- Volume 93, Issue 9, 2012
Volume 93, Issue 9, 2012
- Obituary
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- Review
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Application of next-generation sequencing technologies in virology
More LessThe progress of science is punctuated by the advent of revolutionary technologies that provide new ways and scales to formulate scientific questions and advance knowledge. Following on from electron microscopy, cell culture and PCR, next-generation sequencing is one of these methodologies that is now changing the way that we understand viruses, particularly in the areas of genome sequencing, evolution, ecology, discovery and transcriptomics. Possibilities for these methodologies are only limited by our scientific imagination and, to some extent, by their cost, which has restricted their use to relatively small numbers of samples. Challenges remain, including the storage and analysis of the large amounts of data generated. As the chemistries employed mature, costs will decrease. In addition, improved methods for analysis will become available, opening yet further applications in virology including routine diagnostic work on individuals, and new understanding of the interaction between viral and host transcriptomes. An exciting era of viral exploration has begun, and will set us new challenges to understand the role of newly discovered viral diversity in both disease and health.
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- Animal
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- DNA viruses
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Identification of a novel NLS of herpes simplex virus type 1 (HSV-1) VP19C and its nuclear localization is required for efficient production of HSV-1
More LessHerpes simplex virus type 1 (HSV-1) triplex is a complex of three protein subunits, consisting of two copies of VP23 and one copy of VP19C. Here, we identified a non-classical NLS of VP19C between aa 50 and 61, and the nuclear import of VP19C was mediated by RanGTP and importin β1-, but not importin α5-, dependent pathway. Additionally, recombinant virus harbouring this NLS mutation (NLSm) replicates less efficiently as wild-type. These data strongly suggested that the nuclear import of VP19C is required for efficient HSV-1 production.
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Protein B5 is required on extracellular enveloped vaccinia virus for repulsion of superinfecting virions
More LessVaccinia virus (VACV) spreads across cell monolayers fourfold faster than predicted from its replication kinetics. Early after infection, infected cells repulse some superinfecting extracellular enveloped virus (EEV) particles by the formation of actin tails from the cell surface, thereby causing accelerated spread to uninfected cells. This strategy requires the expression of two viral proteins, A33 and A36, on the surface of infected cells and upon contact with EEV this complex induces actin polymerization. Here we have studied this phenomenon further and investigated whether A33 and A36 expression in cell lines causes an increase in VACV plaque size, whether these proteins are able to block superinfection by EEV, and which protein(s) on the EEV surface are required to initiate the formation of actin tails from infected cells. Data presented show that VACV plaque size was not increased by expression of A33 and A36, and these proteins did not block entry of the majority of EEV binding to these cells. In contrast, expression of proteins A56 and K2 inhibited entry of both EEV and intracellular mature virus. Lastly, VACV protein B5 was required on EEV to induce the formation of actin tails at the surface of cells expressing A33 and A36, and B5 short consensus repeat 4 is critical for this induction.
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Nuclear translocation of adeno-associated virus type 2 capsid proteins for virion assembly
More LessAdeno-associated virus (AAV) capsid assembly occurs in the nucleus. Newly synthesized capsid proteins VP1, VP2 and VP3 contain several basic regions (BRs), which may act as nuclear localization signals (NLSs). Mutation of BR2 and BR3, located at the VP1 and VP2 N termini, marginally reduced nuclear uptake of VP1 or VP2, but not of VP3, when expressed in the context of the whole AAV type 2 (AAV2) genome. Combined mutation of BR1, BR2 and BR3 resulted in capsids with slightly reduced amounts of VP1. Expression of isolated VP1/2 N termini revealed an influence of BR3 on nuclear transport, whilst BR1 or BR2 had no effect. However, deletion of an N-terminal fragment in front of the BR elements strongly reduced nuclear uptake of VP1/2 N termini. Mutation of BR4, present in all three capsid proteins, led to their retention in the cytoplasm and to the formation of speckles, resulting in a lack of capsid formation and a significant reduction in VP levels. In a VP fragment comprising BR2, BR3 and BR4, the BR4 element was not necessary for nuclear localization. Mutation of BR5 in the C-terminal part of the VPs resulted in a speckled protein distribution in the nucleus, strongly reduced capsid assembly, and low VP1 and VP2 levels. Taken together, these results showed that BR2 and BR3 have a weak influence on nuclear transport of VP1 and VP2, whilst combined mutation of BR1, BR2 and BR3 influences the stoichiometry of VPs in assembled capsids. BR4 and BR5 play a crucial role in capsid assembly but have no NLS activity.
