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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.

Human enteroviruses are associated with various clinical syndromes from minor febrile illness to severe, potentially fatal conditions like aseptic meningitis, paralysis, myocarditis, and neonatal enteroviral sepsis. Between June 2000 and August 2008 echovirus (E) type 2, 4, 6, 7, 9, 11, 13, 25, 30, coxsackievirus (CV) -A16, -A19, -B5, and enterovirus 71 (EV71) were reported in Hungary. In this study, 29 previously enterovirus positive samples from 28 patients diagnosed with hand, foot and mouth disease, meningitis and encephalitis, were molecularly typed. The genetic relationships of identified serotypes CV-A16, EV71, and E30 were assessed by direct sequencing of genomic region encoding the capsid protein VP1. The sequences were compared to each other and sequences from other geographical regions possessed in Genbank. The phylogenetic analysis of CV-A16 revealed that the viruses were mostly of Far-Eastern or Asia-Pacific origin. Typing of EV71 showed that one virus from 2000 belonged to genotype C1 and five viruses observed in 2004 and 2005 were identified as genotype C4. The 11 echovirus 30 strains showed homology with those of neighbor European countries. The molecular examination of E30 revealed that three separate lineages circulated in 2000, 2001, and 2004-2006 in Hungary.

A total of 1844 patients with hand, foot, and mouth disease (HFMD), most of them were children of age 1-3-year-old, in Central China were hospitalized from 2011 to 2012. Among them, 422 were infected with coxsackievirus A16 (CVA16), 334 were infected with enterovirus 71 (EV71), 38 were co-infected with EV71 and CVA16, and 35 were infected with other enteroviruses. Molecular epidemiology analysis revealed that EV71 and CVA16 were detected year-round, but EV71 circulated mainly in July and CVA16 circulated predominantly in November, and incidence of HFMD was reduced in January and February and increased in March. Clinical data showed that hyperglycemia and neurologic complications were significantly higher in EV71-infected patients, while upper respiratory tract infection and C-reactive protein were significantly higher in CVA16-associated patients. 124 EV71 and 80 CVA16 strains were isolated, among them 56 and 68 EV71 strains were C4a and C4b, while 25 and 55 CVA16 strains were B1a and B1b, respectively. Similarity plots and bootscan analyses based on entire genomic sequences revealed that the three C4a sub-genotype EV71 strains were recombinant with C4b sub-genotype EV71 in 2B-2C region, and the three CVA16 strains were recombinant with EV71 in 2A-2B region. Thus, CVA16 and EV71 were the major causative agents in a large HFMD outbreak in Central China. HFMD incidence was high for children among household contact and was detected year-round, but outbreak was seasonal dependent. CVA16 B1b and EV71 C4b reemerged and caused a large epidemic in China after a quiet period of many years. Moreover, EV71 and CVA16 were co-circulated during the outbreak, which may have contributed to the genomic recombination between the pathogens. It should gain more attention as there may be an upward trend in co-circulation of the two pathogens globally and the new role recombination plays in the emergence of new enterovirus variants.

Background Rash is a common childhood infection, mainly caused by viruses. Hand, foot, and mouth disease (HFMD), a common viral rash infection, has become one of the most common infectious diseases in Asian countries and caused outbreaks in children and adults worldwide. Following the introduction of enterovirus A71 (EVA71) vaccines, Coxsackievirus A6 (CVA6) has recently emerged. However, the disease is not commonly reported in Africa, where studies are scarce. Methods In the current study, we focused on the HFMD outbreak that occurred in Cape Verde in July 2023 during field investigations around a cluster of patients with rash and fever. Samples collected from patients were tested using Measles and Rubella-specific immunoglobulin M and quantitative reverse transcription PCR (qRT-PCR) of a panel of viruses causing rashes and subjected to genome sequencing followed by phylogenetic analysis. Results Eighteen out of the 22 samples were tested positive for CVA6 RNA by real-time RT-PCR, of which two tested also positive for EVA71 and Coxsackievirus A16 (CVA16). Subsequent sequencing revealed that all CVA6 sequences belonged to the D genotype, particularly the D3 sub-genotype recently described in China. Conclusion Our study uncovers the first-ever reported outbreak of CVA6 associated with atypical HFMD in children from Cape Verde and highlights thus the need to implement an active hospital-based HFMD surveillance in Africa.

