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1
Romanenkova, N. I., N. R. Rozaeva, M. A. Bichurina, O. I. Kanaeva, I. G. Chkhyndzheriya, L. V. Shishkina, A. G. Madoyan, and N. V. Valdaitseva. "Epidemiological aspects of enterovirus infection in the Russian Federation during the period of 2018–2019." Journal Infectology 13, no. 1 (March 30, 2021): 108–16. http://dx.doi.org/10.22625/2072-6732-2021-13-1-108-116.
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Aim: Analysis of enterovirus infection morbidity and characteristics of the etiological agents of this infection on some territories of Russia in 2017.Materials and methods: We investigated 7858 samples of the biological material from the patients suffering from enterovirus infection. The isolation and identification of enteroviruses were conducted by virological and molecular methods.Results: The epidemic process and the clinical picture of enterovirus infection on different territories had some peculiarities. On some territories enterovirus meningitis was the predominant form of infection, on other territories enterovirus infection with exanthema prevailed. In Saint-Petersburg, Archangel and Saratov regions the percentage of enterovirus infection cases with the clinical picture of enterovirus meningitis was significantly higher than the percentage of enterovirus infection with exanthema. In the Komi Republic, Leningrad and Murmansk regions the percentage of infection with exanthema was statistically higher than the enterovirus meningitis portion. Enteroviruses of 30 serotypes were detected in the samples of patients suffering from enterovirus infection. We determined the etiology of sporadic and epidemic cases of enterovirus infection represented by different clinical forms. On some territories the epidemic foci of enterovirus infection among children were revealed. The etiological agents of enterovirus meningitis foci in Saint-Petersburg, Murmansk and Saratov regions were Coxsackievirus B5, Coxsackievirus B4 and Echovirus 30. The foci of enterovirus infection with exanthema in Archangel, Leningrad, Murmansk and Novgorod regions were caused by Coxsackieviruses A10, A16 and A6.Conclusion: The clinical forms of enterovirus infection on some territories were provoked by enteroviruses which dominated in the circulation on one or other territory. Enteroviruses of species B, mainly Echovirus 30, Echovirus 6 and Coxsackieviruses B1–6 were the etiological agents of enterovirus meningitis. The etiological factors of enterovirus infection with exanthema were Enteroviruses of species A, mainly Coxsackieviruses of different serotypes as well as Enterovirus 71.
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Paklonskaya, N. V., T. V. Amvrosieva, Y. A. Shilova, and E. P. Kishkurno. "Molecular epydemiology of enterovirus infection in the Republic of Belarus in 2016–2017." Proceedings of the National Academy of Sciences of Belarus, Medical series 16, no. 3 (September 16, 2019): 339–48. http://dx.doi.org/10.29235/1814-6023-2019-16-3-339-348.
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Enteroviruses are widespread human pathogens characterized by a high level of a genetic diversity. They cause different clinical forms of infection. The aim of the present study was to analyze the molecular epidemiology of enterovirus infection in the application to the structure of its clinical forms in 2016–2017.ECHO viruses predominated among patients with aseptic meningitis and were prevailing group of enteroviruses in 2016 (all ECHO viruses – 58%, including ECHO 9 – 26%, ECHO 6 –14%, ECHO 16 – 10%). In 2017, Coxsackieviruses prevailed (68%), that were including Coxsackievirus B5 (31%), Coxsackievirus B1, Coxsackievirus B4 and Coxsackievirus A6 (9% of each serotype). Coxsackieviruses were detected more frequently in patients with vesicular pharyngitis and unspecified enterovirus infection. The results of the molecular epidemiological analysis indicated that the prevalence of ECHO viruses in 2016 and Coxsackieviruses B in 2017 was due to the emergence of numerous new genovariants of these viruses.
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Romanenkova, N. I., L. N. Golitsyna, M. A. Bichurina, N. R. Rozaeva, O. I. Kanaeva, V. V. Zverev, D. V. Sozonov, et al. "Enterovirus infection morbidity and peculiarities of nonpolio enteroviruses circulation on some territories of Russia in 2017." Journal Infectology 10, no. 4 (December 30, 2018): 124–33. http://dx.doi.org/10.22625/2072-6732-2018-10-4-124-133.
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Aim: Characteristics of enterovirus infection morbidity and study of peculiarities of enterovirus circulation on some territories of Russia in 2017. Materials and methods: We investigated more than 5000 samples from the patients with enterovirus infection. The isolation and identification of enteroviruses were conducted by virological method and by partial sequencing of the genome region VP1. Phylogenic trees were constructed according to the method of Bayesian Monte Carlo Markov Chain. Results: Epidemic process and clinical picture of enterovirus infection were not the same on different territories. Peculiarities of the circulation of different types of enteroviruses on the territories were also different. In Saratov region 65% of cases were represented by enterovirus meningitis. In Murmansk region and in the Komi Republic enterovirus infection with exanthema prevailed, 95% and 60% correspondingly. In Saratov region enterovirus ECHO18 was the etiological agent of enterovirus meningitis. In Murmansk region and in the Komi Republic the cases were connected mainly with Coxsackieviruses A6. The strains of enterovirus ECHO18 were distributed to three clusters. The strains which provoked enterovirus meningitis in Saratov region belonged to cluster 3, they were formed separately from other strains of this enterovirus type and differed from the stains of ECHO18 which circulated in the North-West of Russia. The strains of Coxsackieviruses A6 identified in the North-West of Russia belonged to three sub-genotypes 5, 6, 8 of pandemic genotype of CoxsackievirusesA6. The majority of the strains belonged to sub-genotypes 6 and 8 which in 2017 dominated in the structure of Coxsackieviruses A6 in the North-West of Russia and in Russia. Conclusion: Epidemic peaks of enterovirus infection represented by different clinical forms of the disease were provoked by different types of enteroviruses. Enterovirus ECHO18 was the etiological agent of enterovirus meningitis. The main etiological factors of enterovirus infection with exanthema were Coxsackieviruses A6 of different sub-genotypes.
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Richter, Jan, Dana Koptides, Christina Tryfonos, and Christina Christodoulou. "Molecular typing of enteroviruses associated with viral meningitis in Cyprus, 2000–2002." Journal of Medical Microbiology 55, no. 8 (August 1, 2006): 1035–41. http://dx.doi.org/10.1099/jmm.0.46447-0.
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Human enteroviruses are responsible for a wide spectrum of clinical diseases affecting many different organ systems. Although infection is usually asymptomatic, infections of the central nervous system manifested as meningitis or encephalitis can pose a serious public health problem, especially during outbreaks. In this study, samples from 218 patients diagnosed with enteroviral meningitis between January 2000 and December 2002 were analysed in order to assess the epidemiology of human enteroviruses as a cause of viral meningitis in Cyprus. A new typing strategy, based on partial sequencing of the 5′ non-coding region (5′NCR), prediction of type, and selection of type-specific primers for sensitive VP1 PCR amplification, was developed. As clustering in the 5′NCR was concordant with clustering in the VP1 region, quick and reliable typing by VP1 sequencing was achieved without virus isolation in cell culture. The most frequent enterovirus serotypes identified were Human echovirus 30 (55.5 %), Human echovirus 13 (15.1 %), Human echovirus 6 (13.8 %) and Human echovirus 9 (8.3 %). Human coxsackieviruses B2, B1 and B5, Human echovirus 4, Human enterovirus 71 and Human coxsackievirus A6 represented rather rare serotypes. This is the first molecular epidemiological study of enterovirus meningitis in Cyprus. Serotype distribution corresponded basically with observations in other European countries, suggesting the spread of enteroviruses by tourism.
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Rigonan, Alma S., Linda Mann, and Tasnee Chonmaitree. "Use of Monoclonal Antibodies To Identify Serotypes of Enterovirus Isolates." Journal of Clinical Microbiology 36, no. 7 (1998): 1877–81. http://dx.doi.org/10.1128/jcm.36.7.1877-1881.1998.
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Nonpoliovirus enteroviruses cause a variety of diseases that are common in young children and adults. The “gold standard” for laboratory diagnosis of enteroviruses is cell culture isolation, followed by serotype identification by neutralization assay. These procedures are time-consuming and expensive. Rapid serotype identification of enteroviruses is important in differentiating nonpoliovirus enterovirus pathogens from vaccine strain polioviruses that can be shed for some time after vaccination. In the present investigation, we evaluated a rapid method for serotype identification of enteroviruses by indirect immunofluorescence assay (IFA) using commercially available monoclonal antibodies for polioviruses, coxsackieviruses type B, and six serotypes of commonly circulating echoviruses. Of 291 isolates of enteroviruses included in the study, 95 were polioviruses and 196 were nonpoliovirus enteroviruses. Two hundred thirty-four of these (38 polioviruses and 196 nonpoliovirus enteroviruses) were consecutively grown in the laboratory over a 5-year period. IFA identified the serotypes of 74% of the consecutive isolates and 71% of all enterovirus isolates by yielding a positive staining result. The levels of agreement in the identification of the enterovirus group between IFA and neutralization tests were 92% for consecutively grown isolates and 85% for all enterovirus isolates. The sensitivity of the IFA for the detection of viruses for which specific monoclonal antibodies were applied was 73% for polioviruses, 85% for coxsackieviruses type B, and 94% for echoviruses. Specificity was near 100% for polioviruses and coxsackieviruses type B and 94% for echoviruses. We conclude that IFA can be helpful as a preliminary test for serotype identification of enteroviruses. The results are most accurate when the test identifies the isolate as a poliovirus.
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Wells, Alexandra I., and Carolyn B. Coyne. "Enteroviruses: A Gut-Wrenching Game of Entry, Detection, and Evasion." Viruses 11, no. 5 (May 21, 2019): 460. http://dx.doi.org/10.3390/v11050460.