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Genotyping hepatitis B virus dual infections using population-based sequence data
The hepatitis B virus (HBV) is classified into distinct genotypes A–H that are characterized by different progression of hepatitis B and sensitivity to interferon treatment. Previous computational genotyping methods are not robust enough regarding HBV dual infections with different genotypes. The correct classification of HBV sequences into the present genotypes is impaired due to multiple ambiguous sequence positions. We present a computational model that is able to identify and genotype inter- and intragenotype dual infections using population-based sequencing data. Model verification on synthetic data showed 100 % accuracy for intergenotype dual infections and 36.4 % sensitivity in intragenotype dual infections. Screening patient sera (n = 241) revealed eight putative cases of intergenotype dual infection (one A–D, six A–G and one D–G) and four putative cases of intragenotype dual infection (one A–A, two D–D and one E–E). Clonal experiments from the original patient material confirmed three out of three of our predictions. The method has been integrated into geno2pheno[hbv], an established web-service in clinical use for analysing HBV sequence data. It offers exact and detailed identification of HBV genotypes in patients with dual infections that helps to optimize antiviral therapy regimens. geno2pheno[hbv] is available under http://www.genafor.org/g2p_hbv/index.php.
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- RNA viruses
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Differences in neutralizing antigenicity between laboratory and clinical isolates of HCoV-229E isolated in Japan in 2004–2008 depend on the S1 region sequence of the spike protein
Human coronavirus (HCoV) is a causative agent of the common cold. Although HCoV is highly prevalent in the world, studies of the genomic and antigenic details of circulating HCoV strains have been limited. In this study, we compared four Japanese isolates with the standard HCoV-229E strain obtained from ATCC (ATCC-VR740) by focusing on the spike (S) protein, a major determinant of neutralizing antigen and pathogenicity. The isolates were found to have nucleotide deletions and a number of sequence differences in the S1 region of the S protein. We compared two of the Japanese isolates with the ATCC-VR740 strain by using virus-neutralizing assays consisting of infectious HCoV-229E particles and vesicular stomatitis virus (VSV)-pseudotyped virus carrying the HCoV-229E S protein. The two clinical isolates (Sendai-H/1121/04 and Niigata/01/08) did not react with antiserum to the ATCC-VR740 strain via the neutralizing test. We then constructed a pseudotype VSV-harboured chimeric S protein with the ATCC S1 and Sendai S2 regions or that with Sendai S1 and ATCC S2 regions and compared them by a neutralization test. The results revealed that the difference in the neutralizing antigenicity depends on the S1 region. This different antigenic phenotype was also confirmed by a neutralizing test with clinically isolated human sera. These results suggest that the HCoV-229E viruses prevalent in Japan are quite different from the laboratory strain ATCC-VR740 in terms of the S sequence and neutralization antigenicity, which is attributed to the difference in the S1 region.
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Organ tropism of murine coronavirus does not correlate with the expression levels of the membrane-anchored or secreted isoforms of the carcinoembryonic antigen-related cell adhesion molecule 1 receptor
More LessCarcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is the sole known receptor of murine hepatitis virus (MHV) A59, but the available, often qualitative, data about CEACAM1 expression does not explain MHV organ tropism. Ceacam1 transcripts undergo alternative splicing resulting in multiple isoforms, including secreted CEACAM1 isoforms that can neutralize the virus. We determined the quantities of Ceacam1 transcripts encoding membrane-bound and secreted isoforms in mouse organs and a set of cell lines. In vivo, the lowest receptor mRNA levels were found in brain and muscle and these were similar to those in easily infectable cultured cells. While the quantities of the receptor transcripts varied between mouse organs, their abundance did not correlate with susceptibility to MHV infection. The proportion of transcripts encoding secreted isoforms also could not explain the selection of sites for virus replication, as it was constant in all organs. Our data suggest that neither of the two CEACAM1 isoforms defines MHV organ tropism.
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Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63
Like severe acute respiratory syndrome coronavirus (SARS-CoV), human coronavirus (HCoV)-NL63 employs angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry. SARS-CoV infection causes robust downregulation of cellular ACE2 expression levels and it has been suggested that the SARS-CoV effect on ACE2 is involved in the severity of disease. We investigated whether cellular ACE2 downregulation occurs at optimal replication conditions of HCoV-NL63 infection. The expression of the homologue of ACE2, the ACE protein not used as a receptor by HCoV-NL63, was measured as a control. A specific decrease for ACE2 protein level was observed when HCoV-NL63 was cultured at 34 °C. Culturing the virus at the suboptimal temperature of 37 °C resulted in low replication of the virus and the effect on ACE2 expression was lost. We conclude that the decline of ACE2 expression is dependent on the efficiency of HCoV-NL63 replication, and that HCoV-NL63 and SARS-CoV both affect cellular ACE2 expression during infection.