Outbreaks of hand, foot, and mouth disease caused by enterovirus-A71 (EV-A71) can result in many deaths, due to central nervous system complications. Outbreaks with many fatalities have occurred sporadically in the Asia-Pacific region and have become a serious public health concern. It is hypothesized that virulent mutations in the EV-A71 genome cause these occasional outbreaks. Analysis of EV-A71 neurovirulence determinants is important, but there are no virulence determinants that are widely accepted among researchers. This is because most studies have been done in artificially infected mouse models and because EV-A71 mutates very quickly to adapt to the artificial host environment. Although EV-A71 uses multiple receptors for infection, it is clear that adaptation-related mutations alter the binding specificity of the receptors and allow the virus to adopt the best entry route for each environment. Such mutations have confused interpretations of virulence in animal models. This article will discuss how environment-adapted mutations in EV-A71 occur, how they affect virulence, and how such mutations can be avoided. We also discuss future perspectives for EV-A71 virulence research.

Background Hand, foot, and mouth disease (HFMD) is a widespread infectious disease primarily affecting infants and young children. Enterovirus A71 (EV-A71) comprises eight genogroups, among which subgroup C4 is the dominant viral agent in China and is frequently associated with HFMD and central nervous system infections. The genetic characteristics of an EV-A71 subgroup C4 strain obtained in this study were analyzed using whole-genome sequencing. Its biological characteristics, including infectivity, replication, and cytotoxicity, were investigated in human rhabdomyosarcoma (RD) and African green monkey kidney (Vero) cells. Methods A clinical EV-A71 C4 subgourp GD10 strain isolated in China was examined to evaluate its genetic and biological features. Its relationships with strains listed in GenBank were evaluated using phylogenetic analysis. Viral infectivity and replication were assessed in RD and Vero cells. Cytotoxicity was evaluated by measuring cell viability, lactate dehydrogenase (LDH) release, and ATP levels. Effects on blood–brain barrier (BBB) integrity were investigated in vitro by assessing transendothelial electrical resistance and viral load across the barrier. Results Sequence analysis confirmed that GD10 belonged to subgroup C4 and closely resembled strains from China. GD10 infection induced a pronounced cytopathic effect and elevated viral RNA levels in RD cells but not in Vero cells. The infection time-dependently increased LDH release and reduced ATP levels. GD10 compromised BBB integrity and crossed the cellular barrier in vitro. Conclusion The GD10 strain demonstrated strong adaptability to RD cells and impaired BBB function. Our results improve the understanding of virus–host interactions and may support efforts towards EV-A71 vaccine development. Clinical Trial Not applicable

Background Hand, foot, and mouth disease (HFMD) remains a significant childhood infection in the Asia-Pacific region; however, the emergence of Coxsackievirus A6 (CVA6) since 2008 has reshaped its epidemiology. Despite extensive national surveillance, the evolutionary tempo-spatial dynamics of CVA6 in southern China remain poorly characterized. This study aimed to delineate the temporal phylodynamics of the CVA6 VP1 region in Shenzhen and identify lineage-defining mutations that may inform early-warning systems and control strategies. Methods Epidemiological surveillance data (2022–2024) were integrated with VP1 sequences from 47 Shenzhen isolates and 465 global reference strains (1949–2024). Real-time RT-PCR was used to determine serotype composition. Bayesian relaxed-clock, SkyGrid, and discrete phylogeographic models were applied to reconstruct substitution rates, lineage turnover, and transmission routes. Amino acid variability was mapped onto the VP1 protein structure. Results Among 195,951 notifiable disease cases, 11,427 (5.8%) were identified as HFMD, with seasonal peaks consistently observed in June and a maximum of 3,185 cases recorded in June 2023. CVA6 was detected in 30.9% of tested specimens and predominated in 2023 (64.6%). Root-to-tip regression showed a strong temporal signal (R² = 0.86), and the mean VP1 substitution rate was 4.78 × 10⁻³ substitutions/site/year (95% highest posterior density [HPD]: 4.39–5.16 × 10⁻³), with the estimated time to the most recent common ancestor (tMRCA) around 1945. All Shenzhen isolates belonged to genotype D3 and formed three temporally structured clades interspersed with isolates from various Chinese provinces, suggesting frequent interprovincial transmission and limited geographic clustering. SkyGrid analysis indicated a rapid expansion in the effective population size beginning in 2008, which stabilized after 2010. A total of 31 VP1 amino acid substitutions were identified; twelve (e.g., positions 5, 8, 10, 14, 32, 98, 160, 174, 194, 261, 279, 305) were fixed compared to the prototype strain Gdula, while six variable sites (e.g., S97N, N241D) were located in surface-exposed or BC-loop regions. Pairwise nucleotide distances among local strains were ≤ 6.7%, compared to 19.5–22.0% divergence from Gdula. Conclusions Genotype D3 of Coxsackievirus A6 appears to be a significant contributor to seasonal HFMD peaks in Shenzhen, particularly in early summer. Its high evolutionary rate, rapid lineage turnover, and limited geographic structuring emphasize the importance of coordinated, cross-regional molecular surveillance. The study identifies 31 amino acid substitutions, including surface-exposed sites, which may indicate ongoing antigenic drift and potential immune escape. These findings underscore the need for high-resolution genomic surveillance, early-warning systems, and region-specific control measures for effective management of HFMD. Clinical trial registration Not applicable.