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Enteroviruses are a major source of human disease, particularly in neonates and young children where infections can range from acute, self-limited febrile illness to meningitis, endocarditis, hepatitis, and acute flaccid myelitis. The enterovirus genus includes poliovirus, coxsackieviruses, echoviruses, enterovirus 71, and enterovirus D68. Enteroviruses primarily infect by the fecal–oral route and target the gastrointestinal epithelium early during their life cycles. In addition, spread via the respiratory tract is possible and some enteroviruses such as enterovirus D68 are preferentially spread via this route. Once internalized, enteroviruses are detected by intracellular proteins that recognize common viral features and trigger antiviral innate immune signaling. However, co-evolution of enteroviruses with humans has allowed them to develop strategies to evade detection or disrupt signaling. In this review, we will discuss how enteroviruses infect the gastrointestinal tract, the mechanisms by which cells detect enterovirus infections, and the strategies enteroviruses use to escape this detection.
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Weinzierl, Andreas O., Despina Rudolf, Dominik Maurer, Dorothee Wernet, Hans-Georg Rammensee, Stefan Stevanović, and Karin Klingel. "Identification of HLA-A*01- and HLA-A*02-restricted CD8+ T-cell epitopes shared among group B enteroviruses." Journal of General Virology 89, no. 9 (September 1, 2008): 2090–97. http://dx.doi.org/10.1099/vir.0.2008/000711-0.
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Acute enteroviral infections ranging from meningitis, pancreatitis to myocarditis are common and normally well controlled by the host immune system comprising virus-specific CD8+ cytotoxic T lymphocytes (CTL). However, in some patients enteroviruses and especially coxsackieviruses of group B are capable of inducing severe chronic forms of diseases such as chronic myocarditis. Currently, it is not known whether divergences in the CTL-related immune response may contribute to the different outcome and course of enterovirus myocarditis. A pre-requisite for the study of CTL reactions in patients with acute and chronic myocarditis is the identification of CTL epitopes. In order to define dominant enterovirus CTL epitopes, we have screened, by using gamma interferon (IFN-γ) ELISPOT, 62 HLA-A*01- and 59 HLA-A*02-positive healthy blood donors for pre-existing CTL reactions against 12 HLA-A*01 and 20 HLA-A*02 predicted CTL epitopes derived from coxsackieviruses of group B. Positive CTL reactions were verified by FACS analysis in a combined major histocompatibility complex-tetramer IFN-γ staining. A total of 14.8 % of all donors reacted against one of the three identified epitopes MLDGHLIAFDY, YGDDVIASY or GIIYIIYKL. The HLA-A*02-restricted epitope ILMNDQEVGV was recognized by 25 % of all tested blood donors. For this peptide, we could demonstrate specific granzyme B secretion, a strong cytolytic potential and endogenous processing. All four epitopes were homologous in 36–92 % of group B enteroviruses, providing a strong basis for monitoring the divergence of T-cell-based immune responses in enterovirus-induced acute and chronic diseases.
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Lukashev, Alexander N., Elena Yu Shumilina, Ilya S. Belalov, Olga E. Ivanova, Tatiana P. Eremeeva, Vadim I. Reznik, O. E. Trotsenko, Jan Felix Drexler, and Christian Drosten. "Recombination strategies and evolutionary dynamics of the Human enterovirus A global gene pool." Journal of General Virology 95, no. 4 (April 1, 2014): 868–73. http://dx.doi.org/10.1099/vir.0.060004-0.
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We analysed natural recombination in 79 Human enterovirus A strains representing 13 serotypes by sequencing of VP1, 2C and 3D genome regions. The half-life of a non-recombinant tree node in coxsackieviruses 2, 4 and 10 was only 3.5 years, and never more than 9 years. All coxsackieviruses that differed by more than 7 % of the nucleotide sequence in any genome region were recombinants relative to each other. Enterovirus 71 (EV71), on the contrary, displayed remarkable genetic stability. Three major EV71 clades were stable for 19–29 years, with a half-life of non-recombinant viruses between 13 and 18.5 years in different clades. Only five EV71 strains out of over 150 recently acquired non-structural genome regions from coxsackieviruses, while none of 80 contemporary coxsackieviruses had non-structural genes transferred from the three EV71 clades. In contrast to earlier observations, recombination between VP1 and 2C genome regions was not more frequent than between 2C and 3D regions.
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Duijsings, Daniël, Els Wessels, Sjenet E. van Emst-de Vries, Willem J. G. Melchers, Peter H. G. M. Willems, and Frank J. M. van Kuppeveld. "Reduction of phospholipase D activity during coxsackievirus infection." Journal of General Virology 88, no. 11 (November 1, 2007): 3027–30. http://dx.doi.org/10.1099/vir.0.83169-0.
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During enterovirus infection, host cell membranes are rigorously rearranged and modified. One ubiquitously expressed lipid-modifying enzyme that might contribute to these alterations is phospholipase D (PLD). Here, we investigated PLD activity in coxsackievirus-infected cells. We show that PLD activity is not required for efficient coxsackievirus RNA replication. Instead, PLD activity rapidly decreased upon infection and upon ectopic expression of the viral 3A protein, which inhibits the PLD activator ADP-ribosylation factor 1. However, similar decreases were observed during infection with coxsackieviruses carrying defective mutant 3A proteins. Possible causes for the reduction of PLD activity and the biological consequences are discussed.
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Pons-Salort, Margarita, and Nicholas C. Grassly. "Serotype-specific immunity explains the incidence of diseases caused by human enteroviruses." Science 361, no. 6404 (August 23, 2018): 800–803. http://dx.doi.org/10.1126/science.aat6777.
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Human enteroviruses are a major cause of neurological and other diseases. More than 100 serotypes are known that exhibit unexplained complex patterns of incidence, from regular cycles to more irregular patterns, and new emergences. Using 15 years of surveillance data from Japan (2000–2014) and a stochastic transmission model with accurate demography, we show that acquired serotype-specific immunity can explain the diverse patterns of 18 of the 20 most common serotypes (including Coxsackieviruses, Echoviruses, and Enterovirus-A71). The remaining two serotypes required a change in viral characteristics, including an increase in pathogenicity for Coxsackievirus-A6, which is consistent with its recent global rise in incidence. On the basis of our findings, we are able to predict outbreaks 2 years ahead of time (2015–2016). These results have implications for the impact of vaccines under development.
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Oberste, M. Steven, Kaija Maher, and Mark A. Pallansch. "Evidence for Frequent Recombination within Species Human Enterovirus B Based on Complete Genomic Sequences of All Thirty-Seven Serotypes." Journal of Virology 78, no. 2 (January 15, 2004): 855–67. http://dx.doi.org/10.1128/jvi.78.2.855-867.2004.
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ABSTRACT The species Human enterovirus B (HEV-B) in the family Picornaviridae consists of coxsackievirus A9; coxsackieviruses B1 to B6; echoviruses 1 to 7, 9, 11 to 21, 24 to 27, and 29 to 33; and enteroviruses 69 and 73. We have determined complete genome sequences for the remaining 22 HEV-B serotypes whose sequences were not represented in public databases and analyzed these in conjunction with previously available complete sequences in GenBank. Members of HEV-B were monophyletic relative to all other human enterovirus species in all regions of the genome except in the 5′-nontranslated region (NTR), where they are known to cluster with members of HEV-A. Within HEV-B, phylogenies constructed from the structural (P1) and nonstructural regions of the genome (P2 and P3) are incongruent, suggesting that recombination had occurred. Similarity plots and bootscanning analysis across the complete genome identified multiple sites at which the phylogeny of a given strain's sequence shifted, indicating potential recombination points. These points are distributed in the 5′-NTR and throughout P2 and P3, but no sites with >80% bootstrap support were identified within the capsid. Individual sequence comparisons and phylogenetic analyses suggest that members of HEV-B have recombined with one another on multiple occasions, resulting in a complex mosaic of sequences derived from multiple parental viruses in the nonstructural regions of the genome. We conclude that RNA recombination is a common mechanism for enterovirus evolution and that recombination within the nonstructural regions of the genome (P2 and P3) has been observed only among members of the same species.
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Merilahti, Pirjo, Satu Koskinen, Outi Heikkilä, Eveliina Karelehto, and Petri Susi. "Endocytosis of Integrin-Binding Human Picornaviruses." Advances in Virology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/547530.
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Picornaviruses that infect humans form one of the largest virus groups with almost three hundred virus types. They include significant enteroviral pathogens such as rhino-, polio-, echo-, and coxsackieviruses and human parechoviruses that cause wide range of disease symptoms. Despite the economic importance of picornaviruses, there are no antivirals. More than ten cellular receptors are known to participate in picornavirus infection, but experimental evidence of their role in cellular infection has been shown for only about twenty picornavirus types. Three enterovirus types and one parechovirus have experimentally been shown to bind and use integrin receptors in cellular infection. These include coxsackievirus A9 (CV-A9), echovirus 9, and human parechovirus 1 that are among the most common and epidemic human picornaviruses and bind toαV-integrins via RGD motif that resides on virus capsid. In contrast, echovirus 1 (E-1) has no RGD and uses integrinα2β1 as cellular receptor. Endocytosis of CV-A9 has recently been shown to occur via a novel Arf6- and dynamin-dependent pathways, while, contrary to collagen binding, E-1 binds inactiveβ1 integrin and enters via macropinocytosis. In this paper, we review what is known about receptors and endocytosis of integrin-binding human picornaviruses.
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Thammasonthijarern, Nipa, Nathamon Kosoltanapiwat, Warisa Nuprasert, Pichamon Sittikul, Pimolpachr Sriburin, Wirichada Pan-ngum, Pannamas Maneekan, et al. "Molecular Epidemiological Study of Hand, Foot, and Mouth Disease in a Kindergarten-Based Setting in Bangkok, Thailand." Pathogens 10, no. 5 (May 10, 2021): 576. http://dx.doi.org/10.3390/pathogens10050576.