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Feline infectious peritonitis virus with a large deletion in the 5′-terminal region of the spike gene retains its virulence for cats
In this study, the Japanese strain of type I feline infectious peritonitis virus (FIPV), C3663, was found to have a large deletion of 735 bp within the gene encoding the spike (S) protein, with a deduced loss of 245 aa of the N-terminal region of the S protein. This deletion is similar to that observed in porcine respiratory coronavirus (PRCoV) when compared to transmissible gastroenteritis virus, which correlates with reduced virulence. By analogy to PRCoV, we expected that the pathogenicity of C3663 may be attenuated in cats. However, two of four cats inoculated with C3663 died of FIP, and a third C3663-inoculated cat showed FIP lesions at 91 days after challenge. These results indicate that the 5′-terminal region of the S gene is not essential for the development of FIP.
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A single mutation in capsid protein VP1 (Q145E) of a genogroup C4 strain of human enterovirus 71 generates a mouse-virulent phenotype
More LessWe modified the capsid protein of a human enterovirus 71 (HEV71) belonging to subgenogroup C4 (HEV71-C4) to generate a mouse virulent strain, based on the genetic information derived from our previous subgenogroup B3 mouse-adapted virus. Infectious clone-derived mutant virus populations containing the capsid protein mutations VP1-Q145E and VP1-Q145G were generated by site-directed mutagenesis of an infectious clone of a subgenogroup C4 strain. Viruses expressing the VP1-Q145E were virulent in 5-day-old BALB/c mice with 100 % mortality rate observed. Skeletal muscle appears to be the primary site of replication of this virus with limb muscle showing severe myositis. Virus was also isolated from spleen, liver, heart and brain of infected mice. This study demonstrates that introducing a key mutation into the HEV71 VP1 capsid protein is able to generate a mouse virulent HEV71 strain from a different genogroup as well as providing an alternative strategy for the generation of mouse virulent HEV71.
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Natural interspecies recombinant bovine/porcine enterovirus in sheep
More LessMembers of the genus Enterovirus (family Picornaviridae) are believed to be common and widespread among humans and different animal species, although only a few enteroviruses have been identified from animal sources. Intraspecies recombination among human enteroviruses is a well-known phenomenon, but only a few interspecies examples have been reported and, to our current knowledge, none of these have involved non-primate enteroviruses. In this study, we report the detection and complete genome characterization (using RT-PCR and long-range PCR) of a natural interspecies recombinant bovine/porcine enterovirus (ovine enterovirus type 1; OEV-1) in seven (44 %) of 16 faecal samples from 3-week-old domestic sheep (Ovis aries) collected in two consecutive years. Phylogenetic analysis of the complete coding region revealed that OEV-1 (ovine/TB4-OEV/2009/HUN; GenBank accession no. JQ277724) was a novel member of the species Porcine enterovirus B (PEV-B), implying the endemic presence of PEV-B viruses among sheep. However, the 5′ UTR of OEV-1 showed a high degree of sequence and structural identity to bovine enteroviruses. The presumed recombination breakpoint was mapped to the end of the 5′ UTR at nucleotide position 814 using sequence and SimPlot analyses. The interspecies-recombinant nature of OEV-1 suggests a closer relationship among bovine and porcine enteroviruses, enabling the exchange of at least some modular genetic elements that may evolve independently.
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Worldwide emergence of multiple clades of enterovirus 68
Human enterovirus 68 (EV-D68) is a historically rarely reported virus linked with respiratory disease. In the past 3 years, a large increase in respiratory disease associated with EV-D68 has been reported, with documented outbreaks in North America, Europe and Asia. In several outbreaks, genetic differences were identified among the circulating strains, indicating the presence of multiple clades. In this report, we analyse archived and novel EV-D68 strains from Africa and the USA, obtained from patients with respiratory illness. Phylogenetic analysis of all EV-D68 sequences indicates that, over the past two decades, multiple clades of the virus have emerged and spread rapidly worldwide. All clades appear to be currently circulating and contributing to respiratory disease.
