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Future Microbiology 2015Viruses such as coxsackievirus B3 (CVB3) are entirely host cell-dependent parasites. Indeed, they must cleverly exploit various compartments of host cells to complete... (Review)
Review
Viruses such as coxsackievirus B3 (CVB3) are entirely host cell-dependent parasites. Indeed, they must cleverly exploit various compartments of host cells to complete their life cycle, and consequently launch disease. Evolution has equipped this pico-rna-virus, CVB3, to use different strategies, including CVB3-induced direct damage to host cells followed by a host inflammatory response to CVB3 infection, and cell death to super-additively promote target organ tissue injury, and dysfunction. In this update, the patho-stratagems of CVB3 are explored from molecular, and systems-level approaches. In summarizing recent developments in this field, we focus particularly on mechanisms by which CVB3 can harness different host cell processes including kinases, host cell-killing and cell-eating machineries, matrix metalloproteinases and miRNAs to promote disease.
Topics: Enterovirus B, Human; Host-Pathogen Interactions; Humans; Virulence; Virus Replication
PubMed: 25865198
DOI: 10.2217/fmb.15.5 -
Cell May 2019Enterovirus B (EV-B), a major proportion of the genus Enterovirus in the family Picornaviridae, is the causative agent of severe human infectious diseases. Although...
Enterovirus B (EV-B), a major proportion of the genus Enterovirus in the family Picornaviridae, is the causative agent of severe human infectious diseases. Although cellular receptors for coxsackievirus B in EV-B have been identified, receptors mediating virus entry, especially the uncoating process of echovirus and other EV-B remain obscure. Here, we found that human neonatal Fc receptor (FcRn) is the uncoating receptor for major EV-B. FcRn binds to the virus particles in the "canyon" through its FCGRT subunit. By obtaining multiple cryo-electron microscopy structures at different stages of virus entry at atomic or near-atomic resolution, we deciphered the underlying mechanisms of enterovirus attachment and uncoating. These structures revealed that different from the attachment receptor CD55, binding of FcRn to the virions induces efficient release of "pocket factor" under acidic conditions and initiates the conformational changes in viral particle, providing a structural basis for understanding the mechanisms of enterovirus entry.
Topics: Capsid; Cryoelectron Microscopy; Enterovirus; Enterovirus B, Human; Enterovirus Infections; Histocompatibility Antigens Class I; Humans; Models, Molecular; Phylogeny; Receptors, Fc; Virion; Virus Internalization
PubMed: 31104841
DOI: 10.1016/j.cell.2019.04.035 -
Euro Surveillance : Bulletin Europeen... Jun 2023We report nine severe neonatal infections caused by a new variant of echovirus 11. All were male, eight were twins. At illness onset, they were 3-5 days-old and had...
We report nine severe neonatal infections caused by a new variant of echovirus 11. All were male, eight were twins. At illness onset, they were 3-5 days-old and had severe sepsis and liver failure. This new variant, detected in France since April 2022, is still circulating and has caused more fatal neonatal enterovirus infections in 2022 and 2023 (8/496; 1.6%, seven associated with echovirus 11) compared with 2016 to 2021 (7/1,774; 0.4%). National and international alerts are warranted.
Topics: Infant, Newborn; Humans; Male; Female; Echovirus Infections; Enterovirus B, Human; Enterovirus Infections; Enterovirus; Communicable Diseases; France
PubMed: 37261730
DOI: 10.2807/1560-7917.ES.2023.28.22.2300253 -
Virology Journal Jun 2022Echovirus 9 (E9) is associated with a wide variety of diseases and medical conditions, and the clinical symptoms of sporadic cases caused by E9 often are severe. With a...
BACKGROUND
Echovirus 9 (E9) is associated with a wide variety of diseases and medical conditions, and the clinical symptoms of sporadic cases caused by E9 often are severe. With a high global prevalence, E9 has caused multiple outbreaks worldwide. However, little is known about the genetic and geographic population dynamics of E9.