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Hand, foot, and mouth disease (HFMD) is a contagious childhood illness and annually affects millions of children aged less than 5 years across the Asia–Pacific region. HFMD transmission mainly occurs through direct contact (person-to-person) and indirect contact with contaminated surfaces and objects. Therefore, public health measures to reduce the spread of HFMD in kindergartens and daycare centers are essential. Based on the guidelines by the Department of Disease Control, a school closure policy for HFMD outbreaks wherein every school in Thailand must close when several HFMD classrooms (more than two cases in each classroom) are encountered within a week, was implemented, although without strong supporting evidence. We therefore conducted a prospective cohort study of children attending five kindergartens during 2019 and 2020. We used molecular genetic techniques to investigate the characteristics of the spreading patterns of HFMD in a school-based setting in Bangkok, Thailand. These analyses identified 22 index cases of HFMD (symptomatic infections) and 25 cases of enterovirus-positive asymptomatic contacts (24 students and one teacher). Enterovirus (EV) A71 was the most common enterovirus detected, and most of the infected persons (8/12) developed symptoms. Other enteroviruses included coxsackieviruses (CVs) A4, CV-A6, CV-A9, and CV-A10 as well as echovirus. The pattern of the spread of HFMD showed that 45% of the subsequent enteroviruses detected in each outbreak possessed the same serotype as the first index case. Moreover, we found a phylogenetic relationship among enteroviruses detected among contact and index cases in the same kindergarten. These findings confirm the benefit of molecular genetic assays to acquire accurate data to support school closure policies designed to control HFMD infections.
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Kim, Sung Soo. "A Case of Onychomadesis after Recovering from Hand-Foot-Mouth Disease." Soonchunhyang Medical Science 27, no. 1 (June 30, 2021): 42–44. http://dx.doi.org/10.15746/sms.21.011.
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Onychomadesis is characterized by proximal nail plate separation from the nail matrix and nail bed. It has been associated with autoimmune disease, medications, severe systemic diseases, trauma, periungual dermatitis, nutritional deficiency, and infection. Hand-foot-mouth disease is most frequently caused by coxsackievirus A16 and is associated with a number of other coxsackieviruses and enterovirus 71. It particularly affects children under 5 years of age and is characterized by vesicular eruptions on the hands, feet, and buttocks and ulcerations of the tongue, soft palate, buccal mucosa, or gingiva. Onychomadesis after recovering from hand-foot-mouth disease is a rare and late complication. It occurs several weeks after the onset of hand-foot-mouth disease. The mechanism is still unknown. Generally, there is no need for treatment and there is spontaneous resolution within 1 to 2 months.
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Reshma Thirunavakarasu, Dhanraj Ganapathy, and Subhashree Rohinikumar. "Awareness Of Herpangina And Its Management Among Dental Students." International Journal of Research in Pharmaceutical Sciences 11, SPL3 (October 7, 2020): 1060–64. http://dx.doi.org/10.26452/ijrps.v11ispl3.3335.
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Herpangina or otherwise known as hand-foot and mouth disease is caused by enteroviral infection and are two common related clinical syndromes. These diseases are mostly seen in the paediatric population. It is occasionally seen among adult patients. Herpangina is caused by one particular strain of coxsackievirus A and Enterovirus -A71. The aim of the study was to determine if dental students are aware of the various managements done for herpangina.A survey with nine close-ended questions and three multiple-choice questions were formed and distributed to 100 dental students, respectively. Their responses will determine the level of awareness of students regarding the management of herpangina. The questions elicited awareness on the various aspects of Herpangina disease among dental students. These responses to these questions were tabulated and analysed. 55% of the respondents said Herpangina affected people aged between 3-10yrs . 75% respondents said Herpangina is caused by Group A coxsackieviruses followed by 20% said Streptococcusand 5% said Staphylococcus are responsible. 83% of respondent prescribed antivirals, followed by analgesics 15% and 2% used antibiotics to treat Herpangina. The awareness about the management strategies of Herpangina among dental students was moderate. Awareness of dental students can always be enhanced by promoting more educational programmes regarding various diseases such as herpangina. It is important as they will play an important role in delivering better health care in the future.
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Gullberg, Maria, Conny Tolf, Nina Jonsson, Charlotta Polacek, Jana Precechtelova, Miriam Badurova, Martin Sojka, et al. "A Single Coxsackievirus B2 Capsid Residue Controls Cytolysis and Apoptosis in Rhabdomyosarcoma Cells." Journal of Virology 84, no. 12 (April 7, 2010): 5868–79. http://dx.doi.org/10.1128/jvi.02383-09.
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ABSTRACT Coxsackievirus B2 (CVB2), one of six human pathogens of the group B coxsackieviruses within the enterovirus genus of Picornaviridae, causes a wide spectrum of human diseases ranging from mild upper respiratory illnesses to myocarditis and meningitis. The CVB2 prototype strain Ohio-1 (CVB2O) was originally isolated from a patient with summer grippe in the 1950s. Later on, CVB2O was adapted to cytolytic replication in rhabdomyosarcoma (RD) cells. Here, we present analyses of the correlation between the adaptive mutations of this RD variant and the cytolytic infection in RD cells. Using reverse genetics, we identified a single amino acid change within the exposed region of the VP1 protein (glutamine to lysine at position 164) as the determinant for the acquired cytolytic trait. Moreover, this cytolytic virus induced apoptosis, including caspase activation and DNA degradation, in RD cells. These findings contribute to our understanding of the host cell adaptation process of CVB2O and provide a valuable tool for further studies of virus-host interactions.
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Gangaplara, Arunakumar, Chandirasegaran Massilamany, Ninaad Lasrado, David Steffen, and Jay Reddy. "Evidence for Anti-Viral Effects of Complete Freund’s Adjuvant in the Mouse Model of Enterovirus Infection." Vaccines 8, no. 3 (July 7, 2020): 364. http://dx.doi.org/10.3390/vaccines8030364.
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Group B coxsackieviruses (CVBs) belonging to the genus, Enterovirus and contain six serotypes that induce various diseases, whose occurrence may involve the mediation of more than one serotype. We recently identified immunogenic epitopes within coxsackieviruses B3 (CVB3) viral protein 1 that induce anti-viral T cell responses in mouse models of CVB infections. In our investigations to determine the protective responses of the viral epitopes, we unexpectedly noted that animals immunized with complete Freund’s adjuvant (CFA) alone and later challenged with CVB3 were completely protected against myocarditis. Similarly, the pancreatitis-inducing ability of CVB3 was remarkably reduced to only 10% in the CFA group as opposed to 73.3% in the control group that received no CFA. Additionally, no mortalities were noted in the CFA group, whereas 40% of control animals died during the course of 21 days post-infection with CVB3. Taken together, our data suggest that the adjuvant effects of CFA may be sufficient for protection against CVB infections. These observations may provide new insights into our understanding of the occurrence of viral infections.
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ANGEZ, M., S. SHAUKAT, R. ZAHRA, M. M. ALAM, S. SHARIF, A. KHURSHID, Y. ARSHAD, M. SULEMAN, G. MUJTABA, and S. S. Z. ZAIDI. "Characterization of group B coxsackieviruses isolated from non-polio acute flaccid paralysis patients in Pakistan: vital assessment before polio eradication." Epidemiology and Infection 145, no. 12 (July 25, 2017): 2473–81. http://dx.doi.org/10.1017/s0950268817001522.
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SummaryPakistan is at the verge of polio eradication but isolation of non-polio enteroviruses (NPEVs) from acute flaccid paralysis (AFP) cases may result in serious or even fatal outcome. Many enteroviruses share similar symptoms and epidemiology as is the case with poliovirus and coxsackievirus (CV). The present study was designed to genetically characterize coxsackievirus B (CV-B) serotypes isolated from non-polio acute flaccid paralytic children, as well as to understand their probable role in paralysis. A total of 63 (20·1%) out of 313 stool samples during 2013 were found positive for NPEVs in rhabdomyosarcoma cells. Only 24 (38·0%) NPEVs were typed as CV-B by microneutralization assay and were further characterized by sequencing of the viral protein 1 (VP1) gene. Molecular phylogenetic analyses classified the study strains into six coxsackievirus B serotypes (coxsackievirus B1 to B6) with their respective prototype strains with evidence of epidemiological linkage and distinct clusters. Moreover, four major differences were found within the amino acid sequences of BC-loop in VP1 of CV-B strains. In conclusion, this study presented the molecular evolutionary genetic overview and distinct phylogenetic pattern of CV-B isolates from AFP cases in Pakistan, and explored the possible link between CV-B infections and AFP cases. Furthermore, our data reveal that these viruses might contribute to the incidence of paralysis in population and there is need of time to establish an enterovirus surveillance system for better understanding of epidemiological and virological characteristics of NPEV infections associated with AFP cases in the country.
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TRALLERO, G., I. CASAS, A. TENORIO, J. E. ECHEVARRIA, A. CASTELLANOS, A. LOZANO, and P. P. BREÑA. "Enteroviruses in Spain: virological and epidemiological studies over 10 years (1988–97)." Epidemiology and Infection 124, no. 3 (June 2000): 497–506. http://dx.doi.org/10.1017/s0950268899003726.
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A total of 15662 clinical samples were analysed for enterovirus (EV) isolation in cell cultures during a 10-year period (1988–97). Furthermore, 210 isolates of EV obtained in primary laboratories within Spain from patients with meningitis were characterized. The total number of EV typed was 758, including 727 non-polio EV and 31 Sabin-like (SL) polioviruses. Twenty-eight EV serotypes were represented. Echoviruses comprised 90% (653/727) of fully typed non-polio EV. The four most prevalent serotypes were echovirus 30, echovirus 9, echovirus 6 and echovirus 4. Echovirus 30 was the main serotype associated with meningitis. Echovirus 9 was the aetiological agent in 20 outbreaks of meningitis while the occurrence of echovirus 6 was localized in 1 year (1997). Coxsackieviruses A and B occurred in 3 and 7% of the non-polio EV respectively. Coxsackievirus B5 presented the relative greater abundance. This paper examines the epidemiology of EV in Spain to serotype level over a 10-year period with special attention to non-polio EV associated with meningitis.
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Tokarz, Rafal, Saddef Haq, Stephen Sameroff, Stephen R. C. Howie, and W. Ian Lipkin. "Genomic analysis of coxsackieviruses A1, A19, A22, enteroviruses 113 and 104: viruses representing two clades with distinct tropism within enterovirus C." Journal of General Virology 94, no. 9 (September 1, 2013): 1995–2004. http://dx.doi.org/10.1099/vir.0.053462-0.
