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Volume 101,
Issue 12,
2020
Volume 101, Issue 12, 2020
- Editorial
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- Animal
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- Negative-Strand RNA Viruses
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Aerosolized pH1N1 influenza infection induces less systemic and local immune activation in the lung than combined intrabronchial, nasal and oral exposure in cynomolgus macaques
Non-human primates form an important animal model for the evaluation of immunogenicity and efficacy of novel ‘universal’ vaccine candidates against influenza virus. However, in most studies a combination of intra-tracheal or intra-bronchial, oral and nasal virus inoculation is used with a standard virus dose of between 1 and 10 million tissue culture infective doses, which differs from typical modes of virus exposure in humans. This paper studies the systemic and local inflammatory and immune effects of aerosolized versus combined-route exposure to pandemic H1N1 influenza virus. In agreement with a previous study, both combined-route and aerosol exposure resulted in similar levels of virus replication in nose, throat and lung lavages. However, the acute release of pro-inflammatory cytokines and chemokines, acute monocyte activation in peripheral blood as well as increased cytokine production and T-cell proliferation in the lungs were only observed after combined-route infection and not after aerosol exposure. Longitudinal evaluation by computed tomography demonstrated persistence of lung lesions after resolution of the infection and a tendency for more lesions in the lower lung lobes after combined-route exposure versus upper and middle lung lobes after aerosol exposure. Computed tomography scores were observed to correlate with fever. In conclusion, influenza virus infection by aerosol exposure is accompanied by less immune-activation and inflammation in comparison with direct virus installation, despite similar levels of virus replication and development of lesions in the lungs.
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Neddylation of M1 negatively regulates the replication of influenza A virus
Post-translational modification plays a critical role in viral replication. Previously we reported that neddylation of PB2 of influenza A virus (IAV) can inhibit viral replication. However, we found that NEDD8 overexpression can still inhibit the replication of PB2 K699R mutant viruses, implying that other viral protein(s) can be neddylated. In this study, we revealed that M1 of IAV can also be modified by NEDD8. We found that the E3 ligase HDM2 significantly promotes M1 neddylation. Furthermore, we identified M1 K187 as the major neddylation site. We generated an IAV M1 K187R mutant (WSN-M1 K187R) and compared the growth of wild-type and mutant viruses in Madin–Darby canine kidney (MDCK) cells. The data showed that the replication of WSN-M1 K187R was more efficient than that of wild-type WSN. More importantly, we observed that overexpression of NEDD8 inhibited the replication of the wild-type WSN more effectively than that of WSN-M1 K187R. In addition, we found that the neddylation-deficient M1 mutant (M1 K187R) had a longer half-life than that of wild-type M1, indicating that the neddylation of M1 reduces stability. Then we performed a viral infection assay and found that WSN-M1 K187R exhibited greater virulence in mice than wild-type WSN, suggesting that the neddylation of M1 reduced IAV replication in vivo. In conclusion, we uncovered that neddylation of M1 by HDM2 negatively regulates the stability of M1, which in turn inhibits viral replication.
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- Positive-Strand RNA Viruses
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Predicting the recombination potential of severe acute respiratory syndrome coronavirus 2 and Middle East respiratory syndrome coronavirus
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged to cause widespread infections in humans. SARS-CoV-2 infections have been reported in the Kingdom of Saudi Arabia, where Middle East respiratory syndrome coronavirus (MERS-CoV) causes seasonal outbreaks with a case fatality rate of ~37 %. Here we show that there exists a theoretical possibility of future recombination events between SARS-CoV-2 and MERS-CoV RNA. Through computational analyses, we have identified homologous genomic regions within the ORF1ab and S genes that could facilitate recombination, and have analysed co-expression patterns of the cellular receptors for SARS-CoV-2 and MERS-CoV, ACE2 and DPP4, respectively, to identify human anatomical sites that could facilitate co-infection. Furthermore, we have investigated the likely susceptibility of various animal species to MERS-CoV and SARS-CoV-2 infection by comparing known virus spike protein–receptor interacting residues. In conclusion, we suggest that a recombination between SARS-CoV-2 and MERS-CoV RNA is possible and urge public health laboratories in high-risk areas to develop diagnostic capability for the detection of recombined coronaviruses in patient samples.
