of antiviral IgG in serum samples of long recovered survivors. To this end, longitudinal serum samples from survivors of Sudan ebolavirus (SUDV) infection, studied over years, were examined for the presence of Ebola-GP specific IgG subclasses, and for their binding to FcγRs. We developed a cell-based reporter system to quantitate pathogen-specific antibody binding to FcγRIIIA, FcγRIIA, FcγRIIB and FcγRI. With this system, we demonstrate that anti-GP-specific stimulation of the FcγRI reporter by survivors' sera was substantially high one year after acute infection, with a slight reduction in activity over a decade post infection. We further demonstrate that GP-specific IgG1 is by far the seroprevalent subclass that retained and even enhanced its presence in the sera, over ten years post infection; the prevalence of other GP-specific IgG subclasses was considerably reduced over time. In accordance, GP-specific FcγRI reporter response and GP-specific total IgG1 subclass correlated in the studied group of Ebola survivors. These observations are important for further informing Ebola vaccine and therapeutic development.
The Epstein-Barr Virus BRRF1 Gene Is Dispensable for Viral Replication in HEK293 cells and Transformation
Jul 21, 2017   Scientific Reports
Yoshida M, Watanabe T, Narita Y, Sato Y, Goshima F, Kimura H, Murata T
The Epstein-Barr Virus BRRF1 Gene Is Dispensable for Viral Replication in HEK293 cells and Transformation
Jul 21, 2017
Scientific Reports
The Epstein-Barr virus (EBV) is a gamma-herpesvirus associated with several malignancies. It establishes a latent infection in B lymphocytes and is occasionally reactivated to enter the lytic cycle. Here we examined the role of the EBV gene BRRF1, which is expressed in the lytic state. We first confirmed, using a DNA polymerase inhibitor, that the BRRF1 gene is expressed with early kinetics. A BRRF1-deficient recombinant virus was constructed using a bacterial artificial chromosome system. No obvious differences were observed between the wild-type, BRRF1-deficient mutant and the revertant virus in HEK293 cells in terms of viral lytic protein expression, viral DNA synthesis, progeny production, pre-latent abortive lytic gene expression and transformation of primary B cells. However, reporter assays indicated that BRRF1 may activate transcription in promoter- and cell type-dependent manners. Taken together, BRRF1 is dispensable for viral replication in HEK293 cells and transformation of B cells, but it may have effects on transcription.
An essential EBV latent antigen 3C binds Bcl6 for targeted degradation and cell proliferation
Jul 24, 2017   PLoS Pathogens
Pei Y, Banerjee S, Jha HC, Sun Z, Robertson ES
An essential EBV latent antigen 3C binds Bcl6 for targeted degradation and cell proliferation
Jul 24, 2017
PLoS Pathogens
The latent EBV nuclear antigen 3C (EBNA3C) is required for transformation of primary human B lymphocytes. Most mature B-cell malignancies originate from malignant transformation of germinal center (GC) B-cells. The GC reaction appears to have a role in malignant transformation, in which a major player of the GC reaction is Bcl6, a key regulator of this process. We now demonstrate that EBNA3C contributes to B-cell transformation by targeted degradation of Bcl6. We show that EBNA3C can physically associate with Bcl6. Notably, EBNA3C expression leads to reduced Bcl6 protein levels in a ubiquitin-proteasome dependent manner. Further, EBNA3C inhibits the transcriptional activity of the Bcl6 promoter through interaction with the cellular protein IRF4. Bcl6 degradation induced by EBNA3C rescued the functions of the Bcl6-targeted downstream regulatory proteins Bcl2 and CCND1, which resulted in increased proliferation and G1-S transition. These data provide new insights into the function of EBNA3C in B-cell transformation during GC reaction, and raises the possibility of developing new targeted therapies against EBV-associated cancers.

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