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Coxsackieviruses (CV) A1, CV-A19 and CV-A22 have historically comprised a distinct phylogenetic clade within Enterovirus (EV) C. Several novel serotypes that are genetically similar to these three viruses have been recently discovered and characterized. Here, we report the coding sequence analysis of two genotypes of a previously uncharacterized serotype EV-C113 from Bangladesh and demonstrate that it is most similar to CV-A22 and EV-C116 within the capsid region. We sequenced novel genotypes of CV-A1, CV-A19 and CV-A22 from Bangladesh and observed a high rate of recombination within this group. We also report genomic analysis of the rarely reported EV-C104 circulating in the Gambia in 2009. All available EV-C104 sequences displayed a high degree of similarity within the structural genes but formed two clusters within the non-structural genes. One cluster included the recently reported EV-C117, suggesting an ancestral recombination between these two serotypes. Phylogenetic analysis of all available complete genome sequences indicated the existence of two subgroups within this distinct Enterovirus C clade: one has been exclusively recovered from gastrointestinal samples, while the other cluster has been implicated in respiratory disease.
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Amona, Inestin, Hacène Medkour, Jean Akiana, Bernard Davoust, Mamadou Lamine Tall, Clio Grimaldier, Celine Gazin, et al. "Enteroviruses from Humans and Great Apes in the Republic of Congo: Recombination within Enterovirus C Serotypes." Microorganisms 8, no. 11 (November 13, 2020): 1779. http://dx.doi.org/10.3390/microorganisms8111779.
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Enteroviruses (EVs) are viruses of the family Picornaviridae that cause mild to severe infections in humans and in several animal species, including non-human primates (NHPs). We conducted a survey and characterization of enteroviruses circulating between humans and great apes in the Congo. Fecal samples (N = 24) of gorillas and chimpanzees living close to or distant from humans in three Congolese parks were collected, as well as from healthy humans (N = 38) living around and within these parks. Enteroviruses were detected in 29.4% of gorilla and 13.15% of human feces, including wild and human-habituated gorillas, local humans and eco-guards. Two identical strains were isolated from two humans coming from two remote regions. Their genomes were similar and all genes showed their close similarity to coxsackieviruses, except for the 3C, 3D and 5′-UTR regions, where they were most similar to poliovirus 1 and 2, suggesting recombination. Recombination events were found between these strains, poliovirus 1 and 2 and EV-C99. It is possible that the same EV-C species circulated in both humans and apes in different regions in the Congo, which must be confirmed in other investigations. In addition, other studies are needed to further investigate the circulation and genetic diversity of enteroviruses in the great ape population, to draw a definitive conclusion on the different species and types of enteroviruses circulating in the Republic of Congo.
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HE, S. Z., M. Y. CHEN, X. R. XU, Q. YAN, J. J. NIU, W. H. WU, X. S. SU, S. X. GE, S. Y. ZHANG, and N. S. XIA. "Epidemics and aetiology of hand, foot and mouth disease in Xiamen, China, from 2008 to 2015." Epidemiology and Infection 145, no. 9 (April 3, 2017): 1865–74. http://dx.doi.org/10.1017/s0950268817000309.
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SUMMARYOver the past 8 years, human enteroviruses (HEVs) have caused 27 227 cases of hand, foot and mouth disease (HFMD) in Xiamen, including 99 severe cases and six deaths. We aimed to explore the molecular epidemiology of HFMD in Xiamen to inform the development of diagnostic assays, vaccines and other interventions. From January 2009 to September 2015, 5866 samples from sentinel hospitals were tested using nested reverse transcription PCR that targeted the HEV 5′ untranslated region and viral protein 1 region. Of these samples, 4290 were tested positive for HEV and the amplicons were sequenced and genotyped. Twenty-two genotypes were identified. Enterovirus 71 (EV71) and coxsackieviruses A16, A6 and A10 (CA16, CA6 and CA10) were the most common genotypes, and there were no changes in the predominant lineages of these genotypes. EV71 became the most predominant genotype every 2 years. From 2013, CA6 replaced CA16 as one of the two most common genotypes. The results demonstrate the vast diversity of HFMD pathogens, and that minor genotypes are able to replace major genotypes. We recommend carrying-out long-term monitoring of the full spectrum of HFMD pathogens, which could facilitate epidemic prediction and the development of diagnostic assays and vaccines.
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Oberste, M. Steven, Silvia Peñaranda, Kaija Maher, and Mark A. Pallansch. "Complete genome sequences of all members of the species Human enterovirus A." Journal of General Virology 85, no. 6 (June 1, 2004): 1597–607. http://dx.doi.org/10.1099/vir.0.79789-0.
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The species Human enterovirus A (HEV-A) in the family Picornaviridae consists of coxsackieviruses (CV) A2–A8, A10, A12, A14 and A16 and enterovirus 71. Complete genome sequences for the prototype strains of the 10 serotypes whose sequences were not represented in public databases have been determined and analysed in conjunction with previously available complete sequences in GenBank. Members of HEV-A are monophyletic relative to all other human enterovirus species in all regions of the genome except in the 5′ non-translated region (NTR), where they are known to cluster with members of HEV-B. The HEV-A prototype strains were about 66 to 86 % identical to one another in deduced capsid amino acid sequence. Antigenic cross-reactivity has been reported between CVA3-Olson and CVA8-Donovan, between CVA5-Swartz and CVA12-Texas-12 and between CVA16-G-10 and EV71-BrCr. Similarity plots, individual sequence comparisons and phylogenetic analyses demonstrate a high degree of capsid sequence similarity within each of these three pairs of prototype strains, providing a molecular basis for the observed antigenic relationships. In several cases, phylogenies constructed from the structural (P1) and non-structural regions of the genome (P2 and P3) are incongruent. The incongruent phylogenies and the similarity plot analyses imply that recombination has played a role in the evolution of the HEV-A prototype strains. CVA6-Gdula clearly contains sequences that are also present in CVA10-Kowalik and CVA12-Texas-12, suggesting that these three strains have a shared evolutionary history despite their lack of similarity in the capsid region.
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Toczylowski, Kacper, Magdalena Wieczorek, Ewa Bojkiewicz, Magdalena Wietlicka-Piszcz, Beata Gad, and Artur Sulik. "Pediatric Enteroviral Central Nervous System Infections in Bialystok, Poland: Epidemiology, Viral Types, and Drivers of Seasonal Variation." Viruses 12, no. 8 (August 15, 2020): 893. http://dx.doi.org/10.3390/v12080893.
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Enteroviruses are common causes of infections of the central nervous system (CNS) that in temperate climates tend to peak in the summer. The aim of the study was to describe epidemiology, drivers of seasonality, and types of enteroviruses causing infections of the CNS in children in Northeastern Poland. We prospectively collected data on children hospitalized with infection of the CNS attributed to enteroviruses in Bialystok, Poland, from January 2015 to December 2019. In total, 224 children were included. Nineteen different enterovirus types were identified in isolates collected from 188 children. Coxsackie B5 (32%), echovirus 30 (20%), and echovirus 6 (14%) were the three most common types. Enteroviruses were more prevalent during the summer–fall season. Infections caused by echovirus 30 peaked early in June and coxsackievirus B5 in July, whereas echovirus 6 peaked late in October. Phylogenetic analyses of these three enterovirus types showed multiple lineages co-circulating in this region. Mean air temperatures and precipitation rates were independently associated with monthly number of cases. Considering lack of effective treatment or vaccine, easy transmission of enteroviruses between susceptible individuals, their high mutation rate and prolonged time of viral shedding, continued monitoring and surveillance are imperative to recognize enteroviral infections of the CNS and the changes in circulation of enteroviruses in Poland.
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Zuo, Jun, Steve Kye, Kevin K. Quinn, Paige Cooper, Robert Damoiseaux, and Paul Krogstad. "Discovery of Structurally Diverse Small-Molecule Compounds with Broad Antiviral Activity against Enteroviruses." Antimicrobial Agents and Chemotherapy 60, no. 3 (December 28, 2015): 1615–26. http://dx.doi.org/10.1128/aac.02646-15.
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Antiviral drugs do not currently exist for the treatment of enterovirus infections, which are often severe and potentially life-threatening. We conducted high-throughput molecular screening and identified a structurally diverse set of compounds that inhibit the replication of coxsackievirus B3, a commonly encountered enterovirus. These compounds did not interfere with the function of the viral internal ribosome entry site or with the activity of the viral proteases, but they did drastically reduce the synthesis of viral RNA and viral proteins in infected cells. Sequence analysis of compound-resistant mutants suggests that the viral 2C protein is targeted by most of these compounds. These compounds demonstrated antiviral activity against a panel of the most commonly encountered enteroviruses and thus represent potential leads for the development of broad-spectrum anti-enteroviral drugs.
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Galabov, Angel S., Ivanka Nikolova, Ralitsa Vassileva-Pencheva, and Adelina Stoyanova. "Antiviral Combination Approach as a Perspective to Combat Enterovirus Infections." PRILOZI 36, no. 2 (December 1, 2015): 91–99. http://dx.doi.org/10.1515/prilozi-2015-0057.