METHOD
A total of 131 VP1 gene sequences, including15 generated in this study and 116 obtained from GenBank, were used to coestimate time-resolved phylogenies to infer viral evolution and transmission in worldwide. Overlapping fragments representing whole genomes were amplified by reverse transcription polymerase chain reaction (RT-PCR) using specific primers. Then, we reported the genetic characteristics of fifteen E9 strains in the Chinese Mainland. Similarity plots and bootscanning analysis were used to determine recombination patterns of E9.
RESULTS
The estimated mean evolutionary rate of global E9 VP1 gene was 4.278 × 10 substitutions per site per year (95% confidence interval [CI], 3.822 × 10/site/year to 4.710 × 10/site/year), and the common ancestor of E9 likely emerged around 1868 (95% CI, 1840 to 1892). The full-length genomic sequences of the fifteen E9 strains showed 76.9-79.6% nucleotide identity and 95.3-95.9% amino acid identity with E9 Barty strain. 11 of 15 E9 whole genome sequence present four recombination patterns, and E9 recombinants have extensive genetic exchanges in the 2C and P3 regions with other Enterovirus B (EV-B) circulated in China. Four of six E9 strains were temperature sensitive, and two were temperature resistant, and a comparative genomics analysis suggested that 411, 865 and 867 amino acid substitution in the P1 region was related to temperature sensitivity.
CONCLUSION
This study highlights a persistent transmission network of E9 in worldwide, provides valuable information regarding the molecular epidemiology of E9.
Topics: China; Echovirus 9; Enterovirus B, Human; Evolution, Molecular; Genome, Viral; Phylogeny; Recombination, Genetic
PubMed: 35659318
DOI: 10.1186/s12985-022-01820-3 -
Frontiers in Immunology 2023Among enteroviruses, echovirus can cause severe illnesses in neonates or infants, with high morbidity and mortality. Autophagy, a central component of host defense...
Among enteroviruses, echovirus can cause severe illnesses in neonates or infants, with high morbidity and mortality. Autophagy, a central component of host defense mechanisms, can function against diverse infections. In the present study, we investigated the interplay between echovirus and autophagy. We demonstrated that echovirus infection increases LC3-II expression dose-dependently, accompanied by an increased intracellular LC3 puncta level. In addition, echovirus infection induces the formation of autophagosome. These results suggest that echovirus infection induces autophagy machinery. Furthermore, phosphorylated mTOR and ULK1 were both decreased upon echovirus infection. In contrast, both levels of the vacuolar protein sorting 34 (VPS34) and Beclin-1, the downstream molecules which play essential roles in promoting the formation of autophagic vesicles, increased upon virus infection. These results imply that the signaling pathways involved in autophagosome formation were activated by echovirus infection. Moreover, induction of autophagy promotes echovirus replication and viral protein VP1 expression, while inhibition of autophagy impairs VP1 expression. Our findings suggest that autophagy can be induced by echovirus infection regulating mTOR/ULK1 signaling pathway and exhibits a proviral function, revealing the potential role of autophagy in echovirus infection.
Topics: Infant; Infant, Newborn; Humans; Enterovirus B, Human; TOR Serine-Threonine Kinases; Signal Transduction; Autophagy; Virus Replication; Echovirus Infections; Autophagy-Related Protein-1 Homolog; Intracellular Signaling Peptides and Proteins
PubMed: 37114059
DOI: 10.3389/fimmu.2023.1162208 -
MBio Aug 2022Virus-receptor interactions determine viral host range and tissue tropism. CD55 and human neonatal Fc receptor (FcRn) were found to be the binding and uncoating...
Virus-receptor interactions determine viral host range and tissue tropism. CD55 and human neonatal Fc receptor (FcRn) were found to be the binding and uncoating receptors for some of the echovirus-related enterovirus species B serotypes in our previous study. Echovirus 18 (E18), as a member of enterovirus species B, is a significant causative agent of aseptic meningitis and viral encephalitis in children. However, it does not use CD55 as a critical host factor. We conducted CRISPR/Cas9 knockout screening to determine the receptors and entry mechanisms and identified FcRn working as a dual-function receptor for E18. Knockout of and , which encode the two subunits of FcRn, prevented infection by E18 and other echoviruses in the same physiological cluster. We then elucidated the underlying molecular mechanism of receptor recognition by E18 using cryogenic electron microscopy. The binding of the FCGRT subunit to the canyon region rotates the residues around the pocket, triggering the release of the pocket factor as observed for other enterovirus species B members. E18 is a member of enterovirus species B. As one of the most common enterovirus serotypes in nonpolio enterovirus detection, it easily infects children and causes various clinical symptoms. Aseptic meningitis and viral encephalitis are the most commonly reported syndromes associated with E18. No effective antiviral drugs or approved vaccines are available. Previous studies showed that CD55 and FcRn were the binding and uncoating receptors for some echoviruses. However, we found that CD55 is not the critical host factor for E18. Thus, we want to determine the receptors and elucidate the entry mechanism of E18. Our findings reveal that FcRn is a two-in-one attachment-uncoating receptor for E18.