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A single nucleotide mutation in NS2A of Japanese encephalitis-live vaccine virus (SA14-14-2) ablates NS1’ formation and contributes to attenuation
Japanese encephalitis (JE) remains the leading cause of viral encephalitis in the Asia-Pacific region, and the live vaccine SA14-14-2 is currently recommended by WHO and widely used in Asian countries with a good safety and efficacy profile. In this study, we demonstrated that SA14-14-2 failed to produce NS1’, the larger NS1-related protein, compared with its parental strain SA14 in various cells. Sequence analysis and secondary structure prediction identified a single silent mutation G66A in the NS2A-coding region of SA14-14-2 destabilized the conserved pseudoknot structure, which was associated with a −1 ribosomal frame shift event. Using reverse genetic technology and animal study, we provided solid evidence that this single silent mutation G66A in the NS2A gene abolished the production of NS1’ in vitro and reduced neurovirulence and neuroinvasiveness in mice. These findings provide critical information in understanding the molecular mechanism of JE vaccine attenuation and is critical for JE vaccine quality control.
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Identification of residues in West Nile virus pre-membrane protein that influence viral particle secretion and virulence
More LessThe pre-membrane protein (prM) of West Nile virus (WNV) functions as a chaperone for correct folding of the envelope (E) protein, and prevents premature fusion during virus egress. However, little is known about its role in virulence. To investigate this, we compared the amino acid sequences of prM between a highly virulent North American strain (WNVNY99) and a weakly virulent Australian subtype (WNVKUN). Five amino acid differences occur in WNVNY99 compared with WNVKUN (I22V, H43Y, L72S, S105A and A156V). When expressed in mammalian cells, recombinant WNVNY99 prM retained native antigenic structure, and was partially exported to the cell surface. In contrast, WNVKUN prM (in the absence of the E protein) failed to express a conserved conformational epitope and was mostly retained at the pre-Golgi stage. Substitutions in residues 22 (Ile to Val) and 72 (Leu to Ser) restored the antigenic structure and cell surface expression of WNVKUN prM to the same level as that of WNVNY99, and enhanced the secretion of WNVKUN prME particles when expressed in the presence of E. Introduction of the prM substitutions into a WNVKUN infectious clone (FLSDX) enhanced the secretion of infectious particles in Vero cells, and enhanced virulence in mice. These findings highlight the role of prM in viral particle secretion and virulence, and suggest the involvement of the L72S and I22V substitutions in modulating these activities.
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Hobi-like pestivirus: both biotypes isolated from a diseased animal
A Hobi-like pestivirus pair consisting of cytopathogenic (cp) and non-cytopathogenic (noncp) strains, Italy 83/10cp and Italy 83/10ncp, was isolated from the lung of a heifer that died of respiratory disease. The noncp and cp viruses were isolated on Madin–Darby bovine kidney cells and separated by plaque purification and end point dilution. Analysis of the nearly full-length genomes revealed that the two viruses were very closely related to each other and to the noncp Hobi-like strain Italy 1/10-1, which had been isolated a few weeks earlier from the same herd. One major difference between noncp and cp viruses concerned the presence of a cellular Jiv sequence in the 3′ domain of the NS2-encoding region of the cp strain. This is the first study, to our knowledge, reporting the isolation and molecular characterization of a Hobi-like virus pair.
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Complete coding sequence and molecular epidemiological analysis of Sindbis virus isolates from mosquitoes and humans, Finland
More LessSindbis virus (SINV) is an arthropod-borne alphavirus, which causes rash-arthritis, particularly in Finland. SINV is transmitted by mosquitoes in Finland but thus far no virus has been isolated from mosquitoes. In this study, we report the isolation of the first SINV strain from mosquitoes in Finland and its full-length protein-coding sequence. We furthermore describe the full-length coding sequence of six SINV strains previously isolated from humans in Finland and from a mosquito in Russia. The strain isolated from mosquitoes (Ilomantsi-2005M) was very closely related to all the other Northern European SINV strains. We found 9 aa positions, of which five in the nsP3 protein C terminus, to be distinctive signatures for the Northern European strains that may be associated with vector or host species adaptation. Phylogenetic analyses further indicate that SINV has a local circulation in endemic regions in Northern Europe and no novel strains are frequently being introduced.