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Abstract Human enteroviruses distributed worldwide are causative agents of a broad spectrum of diseases with extremely high morbidity, including a series of severe illnesses of the central nervous system, heart, endocrine pancreas, skeleton muscles, etc., as well as the common cold contributing to the development of chronic respiratory diseases, including the chronic obstructive pulmonary disease. The above mentioned diseases along with the significantly high morbidity and mortality in children, as well as in the high-risk populations (immunodeficiencies, neonates) definitely formulate the chemotherapy as the main tool for the control of enterovirus infections. At present, clinically effective antivirals for use in the treatment of enteroviral infection do not exist, in spite of the large amount of work carried out in this field. The main reason for this is the development of drug resistance. We studied the process of development of resistance to the strongest inhibitors of enteroviruses, WIN compounds (VP1 protein hydrophobic pocket blockers), especially in the models in vivo, Coxsackievirus B (CV-B) infections in mice. We introduced the tracing of a panel of phenotypic markers (MIC50 value, plaque shape and size, stability at 50℃, pathogenicity in mice) for characterization of the drug-mutants (resistant and dependent) as a very important stage in the study of enterovirus inhibitors. Moreover, as a result of VP1 RNA sequence analysis performed on the model of disoxaril mutants of CVB1, we determined the molecular basis of the drug-resistance. The monotherapy courses were the only approach used till now. For the first time in the research for anti-enterovirus antivirals our team introduced the testing of combination effect of the selective inhibitors of enterovirus replication with different mode of action. This study resulted in the selection of a number of very effective in vitro double combinations with synergistic effect and a broad spectrum of sensitive enteroviruses. The most prospective attainment in our examinations in this field was the development of a novel scheme for the combined application of anti-enteroviral substances in coxsackievirus B1 neuroinfection in newborn mice. It consisted of a consecutive, alternating and non simultaneous administration of the substances in the combination. The triple combination - disoxaril- guanidine. HCl-oxoglaucine (DGO) showed a high effectiveness expressed in the marked reduction of the mortality rate in infected mice as compared both to the placebo group, and to the partner compounds used alone every day, and to the same combination applied simultaneously every day. The studies of the drug sensitivity of viral brain isolates from mice treated with DGO combination showed not only preserved, but even increased sensitivity to the drugs included in the combination. Obviously, the consecutive alternating administration of anti-enteroviral substances hinders the occurrence of drug-resistance in the course of the experimental enteroviral infections in mice.
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Min, Nyo, Yasmin Hui Binn Ong, Alvin X. Han, Si Xian Ho, Emmerie Wong Phaik Yen, Kenneth Hon Kim Ban, Sebastian Maurer-Stroh, Chia Yin Chong, and Justin Jang Hann Chu. "An epidemiological surveillance of hand foot and mouth disease in paediatric patients and in community: A Singapore retrospective cohort study, 2013–2018." PLOS Neglected Tropical Diseases 15, no. 2 (February 10, 2021): e0008885. http://dx.doi.org/10.1371/journal.pntd.0008885.
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Background While hand, foot and mouth disease (HFMD) is primarily self-resolving—soaring incidence rate of symptomatic HFMD effectuates economic burden in the Asia-Pacific region. Singapore has seen a conspicuous rise in the number of HFMD cases from 2010s. Here, we aims to identify the serology and genotypes responsible for such outbreaks in hospitals and childcare facilities. Methods We studied symptomatic paediatric HFMD cases from 2013 to 2018 in Singapore. Surveillance for subclinical enterovirus infections was also performed in childcares at the same time period. Results Genotyping 101 symptomatic HFMD samples revealed CV-A6 as the major etiological agent for recent outbreaks. We detected infections with CV-A6 (41.0%), EV-A71 (7%), CV-A16 (3.0%), coxsackievirus A2, CV-A2 (1.0%) and coxsackievirus A10, CV-A10 (1.0%). Phylogenetic analysis of local CV-A6 strains revealed a high level of heterogeneity compared against others worldwide, dissimilar to other HFMD causative enteroviruses for which the dominant strains and genotypes are highly region specific. We detected sub-clinical enterovirus infections in childcare centres; 17.1% (n = 245) tested positive for enterovirus in saliva, without HFMD indicative symptoms at the point of sample collection. Conclusions CV-A6 remained as the dominant HFMD causative strain in Singapore. Silent subclinical enteroviral infections were detected and warrant further investigations.
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Gonzalez, Gabriel, Michael J. Carr, Masaaki Kobayashi, Nozomu Hanaoka, and Tsuguto Fujimoto. "Enterovirus-Associated Hand-Foot and Mouth Disease and Neurological Complications in Japan and the Rest of the World." International Journal of Molecular Sciences 20, no. 20 (October 20, 2019): 5201. http://dx.doi.org/10.3390/ijms20205201.
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Enteroviruses (EVs) are responsible for extremely large-scale, periodic epidemics in pediatric cohorts, particularly in East and Southeast Asia. Clinical presentation includes a diverse disease spectrum, including hand-foot and mouth disease (HFMD), aseptic meningitis, encephalitis, acute flaccid paralysis, and acute flaccid myelitis. HFMD is predominantly attributable to EV-A types, including the major pathogen EV-A71, and coxsackieviruses, particularly CV-A6, CV-A16, and CV-A10. There have been multiple EV-A71 outbreaks associated with a profound burden of neurological disease and fatal outcomes in Asia since the early 1980s. Efficacious vaccines against EV-A71 have been developed in China but widespread pediatric vaccination programs have not been introduced in other countries. Encephalitis, as a consequence of complications arising from HFMD infection, leads to damage to the thalamus and medulla oblongata. Studies in Vietnam suggest that myoclonus is a significant indicator of central nervous system (CNS) complications in EV-A71-associated HFMD cases. Rapid response in HFMD cases in children is imperative to prevent the progression to a CNS infection; however, prophylactic and therapeutic agents have not been well established internationally, therefore surveillance and functional studies including development of antivirals and multivalent vaccines is critically important to reduce disease burden in pediatric populations.
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Caine, Elizabeth, Jeremy Fuchs, Subash Das, Charalambos Partidos, and Jorge Osorio. "Efficacy of a Trivalent Hand, Foot, and Mouth Disease Vaccine against Enterovirus 71 and Coxsackieviruses A16 and A6 in Mice." Viruses 7, no. 11 (November 17, 2015): 5919–32. http://dx.doi.org/10.3390/v7112916.
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Li, Qian, Zhenhua Zheng, Yan Liu, Zhenfeng Zhang, Qingshi Liu, Jin Meng, Xianliang Ke, Qinxue Hu, and Hanzhong Wang. "2C Proteins of Enteroviruses Suppress IKKβ Phosphorylation by Recruiting Protein Phosphatase 1." Journal of Virology 90, no. 10 (March 9, 2016): 5141–51. http://dx.doi.org/10.1128/jvi.03021-15.
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ABSTRACTThe NF-κB signaling network, which is an ancient signaling pathway, plays a pivotal role in innate immunity and constitutes a first line of defense against invading pathogens, including viruses. However, numerous viruses possess evolved strategies to antagonize the activation of the NF-κB signaling pathway. Our previous study demonstrated that the nonstructural protein 2C of enterovirus 71 (EV71), which is the major pathogen of hand, foot, and mouth disease, inhibits tumor necrosis factor alpha (TNF-α)-mediated activation of NF-κB by suppressing IκB kinase β (IKKβ) phosphorylation. Nevertheless, the mechanism underlying the inhibition of IKKβ phosphorylation by EV71 2C remains largely elusive. We demonstrate that EV71 2C interacts with all isoforms of the protein phosphatase 1 (PP1) catalytic subunit (the PP1α, PP1β, and PP1γ isoforms) through PP1-docking motifs. EV71 2C has no influence on the subcellular localization of PP1. In addition, the PP1-binding-deficient EV71 2C mutant 3E3L nearly completely lost the ability to suppress IKKβ phosphorylation and NF-κB activation was markedly restored in the mutant, thereby indicating that PP1 binding is efficient for EV71 2C-mediated inhibition of IKKβ phosphorylation and NF-κB activation. We further demonstrate that 2C forms a complex with PP1 and IKKβ to dephosphorylate IKKβ. Notably, we reveal that other human enteroviruses, including poliovirus (PV), coxsackie A virus 16 (CVA16), and coxsackie B virus 3 (CVB3), use 2C proteins to recruit PP1, leading to the inhibition of IKKβ phosphorylation. Our findings indicate that enteroviruses exploit a novel mechanism to inhibit IKKβ phosphorylation by recruiting PP1 and IKKβ to form a complex through 2C proteins, which ultimately results in the inhibition of the NF-κB signaling pathway.IMPORTANCEThe innate antiviral immunity system performs an essential function in recognizing and eliminating invading viruses. Enteroviruses include a number of important human pathogens, including poliovirus (PV), EV71, and coxsackieviruses (CVs). As 2C is the most conserved and complex nonstructural protein of enteroviruses, its biological function is largely unclear, whereas the 2A and 3C proteinases of enteroviruses are well characterized. We reveal that EV71 2C forms a complex with PP1 and IKKβ to maintain IKKβ in an unphosphorylated and inactive state, resulting in the inactivation of the TNF-α-mediated NF-κB signaling pathway. We provide evidence that the 2C proteins of the enteroviruses PV, CVA16, and CVB3 suppress IKKβ phosphorylation through the same mechanism involving PP1. We demonstrate that enteroviruses exploit a novel mechanism involving PP1 to regulate innate antiviral immunity, and our findings may be particularly important for understanding the pathogenicity of enteroviruses.
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Merkle, Ingrid, Mark J. M. van Ooij, Frank J. M. van Kuppeveld, Dirk H. R. F. Glaudemans, Jochem M. D. Galama, Andreas Henke, Roland Zell, and Willem J. G. Melchers. "Biological Significance of a Human Enterovirus B-Specific RNA Element in the 3′ Nontranslated Region." Journal of Virology 76, no. 19 (October 1, 2002): 9900–9909. http://dx.doi.org/10.1128/jvi.76.19.9900-9909.2002.
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ABSTRACT The secondary structures predicted for the enteroviral 3′ nontranslated region (3′NTR) all seem to indicate a conformation consisting of two (X and Y) hairpin structures. The higher-order RNA structure of the 3′NTR appears to exist as an intramolecular kissing interaction between the loops of these two hairpin structures. The enterovirus B-like subgroup possesses an additional stem-loop structure, domain Z, which is not present in the poliovirus-like enteroviruses. It has been suggested that the Z domain originated from a burst of short sequence repetitions (E. V. Pilipenko, S. V. Maslova, A. N. Sinyakov, and V. I. Agol, Nucleic Acids Res. 20:1739-1745, 1992). However, no functional features have yet been ascribed to this enterovirus B-like-specific RNA element in the 3′NTR. In this study, we tested the functional characteristics and biological significance of domain Z. A mutant of the cardiovirulent coxsackievirus group B3 strain Nancy which completely lacked the Z domain and which therefore acquired enterovirus C-like secondary structures exhibited a wild-type growth phenotype, as determined by single-cycle growth analysis with BGM cells. This result proves that the Z domain is virtually dispensable for viral growth in tissue cultures. Partial distortion of the Z domain structure resulted in a disabled virus with reduced growth kinetics, probably due to alternative conformations of the overall structure of the domain. Infection of mice showed that the recombinant coxsackievirus group B3 mutant which completely lacked the Z domain was less virulent. Pancreatic tissues from mice infected with wild-type virus and recombinant virus were equally affected. However, the heart tissue from mice infected with the recombinant virus showed only slight signs of myocarditis. These results suggest that the enterovirus B-like-specific Z domain plays a role in coxsackievirus-induced pathogenesis.