Topics: CD55 Antigens; Child; Encephalitis, Viral; Enterovirus; Enterovirus B, Human; Enterovirus Infections; Humans; Infant, Newborn; Meningitis, Aseptic
PubMed: 35862785
DOI: 10.1128/mbio.01166-22 -
Viruses Dec 2015Enterovirus B species (EV-B) are responsible for a vast number of mild and serious acute infections. They are also suspected of remaining in the body, where they cause... (Review)
Review
Enterovirus B species (EV-B) are responsible for a vast number of mild and serious acute infections. They are also suspected of remaining in the body, where they cause persistent infections contributing to chronic diseases such as type I diabetes. Recent studies of the infectious entry pathway of these viruses revealed remarkable similarities, including non-clathrin entry of large endosomes originating from the plasma membrane invaginations. Many cellular factors regulating the efficient entry have recently been associated with macropinocytic uptake, such as Rac1, serine/threonine p21-activated kinase (Pak1), actin, Na/H exchanger, phospholipace C (PLC) and protein kinase Cα (PKCα). Another characteristic feature is the entry of these viruses to neutral endosomes, independence of endosomal acidification and low association with acidic lysosomes. The biogenesis of neutral multivesicular bodies is crucial for their infection, at least for echovirus 1 (E1) and coxsackievirus A9 (CVA9). These pathways are triggered by the virus binding to their receptors on the plasma membrane, and they are not efficiently recycled like other cellular pathways used by circulating receptors. Therefore, the best "markers" of these pathways may be the viruses and often their receptors. A deeper understanding of this pathway and associated endosomes is crucial in elucidating the mechanisms of enterovirus uncoating and genome release from the endosomes to start efficient replication.
Topics: Endocytosis; Endosomes; Enterovirus B, Human; Host-Pathogen Interactions; Virus Attachment; Virus Internalization
PubMed: 26690201
DOI: 10.3390/v7122945 -
Viruses Mar 2022Rigvir is a cell-adapted, oncolytic virotherapy enterovirus, which derives from an echovirus 7 (E7) isolate. While it is claimed that Rigvir causes cytolytic infection...
Rigvir is a cell-adapted, oncolytic virotherapy enterovirus, which derives from an echovirus 7 (E7) isolate. While it is claimed that Rigvir causes cytolytic infection in several cancer cell lines, there is little molecular evidence for its oncolytic and oncotropic potential. Previously, we genome-sequenced Rigvir and five echovirus 7 isolates, and those sequences are further analyzed in this paper. A phylogenetic analysis of the full-length data suggested that Rigvir was most distant from the other E7 isolates used in this study, placing Rigvir in its own clade at the root of the phylogeny. Rigvir contained nine unique mutations in the viral capsid proteins VP1-VP4 across the whole data set, with a structural analysis showing six of the mutations concerning residues with surface exposure on the cytoplasmic side of the viral capsid. One of these mutations, E/Q/N162G, was located in the region that forms the contact interface between decay-accelerating factor (DAF) and E7. Rigvir and five other isolates were also subjected to cell infectivity assays performed on eight different cell lines. The used cell lines contained both cancer and non-cancer cell lines for observing Rigvir's claimed properties of being both oncolytic and oncotropic. Infectivity assays showed that Rigvir had no discernable difference in the viruses' oncolytic effect when compared to the Wallace prototype or the four other E7 isolates. Rigvir was also seen infecting non-cancer cell lines, bringing its claimed effect of being oncotropic into question. Thus, we conclude that Rigvir's claim of being an effective treatment against multiple different cancers is not warranted under the evidence presented here. Bioinformatic analyses do not reveal a clear mechanism that could elucidate Rigvir's function at a molecular level, and cell infectivity tests do not show a discernable difference in either the oncolytic or oncotropic effect between Rigvir and other clinical E7 isolates used in the study.