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Construction of an infectious Chikungunya virus cDNA clone and stable insertion of mCherry reporter genes at two different sites
More LessChikungunya virus (CHIKV) has caused massive epidemics in the Indian Ocean region since 2005. It belongs to the genus Alphavirus and possesses a positive-stranded RNA genome of nearly 12 kb in size. To produce genetically modified viruses for the study of various aspects of the CHIKV life cycle, a reverse genetic system is needed. We report the generation of a T7 RNA polymerase-driven infectious cDNA clone of CHIKV. Electroporation of in vitro-transcribed RNA resulted in the recovery of a recombinant virus with growth characteristics comparable to the parental strain. Using the established cDNA clone, the red fluorescent marker gene mCherry was introduced into two different sites within the CHIKV nsP3 gene. Both constructs allowed the rescue of stable fluorescent reporter viruses with growth characteristics similar to the wild-type virus. The latter reporter viruses represent valuable tools for easy follow-up of replicating CHIKV useful in several applications of CHIKV research.
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Genetic evolution of the neuraminidase of influenza A (H3N2) viruses from 1968 to 2009 and its correspondence to haemagglutinin evolution
Each year, influenza viruses cause epidemics by evading pre-existing humoral immunity through mutations in the major glycoproteins: the haemagglutinin (HA) and the neuraminidase (NA). In 2004, the antigenic evolution of HA of human influenza A (H3N2) viruses was mapped (Smith et al., Science 305, 371–376, 2004) from its introduction in humans in 1968 until 2003. The current study focused on the genetic evolution of NA and compared it with HA using the dataset of Smith and colleagues, updated to the epidemic of the 2009/2010 season. Phylogenetic trees and genetic maps were constructed to visualize the genetic evolution of NA and HA. The results revealed multiple reassortment events over the years. Overall rates of evolutionary change were lower for NA than for HA1 at the nucleotide level. Selection pressures were estimated, revealing an abundance of negatively selected sites and sparse positively selected sites. The differences found between the evolution of NA and HA1 warrant further analysis of the evolution of NA at the phenotypic level, as has been done previously for HA.
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Characterization of a porcine intestinal epithelial cell line for influenza virus production
We have developed a porcine intestine epithelial cell line, designated SD-PJEC for the propagation of influenza viruses. The SD-PJEC cell line is a subclone of the IPEC-J2 cell line, which was originally derived from newborn piglet jejunum. Our results demonstrate that SD-PJEC is a cell line of epithelial origin that preferentially expresses receptors of oligosaccharides with Sia2-6Gal modification. This cell line is permissive to infection with human and swine influenza A viruses and some avian influenza viruses, but poorly support the growth of human-origin influenza B viruses. Propagation of swine-origin influenza viruses in these cells results in a rapid growth rate within the first 24 h post-infection and the titres ranged from 4 to 8 log10 TCID50 ml−1. The SD-PJEC cell line was further tested as a potential alternative cell line to Madin–Darby canine kidney (MDCK) cells in conjunction with 293T cells for rescue of swine-origin influenza viruses using the reverse genetics system. The recombinant viruses A/swine/North Carolina/18161/02 (H1N1) and A/swine/Texas/4199-2/98 (H3N2) were rescued with virus titres of 7 and 8.25 log10 TCID50 ml−1, respectively. The availability of this swine-specific cell line represents a more relevant substrate for studies and growth of swine-origin influenza viruses.
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A doxycycline-dependent human immunodeficiency virus type 1 replicates in vivo without inducing CD4+ T-cell depletion
A novel genetic approach for the control of virus replication was used for the design of a conditionally replicating human immunodeficiency virus (HIV) variant, HIV-rtTA. HIV-rtTA gene expression and virus replication are strictly dependent on the presence of a non-toxic effector molecule, doxycycline (dox), and thus can be turned on and off at will in a graded and reversible manner. The in vivo replication capacity, pathogenicity and genetic stability of this HIV-rtTA variant were evaluated in a humanized mouse model of haematopoiesis that harbours lymphoid and myeloid components of the human immune system (HIS). Infection of dox-fed BALB Rag/γc HIS (BRG-HIS) mice with HIV-rtTA led to the establishment of a productive infection without CD4+ T-cell depletion. The virus did not show any sign of escape from dox control for up to 10 weeks after the onset of infection. No reversion towards a functional Tat–transactivating responsive (TAR) RNA element axis was observed, confirming the genetic stability of the HIV-rtTA variant in vivo. These results demonstrate the proof of concept that HIV-rtTA replicates efficiently in vivo. HIV-rtTA is a promising tool for fundamental research to study virus–host interactions in vivo in a controlled fashion.