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Radovanov, Jelena, Vesna Milosevic, Dragan Radnovic, Vera Jerant-Patic, Ivana Hrnjakovic-Cvjetkovic, and Gordana Kovacevic. "Detection of enteroviruses in clinical samples of patients with aseptic meningitis by rapid antigen detection assay." Srpski arhiv za celokupno lekarstvo 139, no. 11-12 (2011): 759–64. http://dx.doi.org/10.2298/sarh1112759r.
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Introduction. Human enteroviruses represent the most common etiological agents of aseptic meningitis. Rapid diagnosis of aseptic meningitis affects the management of patients. Objective. The aim of this work was to assess the efficacy of rapid antigen detection (RAD) assay for the confirmation of human enteroviruses in comparison to that of the conventional cell culture (CCC), and to identify the serotypes associated with aseptic meningitis cases in the Autonomous Province of Vojvodina. Methods. RAD assay was carried out using centrifugation of inoculated Vero, RD and HEp-2 cell cultures and indirect immunofluorescence with Pan-Enterovirus 2E11 reagent (Millipore-Chemicon). CCC was performed using the same type of cells and the same immunofluorescence reagent for enterovirus confirmation. Results. Out of 70 analyzed samples (29 cerebrospinal fluid specimens, 27 stool specimens, 9 rectal and 5 throat swabs) , 36 (51.4%) were positive by immunofluorescence after CCC and 34 (48.6%) by the RAD assay. The sensitivity of RAD assay was 94.4% and specificity 100%. Detection time of enteroviruses by the RAD assay was 3 days, and by CCC varied from 3 to 13 days (mean time 6.1 days). Within 72 h from inoculation, a cytopathic effect (CPE) occurred in only 19 (47.5%) of 40 CPE positive samples. Serotyping revealed 11 types of enteroviruses: coxsackievirus A16, B3, B4, B5, and echovirus 2, 4, 6, 11, 13, 16 and 30. Conclusion. The RAD assay was slightly less sensitive than CCC and significantly shortened the detection time of enteroviruses, so it may be useful in rapid diagnosis of enteroviral meningitis.
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Techasaensiri, Chonnamet, Artit Wongsa, Thanyawee Puthanakit, Kulkanya Chokephaibulkit, Tawee Chotpitayasunondh, Ubonwon Charoonruangrit, Somjai Sombatnimitsakul, et al. "Response of Severe EV71-Infected Patients to Hyperimmune Plasma Treatment: A Pilot Study." Pathogens 10, no. 5 (May 19, 2021): 625. http://dx.doi.org/10.3390/pathogens10050625.
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Hand, foot, and mouth disease (HFMD) is highly prevalent in East and Southeast Asia. It particularly affects children under five years of age. The most common causative agents are coxsackieviruses A6 and A16, and enterovirus A71 (EV71). The clinical presentation is usually mild and self-limited, but, in some cases, severe and fatal complications develop. To date, no specific therapy or worldwide vaccine is available. In general, viral infection invokes both antibody and cell-mediated immune responses. Passive immunity transfer can ameliorate the severe symptoms of diseases such as COVID-19, influenza, MERS, and SARS. Hyperimmune plasma (HIP) from healthy donors with high anti-EV71 neutralizing titer were used to transfuse confirmed EV71-infected children with neurological involvement (n = 6). It resulted in recovery within three days, with no neurological sequelae apparent upon examination 14 days later. Following HIP treatment, plasma chemokines were decreased, whereas anti-inflammatory and pro-inflammatory cytokines gradually increased. Interestingly, IL-6 and G-CSF levels in cerebrospinal fluid declined sharply within three days. These findings indicate that HIP has therapeutic potential for HFMD with neurological complications. However, given the small number of patients who have been treated, a larger cohort study should be undertaken. Successful outcomes would stimulate the development of anti-EV71 monoclonal antibody therapy.
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Pevear, Daniel C., Tina M. Tull, Martin E. Seipel, and James M. Groarke. "Activity of Pleconaril against Enteroviruses." Antimicrobial Agents and Chemotherapy 43, no. 9 (September 1, 1999): 2109–15. http://dx.doi.org/10.1128/aac.43.9.2109.
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ABSTRACT The activity of pleconaril in cell culture against prototypic enterovirus strains and 215 clinical isolates of the most commonly isolated enterovirus serotypes was examined. The latter viruses were isolated by the Centers for Disease Control and Prevention during the 1970s and 1980s from clinically ill subjects. Pleconaril at a concentration of ≤0.03 μM inhibited the replication of 50% of all clinical isolates tested. Ninety percent of the isolates were inhibited at a drug concentration of ≤0.18 μM. The most sensitive serotype, echovirus serotype 11, was also the most prevalent enterovirus in the United States from 1970 to 1983. Pleconaril was further tested for oral activity in three animal models of lethal enterovirus infection: coxsackievirus serotype A9 infection in suckling mice, coxsackievirus serotype A21 strain Kenny infection in weanling mice, and coxsackievirus serotype B3 strain M infection in adult mice. Treatment with pleconaril increased the survival rate in all three models for both prophylactic and therapeutic dosing regimens. Moreover, pleconaril dramatically reduced virus levels in target tissues of coxsackievirus serotype B3 strain M-infected animals. Pleconaril represents a promising new drug candidate for potential use in the treatment of human enteroviral infections.
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Nygårdas, Michaela, Tytti Vuorinen, Antti P. Aalto, Dennis H. Bamford, and Veijo Hukkanen. "Inhibition of coxsackievirus B3 and related enteroviruses by antiviral short interfering RNA pools produced using φ6 RNA-dependent RNA polymerase." Journal of General Virology 90, no. 10 (October 1, 2009): 2468–73. http://dx.doi.org/10.1099/vir.0.011338-0.
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Coxsackievirus B3 (CBV3) is a member of the human enterovirus B species and a common human pathogen. Even though much is known about the enteroviral life cycle, no specific drugs are available to treat enterovirus infections. RNA interference (RNAi) has evolved to be an important tool for antiviral experimental therapies and gene function studies. We describe here a novel approach for RNAi against CBVs by using a short interfering (siRNA) pool covering 3.5 kb of CBV3 genomic sequence. The RNA-dependent RNA polymerase (RdRP) of bacteriophage φ6 was used to synthesize long double-stranded RNA (dsRNA) from a cloned region (nt 3837–7399) of the CBV3 genome. The dsRNA was cleaved using Dicer, purified and introduced to cells by transfection. The siRNA pool synthesized using the φ6 RdRP (φ6–siRNAs) was considerably more effective than single-site siRNAs. The φ6–siRNA pool also inhibited replication of other enterovirus B species, such as coxsackievirus B4 and coxsackievirus A9.
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Drummond, Coyne G., Alexa M. Bolock, Congrong Ma, Cliff J. Luke, Misty Good, and Carolyn B. Coyne. "Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner." Proceedings of the National Academy of Sciences 114, no. 7 (January 30, 2017): 1672–77. http://dx.doi.org/10.1073/pnas.1617363114.
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Enteroviruses are among the most common viral infectious agents of humans and are primarily transmitted by the fecal–oral route. However, the events associated with enterovirus infections of the human gastrointestinal tract remain largely unknown. Here, we used stem cell-derived enteroids from human small intestines to study enterovirus infections of the intestinal epithelium. We found that enteroids were susceptible to infection by diverse enteroviruses, including echovirus 11 (E11), coxsackievirus B (CVB), and enterovirus 71 (EV71), and that contrary to an immortalized intestinal cell line, enteroids induced antiviral and inflammatory signaling pathways in response to infection in a virus-specific manner. Furthermore, using the Notch inhibitor dibenzazepine (DBZ) to drive cellular differentiation into secretory cell lineages, we show that although goblet cells resist E11 infection, enteroendocrine cells are permissive, suggesting that enteroviruses infect specific cell populations in the human intestine. Taken together, our studies provide insights into enterovirus infections of the human intestine, which could lead to the identification of novel therapeutic targets and/or strategies to prevent or treat infections by these highly clinically relevant viruses.
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PORTES, Silvana A. R., Edson E. DA SILVA, Marilda M. SIQUEIRA, Ana Maria B. DE FILIPPIS, Murilo M. KRAWCZUK, and Jussara P. NASCIMENTO. "ENTEROVIRUSES ISOLATED FROM PATIENTS WITH ACUTE RESPIRATORY INFECTIONS DURING SEVEN YEARS IN RIO DE JANEIRO (1985-1991)." Revista do Instituto de Medicina Tropical de São Paulo 40, no. 6 (November 1998): 337–42. http://dx.doi.org/10.1590/s0036-46651998000600001.
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Enteroviruses were investigated in respiratory secretions collected from patients with acute respiratory infections (ARI) over a seven year period (1985-1991), as part of a longitudinal study of ARI aetiology. All the viruses that are most commonly associated with ARI were found in this study. Among the virus isolates, enteroviruses were only less frequent than respiratory syncytial viruses, adenoviruses and influenzaviruses. Forty five enterovirus samples were isolated from patients with either upper respiratory tract infections (URTI) or lower respiratory tract infections (LRTI). From these enterovirus isolates, thirty one samples were identified as poliovirus (n=18) and non polio enterovirus (n=13) by serum neutralization. Poliovirus were identified as type 1 and 2 and all of them were vaccinal strains. From thirteen non polio enterovirus, twelve were identified as echovirus serotypes 1, 2, 7, 11, 19 and 31. The remainder was identified as coxsackievirus B4.