Hand, foot and mouth disease (HFMD), a common contagious disease that usually affects children, is normally mild but can have life-threatening manifestations. It can be caused by enteroviruses, particularly Coxsackieviruses and human enterovirus 71 (HEV71) with highly variable clinical manifestations. In the spring of 2008, a large, unprecedented HFMD outbreak in Fuyang city of Anhui province in the central part of southeastern China resulted in a high aggregation of fatal cases. In this study, epidemiologic and clinical investigations, laboratory testing, and genetic analyses were performed to identify the causal pathogen of the outbreak. Of the 6,049 cases reported between 1 March and 9 May of 2008, 3023 (50%) were hospitalized, 353 (5.8%) were severe and 22 (0.36%) were fatal. HEV71 was confirmed as the etiological pathogen of the outbreak. Phylogenetic analyses of entire VP1 capsid protein sequence of 45 Fuyang HEV71 isolates showed that they belong to C4a cluster of the C4 subgenotype. In addition, genetic recombinations were found in the 3D region (RNA-dependent RNA polymerase, a major component of the viral replication complex of the genome) between the Fuyang HEV71 strain and Coxsackievirus A16 (CV-A16), resulting in a recombination virus. In conclusion, an emerging recombinant HEV71 was responsible for the HFMD outbreak in Fuyang City of China, 2008.

Genetic recombination is a well-known phenomenon for enteroviruses. To investigate the genetic characterization and the potential recombination of enterovirus 71 (EV71) circulating in China, we determined the 16 complete genome sequences of EV71 isolated from Hand Foot Mouth Disease (HFMD) patients during the large scale outbreak and non-outbreak years since 1998 in China. The full length genome sequences of 16 Chinese EV71 in present study were aligned with 186 genome sequences of EV71 available from GenBank, including 104 China mainland and 82 international sequences, covering the time period of 1970-2011. The oldest strains of each subgenotype of EV71 and prototype strains of HEV-A were included to do the phylogenetic and Simplot analysis. Phylogenetic analysis indicated that all Chinese strains were clustered into C4 subgenotype of EV71, except for HuB/CHN/2009 clustered into A and Xiamen/CHN/2009 clustered into B5 subgenotype. Most of C4 EV71 were clustered into 2 predominant evolutionary branches: C4b and C4a evolutionary brunches. Our comprehensive recombination analysis showed the evidence of genome recombination of subgenotype C4 (including C4a and C4b) sequences between structural genes from genotype C EV71 and non-structural genes from the prototype strains of CAV16, 14 and 4, but the evidence of intratypic recombination between C4 strains and B subgenotype was not enough strong. This intertypic recombination C4 viruses were first seen in 1998 and became the predominant endemic viruses circulating in China mainland for at least 14 years. A shift between C4a and C4b evolutionary brunches of C4 recombination viruses were observed, and C4a viruses have been associated with large scale nationwide HFMD outbreak with higher morbidity and mortality since 2007.

Southeast Asia, and Vietnam in particular, experience a significant burden of enterovirus A71 disease, with frequent outbreaks reported. This study reveals the endemicity, importation, and exportation of strains within the region informing public health measures and vaccination strategies. Abstract Background Enterovirus A71 (EV-A71) is the major cause of severe hand, foot, and mouth disease and viral encephalitis in children across the Asia-Pacific region, including in Vietnam, which has experienced a high burden of disease in recent years. Multiple subgenogroups (C1, C4, C5, and B5) concurrently circulate in the region with a large variation in epidemic severity. The relative differences in their evolution and epidemiology were examined within Vietnam and globally. Methods A total of 752 VP1 gene sequences were analyzed (413 generated in this study combined with 339 obtained from GenBank), collected from patients in 36 provinces in Vietnam during 2003–2013, along with epidemiological metadata. Globally representative VP1 gene datasets of subgenogroups were used to coestimate time-resolved phylogenies and relative genetic diversity to infer virus origins and regional transmission network. Results Despite frequent virus migration between countries, the highest genetic diversity of individual subgenogroups was maintained independently for several years in specific Asian countries representing genogroup-specific sources of EV-A71 diversity. Conclusion This study highlights a persistent transmission network of EV-A71, with specific Asian countries seeding other countries in the region and beyond, emphasizing the need for improved EV-A71 surveillance and detailed genetic and antigenic characterization.