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Analysis of partial sequences of the RNA-dependent RNA polymerase gene as a tool for genus and subgenus classification of coronaviruses
More LessThe recent reclassification of the Riboviria, and the introduction of multiple new taxonomic categories including both subfamilies and subgenera for coronaviruses (family Coronaviridae, subfamily Orthocoronavirinae), represents a major shift in how official classifications are used to designate specific viral lineages. While the newly defined subgenera provide much-needed standardization for commonly cited viruses of public health importance, no method has been proposed for the assignment of subgenus based on partial sequence data, or for sequences that are divergent from the designated holotype reference genomes. Here, we describe the genetic variation of a 387 nt region of the coronavirus RNA-dependent RNA polymerase (RdRp), which is one of the most used partial sequence loci for both detection and classification of coronaviruses in molecular epidemiology. We infer Bayesian phylogenies from more than 7000 publicly available coronavirus sequences and examine clade groupings relative to all subgenus holotype sequences. Our phylogenetic analyses are largely coherent with whole-genome analyses based on designated holotype members for each subgenus. Distance measures between sequences form discrete clusters between taxa, offering logical threshold boundaries that can attribute subgenus or indicate sequences that are likely to belong to unclassified subgenera both accurately and robustly. We thus propose that partial RdRp sequence data of coronaviruses are sufficient for the attribution of subgenus-level taxonomic classifications and we supply the R package, MyCoV, which provides a method for attributing subgenus and assessing the reliability of the attribution.
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- Large DNA Virus
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Identification and functional analyses of a cell-death inhibitor encoded by guinea pig cytomegalovirus gp38.1 in cell culture and in animals
Cytomegaloviruses (CMVs) employ an array of strategies designed to interfere with host defence responses against pathogens. Studies on such evasion mechanisms are important for understanding the pathogenesis of CMV diseases. Although guinea pig CMV (GPCMV) provides a useful animal model for congenital CMV infection, its evasion strategies are not fully elucidated. Here, we analysed a genome locus that may encode gene products for the GPCMV evasion mechanisms and found the following. (1) RACE analyses identified five transcripts in the GP38-gp38.4 locus, one of which was a spliced product encoding gp38.1. Similarities in the splicing pattern and gene position of gp38.1 to human CMV UL37 and its exon 1 encoding vMIA (viral mitochondria-localized inhibitor of apoptosis) suggest that the gp38.1 gene encodes an apoptosis inhibitor. (2) In a transient transfection assay, gp38.1 localized in the mitochondria and relocated BAX from the cytoplasm to the mitochondria, although its co-localization with BAK was not evident. Further, the expression of gp38.1 partially reduced staurosporine-induced apoptosis. (3) GPCMV defective in the gp38.1 ORF (Δ38.1) and the virus that rescues the defect (r38.1) were generated. Guinea pig fibroblast cells infected with Δ38.1 died earlier than r38.1-infected cells, which resulted in the lower yields of Δ38.1. (4) In animals, viral loads in the spleens of r38.1-infected guinea pigs were higher than those in the spleens of Δ38.1-infected animals. In conclusion, although GPCMV gp38.1 exerts a vMIA-like function, its inhibitory effect was not robust, suggesting the presence of additional inhibitory molecule(s), such as a BAK-specific inhibitor.
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Viral gastroenteritis in Tocantins, Brazil: characterizing the diversity of human adenovirus F through next-generation sequencing and bioinformatics
Roozbeh Tahmasebi, Adriana Luchs, Kaelan Tardy, Philip Michael Hefford, Rory J. Tinker, Owrang Eilami, Flavio Augusto de Padua Milagres, Rafael Brustulin, Maria da Aparecida Rodrigues Teles, Vanessa dos Santos Morais, Carlos Henrique Valente Moreira, Renata Buccheri, Emerson Luiz Lima Araújo, Fabiola Villanova, Xutao Deng, Ester Cerdeira Sabino, Eric Delwart, Élcio Leal and Antonio Charlys da CostaHuman enteric adenovirus species F (HAdV-F) is one of the most common pathogens responsible for acute gastroenteritis worldwide. Brazil is a country with continental dimensions where continuous multiregional surveillance is vital to establish a more complete picture of the epidemiology of HAdV-F. The aim of the current study was to investigate the molecular epidemiology of HAdV-F using full-genome data in rural and low-income urban areas in northern Brazil. This will allow a genetic comparison between Brazilian and global HAdV-F strains. The frequency of HAdV-F infections in patients with gastroenteritis and molecular typing of positive samples within this period was also analysed. A total of 251 stool samples collected between 2010 and 2016 from patients with acute gastroenteritis were screened for HAdV-F using next-generation sequencing techniques. HAdV-F infection was detected in 57.8 % (145/251) of samples. A total of 137 positive samples belonged to HAdV-F41 and 7 to HAdV-F40. HAdV-F40/41 dual infection was found in one sample. Detection rates did not vary significantly according to the year. Single HAdV-F infections were detected in 21.9 % (55/251) of samples and mixed infections in 37.4 % (94/251), with RVA/HAdV-F being the most frequent association (21.5 %; 54/251). Genetic analysis indicated that the HAdV-F strains circulating in Brazil were closely related to worldwide strains, and the existence of some temporal order was not observed. This is the first large-scale HAdV-F study in Brazil in which whole-genome data and DNA sequence analyses were used to characterize HAdV-F strains. Expanding the viral genome database could improve overall genotyping success and assist the National Center for Biotechnology Information (NCBI)/GenBank in standardizing the HAdV genome records by providing a large set of annotated HAdV-F genomes.