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Hoang, C. Q., H. D. Nguyen, N. X. Ho, T. H. T. Vu, T. T. M. Pham, K. T. Nguyen, H. T. Nguyen, et al. "Incidence of Infection of Enterovirus 71 and Coxsackieviruses A6 and A16 among Household Contacts of Index Cases in Dong Thap Province, Southern Vietnam." BioMed Research International 2020 (November 19, 2020): 1–8. http://dx.doi.org/10.1155/2020/9850351.
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Background. Scarce information exists about immunity to hand, foot, and mouth disease (HFMD) among household contacts of index cases in Vietnam and what that means for reducing ongoing HFMD transmission in the community. Methods. We analyzed neutralizing antibodies (NT) and the incidence of enterovirus (EVs) infection among household contacts of index cases in a province where HFMD remains endemic. Throat swab and 2 mL blood samples from household contacts were collected at enrollment, during and after 2 weeks follow-up. Results. The incidence of EV-A71 infection among household contacts was 40/84 (47.6%, 95% Cl: 36.9-58.3%), compared with 106/336 (31.5%, 95% Cl: 26.6-36.5%) for CV-A6 and 36/107 (33.6%, 95% Cl: 24.7-42.6%) for CV-A16. The incidence of CV-A6 infection was fairly constant across ages; in contrast, CV-A71 and CV-A16 had some variation across ages. At baseline, higher geometric mean titer (GMT) of EV-A71, CV-A6, and CV-A16 antibody titers was found for 25-34-year groups (range 216.3 to 305.0) compared to the other age groups. There was a statistically significant difference in GMT values of CV-A6 and CV-A16 between those who had an infection or did not have infection among households with an index case of these serotypes. Conclusions. Our results indicated that adults were becoming infected with HFMD and could be contributing to the transmission. There is, therefore, a need for considering the household setting as an additional target for intervention programs for HFMD.
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Hovi, T., M. Stenvik, and M. Rosenlew. "Relative abundance of enterovirus serotypes in sewage differs from that in patients: clinical and epidemiological implications." Epidemiology and Infection 116, no. 1 (February 1996): 91–97. http://dx.doi.org/10.1017/s0950268800058982.
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SummaryOne thousand one hundred and sixty-one non-polio enterovirus strains, isolated during regular screening of Finnish sewage specimens, were analysed for serotype distribution seasonally through 20 years, and the findings were compared with similar data based on 1681 clinical isolates. Coxsackievirus B4 (CBV-4), CBV-5, echovirus 11 (EV-11), EV-6, CBV-2 and CBV-3 were the most common serotypes in sewage, whilst CBV-5, EV-11, coxsackievirus A9, EV-22, CBV-3 and EV-30 were the most common clinical isolates. Reasons for the differences are not known but several explanations are possible. Seasonal variation of enterovirus occurrence in both sources showed an expected peak in the autumn with a trough in the spring. The occurrence of enteroviruses was closely correlated with monthly recordings of mean relative humidity. A further observation concerning the clinical specimens in Finland was the relative excess of some serotypes, such as echovirus 22 and coxsackievirus A9, and paucity of others, for instance, echoviruses 4 and 9, when compared to published data from other countries. This is consistent with the idea of geographically restricted circulation of enteroviruses.
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Karnauchow, Timothy M., Sandra Dawe, Douglas M. Lublin, and Kenneth Dimock. "Short Consensus Repeat Domain 1 of Decay-Accelerating Factor Is Required for Enterovirus 70 Binding." Journal of Virology 72, no. 11 (November 1, 1998): 9380–83. http://dx.doi.org/10.1128/jvi.72.11.9380-9383.1998.
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ABSTRACT Enterovirus 70 (EV70), like several other human enteroviruses, can utilize decay-accelerating factor (DAF [CD55]) as an attachment protein. Using chimeric molecules composed of different combinations of the short consensus repeat domains (SCRs) of DAF and membrane cofactor protein (CD46), we show that sequences in SCR1 of DAF are essential for EV70 binding. Of the human enteroviruses that can bind to DAF, only EV70 and coxsackievirus A21 require sequences in SCR1 for this interaction.
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Roivainen, Merja, Petri Ylipaasto, Jarkko Ustinov, Tapani Hovi, and Timo Otonkoski. "Screening enteroviruses for β-cell tropism using foetal porcine β-cells." Journal of General Virology 82, no. 8 (August 1, 2001): 1909–16. http://dx.doi.org/10.1099/0022-1317-82-8-1909.
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Primary adult human insulin-producing β-cells are susceptible to infection by prototype strains of coxsackieviruses (CV) and infection may result in impaired β-cell function and/or cell death, as shown for coxsackie B virus (CVB) types 4 and 5, or have no apparent immediate adverse effects, as shown for CVA-9. Because of the limited availability of human pancreatic β-cells, the aim of this study was to find out if foetal porcine pancreatic islets could be used as a substitute in enterovirus (EV) screening. These cells resemble human β-cells in several biological properties. CVB infection resulted in a rapid progressive decline of insulin content and reponsiveness to insulin release. The amount of virus inoculum sufficient for this destruction was small, corresponding to only 55 infectious units per pancreas. In contrast to CVBs, CVA-9 replicated poorly, and sometimes not at all, in foetal porcine β-cells. The first signs of functional impairment and cell destruction, if present at all, were seen only after 1–3 weeks of incubation. Furthermore, CVA-16, several strains of echoviruses and human parechovirus type 1 were unable to replicate in foetal porcine pancreatic β-cells. Based on these results, foetal porcine islets are somewhat more sensitive to CVB infection than adult human islets, whereas many other human EV strains do not infect porcine β-cells. Therefore, foetal porcine β-cells cannot be used for systematic screening of human EV strains and isolates for β-cell tropism, but they might provide a useful model for detailed studies on the interaction of CVBs with β-cells.
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Usoltseva, P. S., A. V. Alimov, A. V. Rezaykin, A. G. Sergeev, and A. V. Novoselov. "THE ROLE OF THE NEONATAL FC RECEPTOR IN THE UNCOATING OF ECHOVIRUSES AND COXSACKIEVIRUS A9." Problems of Virology, Russian journal 64, no. 3 (June 20, 2019): 132–39. http://dx.doi.org/10.18821/0507-4088-2019-64-3-132-139.
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The aim of this study was to determine the role of the human neonatal receptor for the Fc fragment of IgG (hFcRn) as a common uncoating cellular receptor for echoviruses and coxsackievirus A9 during infection of human rhabdomyosarcoma (RD) cells. Material and methods. The protective effect of the human serum albumin, purified from globulins, (HSA-GF) and antibodies to hFcRn was studied in RD cells infected with several strains and clones of species B enteroviruses possessing different receptor specificity (echoviruses 3, 9, 11, 30 and coxsackieviruses A9, B4, B5). Results. It was shown that HSA-GF at concentrations of 4% or less protected RD cells from infection with echoviruses 3, 9, 11 and coxsackievirus A9. The antibodies to hFcRn at concentrations of 2.5 ug/mL or less demonstrated the similar spectrum of protective activity in RD cells against infection with echoviruses 3, 9, 11, 30 and coxsackievirus A9. The protective effect of HSA-GF or the antibodies to hFcRn was not observed in RD cells infected with coxsackieviruses B4 and B5 that need coxsackievirus-adenovirus receptor for uncoating. Discussion. The usage of the previously characterized echovirus 11 clonal variants with different receptor specificity allowed us to define the function of hFcRn as a canyon-binding uncoating receptor in RD cells. The kinetics and magnitude of the observed protective effects correlated with receptor specificity of the enteroviruses used in this work supporting the two-step interaction of DAF-dependent echoviruses with the cellular receptors. Conclusions. In this study, the function of hFcRn was defined in RD cells as a canyon-binding and uncoating receptor for echoviruses and coxsackievirus A9. The two-step interaction of DAF-dependent echoviruses during entry into the cells was confirmed: initially with the binding receptor DAF and subsequently with the uncoating receptor hFcRn.
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Lizasoain, Andrés, Daiana Mir, Matías Salvo, Viviana Bortagaray, Gisela Masachessi, Adrián Farías, Nélida Rodríguez-Osorio, Silvia Nates, Matías Victoria, and Rodney Colina. "First evidence of enterovirus A71 and echovirus 30 in Uruguay and genetic relationship with strains circulating in the South American region." PLOS ONE 16, no. 8 (August 12, 2021): e0255846. http://dx.doi.org/10.1371/journal.pone.0255846.
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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.
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Butakova, Lyudmila V., Elena Yu Sapega, and Olga E. Trotsenko. "Molecular epidemiological features of the Coxsackievirus A10 circulation in the Far Eastern Federal District of Russia." Journal of microbiology, epidemiology and immunobiology 97, no. 4 (September 2, 2020): 324–30. http://dx.doi.org/10.36233/0372-9311-2020-97-4-4.
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Background. Increase in incidence rates of enterovirus infections in the Far Eastern Federal District of Russia is observed annually. There is a wide genetic diversity of circulating non-polio enteroviruses. Some of them have been constantly identified for a number of years in the population of the district, including the Coxsackie A10 virus.Purpose. To study the features of the Coxsackievirus A10 circulation in the Far Eastern Federal District of Russia in 2014–2018.Methods. For this work, 117 Coxsackievirus A10 complete sequences of the VP1 gene were used, which were isolated in the Far Eastern Federal District of Russia in 2014–2018.Results. Phylogenetic analysis revealed two Coxsackievirus A10 lineages in the Far Eastern Federal District of Russia in 2014-2018, while their simultaneous circulation was noted in the Sakhalin region in 2017. Active population migration contributes to the widespread distribution of Coxsackievirus A10 in border areas with the formation of epidemic variants.Conclusion. Coxsackievirus A10 is one of the most relevant types of non-polio enteroviruses for the Far Eastern Federal District of Russia. Phylogenetic analysis revealed its genetic diversity and suggested both European and Asian origin of the obtained strains.