Topics: DNA Viruses; Enterovirus B, Human; Humans; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Phylogeny; Viruses, Unclassified
PubMed: 35336934
DOI: 10.3390/v14030525 -
Emerging Infectious Diseases Jun 2021In 2018, an upsurge in echovirus 30 (E30) infections was reported in Europe. We conducted a large-scale epidemiologic and evolutionary study of 1,329 E30 strains...
In 2018, an upsurge in echovirus 30 (E30) infections was reported in Europe. We conducted a large-scale epidemiologic and evolutionary study of 1,329 E30 strains collected in 22 countries in Europe during 2016-2018. Most E30 cases affected persons 0-4 years of age (29%) and 25-34 years of age (27%). Sequences were divided into 6 genetic clades (G1-G6). Most (53%) sequences belonged to G1, followed by G6 (23%), G2 (17%), G4 (4%), G3 (0.3%), and G5 (0.2%). Each clade encompassed unique individual recombinant forms; G1 and G4 displayed >2 unique recombinant forms. Rapid turnover of new clades and recombinant forms occurred over time. Clades G1 and G6 dominated in 2018, suggesting the E30 upsurge was caused by emergence of 2 distinct clades circulating in Europe. Investigation into the mechanisms behind the rapid turnover of E30 is crucial for clarifying the epidemiology and evolution of these enterovirus infections.
Topics: Echovirus Infections; Enterovirus B, Human; Enterovirus Infections; Europe; Genotype; Humans; Molecular Epidemiology; Phylogeny; Sequence Analysis, DNA
PubMed: 34013874
DOI: 10.3201/eid2706.203096 -
PloS One 2021Human enteroviruses (EVs) comprise more than 100 types of coxsackievirus, echovirus, poliovirus and numbered enteroviruses, which are mainly transmitted by the...
Human enteroviruses (EVs) comprise more than 100 types of coxsackievirus, echovirus, poliovirus and numbered enteroviruses, which are mainly transmitted by the faecal-oral route leading to diverse diseases such as aseptic meningitis, encephalitis, and acute flaccid paralysis, among others. Since enteroviruses are excreted in faeces, wastewater-based epidemiology approaches are useful to describe EV diversity in a community. In Uruguay, knowledge about enteroviruses is extremely limited. This study assessed the diversity of enteroviruses through Illumina next-generation sequencing of VP1-amplicons obtained by RT-PCR directly applied to viral concentrates of 84 wastewater samples collected in Uruguay during 2011-2012 and 2017-2018. Fifty out of the 84 samples were positive for enteroviruses. There were detected 27 different types belonging to Enterovirus A species (CVA2-A6, A10, A16, EV-A71, A90), Enterovirus B species (CVA9, B1-B5, E1, E6, E11, E14, E21, E30) and Enterovirus C species (CVA1, A13, A19, A22, A24, EV-C99). Enterovirus A71 (EV-A71) and echovirus 30 (E30) strains were studied more in depth through phylogenetic analysis, together with some strains previously detected by us in Argentina. Results unveiled that EV-A71 sub-genogroup C2 circulates in both countries at least since 2011-2012, and that the C1-like emerging variant recently entered in Argentina. We also confirmed the circulation of echovirus 30 genotypes E and F in Argentina, and reported the detection of genotype E in Uruguay. To the best of our knowledge this is the first report of the EV-A71 C1-like emerging variant in South-America, and the first report of EV-A71 and E30 in Uruguay.
Topics: Capsid Proteins; Enterovirus A, Human; Enterovirus B, Human; Enterovirus C, Human; Genetic Linkage; Genotype; Humans; Phylogeny; RNA, Viral; Seasons; South America; Uruguay; Wastewater
PubMed: 34383835
DOI: 10.1371/journal.pone.0255846