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- Retroviruses
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Effect of combination antiretroviral therapy on human immunodeficiency virus 1 specific antibody responses in subtype-C infected children
Protective antibody responses to human immunodeficiency virus (HIV)-1 infection evolve only in a fraction of infected individuals by developing broadly neutralizing antibodies (bnAbs) and/or effector functions such as antibody-dependent cellular cytotoxicity (ADCC). HIV-1 chronically infected adults and children on combination antiretroviral therapy (cART) showed a reduction in ADCC activity and improvement in HIV-1 specific neutralizing antibody (nAb) responses. Early initiation of cART in infected adults is found to be beneficial in reducing the viral load and delaying disease progression. Herein, we longitudinally evaluated the effect of cART on HIV-1 specific plasma ADCC and nAb responses in a cohort of 20 perinatally HIV-1 subtype-C infected infants and children ≤2 years of age, pre-cART and up to 1 year post-cART initiation. Significant reductions in HIV-1 specific plasma ADCC responses to subtype-C and subtype-B viruses and improvement in HIV-1 neutralization were observed in HIV-1 infected children 1 year post-cART initiation. A positive correlation between reduction in viral load and the loss of ADCC response was observed. This study provides information aiding the understanding of the effects of early initiation of cART on antibody effector functions and viral neutralization in HIV-1 infected children, which needs to be further evaluated in large cohorts of HIV-1 infected children on cART to plan future intervention strategies.
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- Insect
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- DNA Virus
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Determination of the virulence of single nucleopolyhedrovirus occlusion bodies using a novel laser capture microdissection method
More LessDetermination of the virulence of occlusion bodies (OBs), which are the horizontal transmission structures of nucleopolyhedroviruses (NPVs), is an important area of baculovirology. A method for inoculating an insect with an isolated OB was developed using Helicoverpa armigera nucleopolyhedrovirus (HearNPV) infection of second instar Helicoverpa armigera larvae as a model NPV–host pathosystem. In this novel method, laser capture microdissection (LCM) was used to directly catapult single OBs onto the surface of insect diet in bioassay containers. Since exposure via the natural oral horizontal transmission route of each larva to a single OB was established and not subject to chance variation, the method facilitated determination of the insect mortality rate (4.8%) associated with exposure to single HearNPV OBs. Droplet feeding bioassays confirmed that the novel method did not reduce OB virulence. The LCM method sets a foundation for virulence and genetic diversity studies based on single NPV OBs.
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- Plant
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- DNA Virus
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Identification of putative viroplasms within banana cells infected by banana streak MY virus
More LessThe badnavirus replication cycle is poorly understood and most knowledge is based on extrapolations from model viruses such as Cauliflower mosaic virus (CaMV). However, in contrast to CaMV, badnaviruses are thought not to produce viroplasms and therefore it has been a mystery as to where virion assembly occurs. In this study, ultrathin sections of a banana leaf infected with a badnavirus, banana streak MY virus (BSMYV), were examined by transmission electron microscopy. Electron-dense inclusion bodies (EDIBs) were sporadically distributed in parenchymatous tissues of the leaf, most commonly in the palisade and spongy mesophyll cells. These EDIBs had a characteristic structure, comprising an electron-dense core, a single, encircling lacuna and an outer ring of electron-dense material. However, much less frequently, EDIBs with two or three lacunae were observed. In the outer ring, densely packed virions were visible with a shape and size consistent with that expected for badnaviruses. Immunogold labelling was done with primary antibodies that detected the N-terminus of the capsid protein and strong labelling of the outer ring but not the central core or lacuna was observed. It is concluded that the EDIBs that were observed are equivalent in function to the viroplasms of CaMV, although obviously different in composition as there is not a paralogue of the transactivation/viroplasm protein in the badnavirus genome. It is postulated that production of a viroplasm could be a conserved characteristic of all members of the Caulimoviridae.
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Volumes and issues
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