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Chen, Qian, Qihua Zhang, and Zheng Hu. "Profiles of Human Enteroviruses Associated with Hand, Foot, and Mouth Disease in Nanjing, China." Disaster Medicine and Public Health Preparedness 13, no. 4 (February 1, 2019): 740–44. http://dx.doi.org/10.1017/dmp.2018.155.
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ABSTRACTObjectiveHand, foot, and mouth disease (HFMD) is a common infectious disease caused by a group of viruses. The causative viruses have changed over time, and there is a need for a more effective protective vaccine. In this study, we investigated the profiles of human enteroviruses that caused HFMD outbreaks in Nanjing in 2015, with the goal of guiding the future prevention and treatment of HFMD.MethodsSpecimens were collected from 1097 patients admitted to our hospital and diagnosed with HFMD. Enteroviruses in the specimens were identified by real-time polymerase chain reaction and epidemiological patterns were analyzed with the clinical data.ResultsAmong the 1097 clinically diagnosed HFMD cases, 916 cases were confirmed by laboratory tests. The results showed that the main infectious virus was coxsackievirus A6 (CVA6) (41.75%), followed by enterovirus 71 (EV71) (27.48%), coxsackievirus A16 (7.43%), coxsackievirus A10 (6.84%), and others (16.51%). Further investigation indicated that CVA6 caused mild cases of HFMD, while EV71 caused severe cases. More enterovirus positive cases were reported from rural areas than from urban areas.ConclusionsCA6 and EV71 were the chief pathogenic viruses of HFMD cases in the present study. Schools, childcare centers, and families from rural areas should be the major targets for prevention and awareness of HFMD. This study will provide information useful in the prevention and management of HFMD and the development of relevant vaccines for HFMD in the future. (Disaster Med Public Health Preparedness. 2019;13:740–744).
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CHANSAENROJ, J., S. VONGPUNSAWAD, J. PUENPA, A. THEAMBOONLERS, V. VUTHITANACHOT, P. CHATTAKUL, D. AREECHOKCHAI, and Y. POOVORAWAN. "Epidemic outbreak of acute haemorrhagic conjunctivitis caused by coxsackievirus A24 in Thailand, 2014." Epidemiology and Infection 143, no. 14 (March 31, 2015): 3087–93. http://dx.doi.org/10.1017/s0950268815000643.
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SUMMARYAcute haemorrhagic conjunctivitis outbreaks are often attributed to viral infection. In 2014, an unprecedented nationwide outbreak of infectious conjunctivitis occurred in Thailand, which affected >300 000 individuals over 3 months. To identify and characterize the virus responsible for the epidemic, eye swab specimens from 119 patients were randomly collected from five different provinces. Conserved regions in the enteroviral 5′-UTR and adenovirus hexon gene were analysed. Enterovirus was identified in 71·43% (85/119) of the samples, while no adenovirus was detected. From enterovirus-positive samples, the coxsackievirus A24 variant (70·59%, 84/119) and echovirus (0·84%, 1/119) were identified. Additional sequencing of full-length VP1 and 3C genes and subsequent phylogenetic analysis revealed that these clinical isolates form a new lineage cluster related to genotype IV-C5. In summary, the coxsackievirus A24 variant was identified as an aetiological agent for the recent acute haemorrhagic conjunctivitis outbreak in Thailand.
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Khetsuriani, N., T. Kutateladze, E. Zangaladze, T. Shutkova, S. Peñaranda, W. A. Nix, M. A. Pallansch, and M. S. Oberste. "High degree of genetic diversity of non-polio enteroviruses identified in Georgia by environmental and clinical surveillance, 2002–2005." Journal of Medical Microbiology 59, no. 11 (November 1, 2010): 1340–47. http://dx.doi.org/10.1099/jmm.0.023028-0.
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Enterovirus surveillance data are useful for establishing temporal and geographical patterns of circulation and for virus characterization to determine phylogenetic relationships between strains. Almost no information is available on circulating enteroviruses in Georgia and the surrounding region. To describe enterovirus circulation in Georgia, determine relationships with previously characterized strains and assess the role of environmental and clinical enterovirus surveillance, this study analysed a total of 112 non-polio enterovirus isolates identified during 2002–2005 from sewage and human stool samples. Viruses were isolated in cell culture using standard methods and typed by partial sequencing of the VP1 gene. A total of 20 different non-polio enterovirus serotypes were identified over the 4-year period. The most commonly detected enteroviruses included echovirus (E) 6 (21 isolates; 18.8 %), E20, E3 and E7 (11 isolates each; 9.8 %), E11, coxsackievirus (CV) B4 and CVB5 (seven isolates each; 6.3 %), and E13, E19 and E30 (six isolates each; 5.4 %). Phylogenetic analysis showed that many serotypes were represented by more than one genetic lineage. The present study showed a very high degree of enterovirus diversity in Georgia and demonstrated the added value of environmental enterovirus surveillance, particularly in settings with limited clinical surveillance. Several serotypes would not have been detected without having both clinical and environmental surveillance in place. Several serotypes detected in Georgia were among those rarely reported in the USA and Europe (e.g. E3, E20 and E19). As the emergence of new genetic lineages of enterovirus in a particular area is often associated with large-scale outbreaks, continued monitoring of enterovirus strains by both environmental and clinical surveillance and genetic characterization should be encouraged.
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Dorobantu, Cristina M., Lauren A. Ford-Siltz, Simone P. Sittig, Kjerstin H. W. Lanke, George A. Belov, Frank J. M. van Kuppeveld, and Hilde M. van der Schaar. "GBF1- and ACBD3-Independent Recruitment of PI4KIIIβ to Replication Sites by Rhinovirus 3A Proteins." Journal of Virology 89, no. 3 (November 19, 2014): 1913–18. http://dx.doi.org/10.1128/jvi.02830-14.
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PI4KIIIβ recruitment to Golgi membranes relies on GBF1/Arf and ACBD3. Enteroviruses such as poliovirus and coxsackievirus recruit PI4KIIIβ to their replication sites via their 3A proteins. Here, we show that human rhinovirus (HRV) 3A also recruited PI4KIIIβ to replication sites. Unlike other enterovirus 3A proteins, HRV 3A failed to bind GBF1. Although HRV 3A was previously shown to interact with ACBD3, our data suggest that PI4KIIIβ recruitment occurred independently of both GBF1 and ACBD3.
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Hankaniemi, Minna M., Mo A. Baikoghli, Virginia M. Stone, Li Xing, Outi Väätäinen, Saana Soppela, Amirbabak Sioofy-Khojine, et al. "Structural Insight into CVB3-VLP Non-Adjuvanted Vaccine." Microorganisms 8, no. 9 (August 24, 2020): 1287. http://dx.doi.org/10.3390/microorganisms8091287.
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Coxsackievirus B (CVB) enteroviruses are common pathogens that can cause acute and chronic myocarditis, dilated cardiomyopathy, aseptic meningitis, and they are hypothesized to be a causal factor in type 1 diabetes. The licensed enterovirus vaccines and those currently in clinical development are traditional inactivated or live attenuated vaccines. Even though these vaccines work well in the prevention of enterovirus diseases, new vaccine technologies, like virus-like particles (VLPs), can offer important advantages in the manufacturing and epitope engineering. We have previously produced VLPs for CVB3 and CVB1 in insect cells. Here, we describe the production of CVB3-VLPs with enhanced production yield and purity using an improved purification method consisting of tangential flow filtration and ion exchange chromatography, which is compatible with industrial scale production. We also resolved the CVB3-VLP structure by Cryo-Electron Microscopy imaging and single particle reconstruction. The VLP diameter is 30.9 nm on average, and it is similar to Coxsackievirus A VLPs and the expanded enterovirus cell-entry intermediate (the 135s particle), which is ~2 nm larger than the mature virion. High neutralizing and total IgG antibody levels, the latter being a predominantly Th2 type (IgG1) phenotype, were detected in C57BL/6J mice immunized with non-adjuvanted CVB3-VLP vaccine. The structural and immunogenic data presented here indicate the potential of this improved methodology to produce highly immunogenic enterovirus VLP-vaccines in the future.
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Patick, A. K., S. L. Binford, M. A. Brothers, R. L. Jackson, C. E. Ford, M. D. Diem, F. Maldonado, et al. "In Vitro Antiviral Activity of AG7088, a Potent Inhibitor of Human Rhinovirus 3C Protease." Antimicrobial Agents and Chemotherapy 43, no. 10 (October 1, 1999): 2444–50. http://dx.doi.org/10.1128/aac.43.10.2444.
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ABSTRACT AG7088 is a potent, irreversible inhibitor of human rhinovirus (HRV) 3C protease {inactivation rate constant (k obs/[I]} = 1,470,000 ± 440,000 M−1 s−1 for HRV 14) that was discovered by protein structure-based drug design methodologies. In H1-HeLa and MRC-5 cell protection assays, AG7088 inhibited the replication of all HRV serotypes (48 of 48) tested with a mean 50% effective concentration (EC50) of 0.023 μM (range, 0.003 to 0.081 μM) and a mean EC90 of 0.082 μM (range, 0.018 to 0.261 μM) as well as that of related picornaviruses including coxsackieviruses A21 and B3, enterovirus 70, and echovirus 11. No significant reductions in the antiviral activity of AG7088 were observed when assays were performed in the presence of α1-acid glycoprotein or mucin, proteins present in nasal secretions. The 50% cytotoxic concentration of AG7088 was >1,000 μM, yielding a therapeutic index of >12,346 to >333,333. In a single-cycle, time-of-addition assay, AG7088 demonstrated antiviral activity when added up to 6 h after infection. In contrast, a compound targeting viral attachment and/or uncoating was effective only when added at the initiation of virus infection. Direct inhibition of 3C proteolytic activity in infected cells treated with AG7088 was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of radiolabeled proteins, which showed a dose-dependent accumulation of viral precursor polyproteins and reduction of processed protein products. The broad spectrum of antiviral activity of AG7088, combined with its efficacy even when added late in the virus life cycle, highlights the advantages of 3C protease as a target and suggests that AG7088 will be a promising clinical candidate.