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Retrovirus-induced lymphomagenesis: a correlation between disease pathogenesis and flow cytometric analysis
More LessPerinatal infection with a temperature-sensitive mutant (ts-1) of Moloney murine leukemia virus (MoMuLV) results in massive splenomegaly and thymomegaly in mice and development of lymphoma in >55 % of infected pups. Previous flow cytometry studies showed a decrease in CD4+ cells in perinatally infected pups, but cell population changes in infected animals with lymphoma compared with infected animals without lymphoma has not yet been reported. In the current study, BALB/c mice were infected with ts-1 through breast milk transmission and observed until development of clinical signs and symptoms of lymphoma and/or symptomatic ts-1 infection. Flow cytometry studies were performed on blood, spleen and thymus samples and correlated with gross morphology and histological changes, resulting from the development of lymphoma. Infected animals with lymphoma had significant decreases in CD4+ and CD8+ cell counts in blood and spleen compared with controls. The spleens of infected animals without lymphoma showed a decrease in CD4+ and CD8+ cell counts, but this was not significant compared with controls. In the thymus, CD4+ and CD8+ cell counts also decreased, but this was not significant in infected animals with and without lymphoma compared with controls. Markers of myeloid cell dysfunction increased in the thymus of animals with infection with and without lymphoma compared with controls. Thus, immunosuppression and CD4+/CD8+ cell decreases in the spleen and thymus are associated with malignant transformation and development of lymphoma in this animal model.
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Identification of diverse groups of endogenous gammaretroviruses in mega- and microbats
More LessA previous phylogenetic study suggested that mammalian gammaretroviruses may have originated in bats. Here we report the discovery of RNA transcripts from two putative endogenous gammaretroviruses in frugivorous (Rousettus leschenaultii retrovirus, RlRV) and insectivorous (Megaderma lyra retrovirus, MlRV) bat species. Both genomes possess a large deletion in pol, indicating that they are defective retroviruses. Phylogenetic analysis places RlRV and MlRV within the diversity of mammalian gammaretroviruses, with the former falling closer to porcine endogenous retroviruses and the latter to Mus dunni endogenous virus, koala retrovirus and gibbon ape leukemia virus. Additional genomic mining suggests that both microbat (Myotis lucifugus) and megabat (Pteropus vampyrus) genomes harbour many copies of endogenous retroviral forms related to RlRV and MlRV. Furthermore, phylogenetic analysis reveals the presence of three genetically diverse groups of endogenous gammaretroviruses in bat genomes, with M. lucifugus possessing members of all three groups. Taken together, this study indicates that bats harbour distinct gammaretroviruses and may have played an important role as reservoir hosts during the diversification of mammalian gammaretroviruses.
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- Phage
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Characterization of the Salmonella bacteriophage vB_SenS-Ent1
More LessThe bacteriophage vB_SenS-Ent1 (Ent1) is a member of the family Siphoviridae of tailed bacteriophages and infects a broad range of serovars of the enteric pathogen Salmonella enterica. The virion particle is composed of an icosahedral head 64 nm in diameter and a flexible, non-contractile tail of 116 × 8.5 nm possessing terminal fibres. The adsorption rate constant at 37 °C is 6.73 × 10−9 ml min−1. Latent and eclipse periods are 25 and 20 min, respectively, and the burst size is 35 progeny particles per cell after 35 min at 37 °C. Sequencing revealed a circularly permuted, 42 391 bp dsDNA genome containing 58 ORFs organized into four major transcriptional units. Comparisons with the genome sequences of other bacteriophages revealed a high level of nucleotide sequence identity and shared orthologous proteins with the Salmonella phages SETP3, SE2 and KS7 (SS3e) and the Escherichia phages K1G, K1H, K1ind1 and K1ind3.
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- Other agents
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Deletion of protease-activated receptor 2 prolongs survival of scrapie-inoculated mice
More LessProteinase-activated receptor 2 (PAR2) has recently been identified to be a possible modulator of neurodegeneration. To investigate whether PAR2 plays a role in prion infection, we inoculated PAR2-deficient (PAR2−/−) and wild-type (WT) mice intracerebrally with the Rocky Mountain Laboratory strain of scrapie. PAR2−/− mice demonstrated a delayed onset of clinical symptoms, including weight loss, and demonstrated moderate but highly significant prolongation of survival over WT controls. Concomitantly, no apparent differences in brain pathology, infectivity or features of brain prion protein between deceased WT and PAR2−/− mice were found. Our study suggests that PAR2 deletion modulates dynamics of the disease without gross perturbation of its pathogenesis.
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Volumes and issues
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