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At least 19 recordsLinked to original sources
PubMed2005

Enteroviruses as agents of emerging infectious diseases.

Although the enteroviruses as a group are ubiquitous and not normally considered as "emerging pathogens," the many different serotypes circulate at different frequencies in any given year and the prevalence of a given serotype may fluctuate wildly from year to year. As a result, several enterovirus serotypes have been associated with the emergence of specific diseases (for example, pandemic acute hemorrhagic conjunctivitis) and specific serotypes have emerged to cause outbreaks of major public health concern. Enterovirus 71 is a recognized cause of epidemic severe central nervous system disease in Southeast Asia. Acute hemorrhagic conjunctivitis was a newly described disease in the 1970s associated with emergence of enterovirus 70 and coxsackievirus A24 variant. In addition, the impending eradication of poliovirus and some of the challenges currently faced by the eradication program present the possibility that poliomyelitis could emerge in the posteradication era. These links between enterovirus infections and emerging diseases are reviewed.

Animals↗
PubMed2002

Human rhinovirus 87 identified as human enterovirus 68 by VP4-based molecular diagnosis.

Human rhinoviruses (HRVs) are the major cause of respiratory infections. We developed a diagnostic method for HRVs based on the reverse-transcription polymerase chain reaction (RT-PCR) and VP4-based phylogenetic analysis. A set of primers used in the RT-PCR of human enteroviruses (EVs) appeared to be capable of amplifying all prototype strains of HRVs, each of which generated a 530-bp fragment. The single exception was HRV-87, which generated a 650-bp fragment, as observed in human EVs. The VP4 nucleotide sequence of HRV-87 showed more than 97% nucleotide identity with human EV-68, and formed a monophyletic cluster along with the prototype strain of EV-68 in the human EV-D cluster. HRV-87 showed the second highest homology (76.8%) with EV-70, another member of the human EV-D, in a sample of 66 human EVs and 12 HRVs. Therefore, HRV-87 should be reclassified into the cluster containing human EV-68.

Capsid Proteins↗
PubMed2025

Global Evolution and Transmission Dynamics of Enterovirus D68.

Enterovirus D68 (EV-D68), a serotype of the enterovirus species D, has garnered significant attention due to outbreaks reported in 2014, 2016, and 2018. In this study, 36 Chinese EV-D68 strains were isolated, sequenced, and combined with all EV-D68 VP1 sequences from GenBank to form a data set of 1679 sequences. This data set served as the basis for phylogenetic, evolutionary dynamics, phylogeographic, and key amino acid site mutation analyses of EV-D68. Based on the VP1 region, EV-D68 is classified into four genotypes (A-D), and seven subgenotypes (B1-B3, D1-D4), with B3 and D3 being the predominant subgenotypes. Bayesian skyline plots indicated that genotypes B and D experienced multiple population expansions, aligning with reported EV-D68 outbreaks. Phylogeographic analyses of the B3 subgenotypes revealed sequences from Europe and North America clustering into a single evolutionary branch, suggesting significant transmission between these regions. Additionally, mutation analysis identified VP1-98 as a high-frequency mutation site, differing significantly between the previously prevalent A and C genotypes and the currently prevalent B and D genotypes. However, the functional implications of this mutation require further investigation. This study provides a solid theoretical basis for epidemiological research, disease surveillance, and prevention efforts related to EV-D68.

Enterovirus Infections↗
PubMed2003

Systemic and ocular antibody responses to inactivated acute hemorrhagic conjunctivitis (AHC) virus; enterovirus 70 (EV70).

PURPOSE: Evaluate the immune response in rabbits injected with EV70, the agent of acute hemorrhagic conjunctivitis (AHC) and AHC associated neuropathy. METHODS: Rabbits were injected intramuscularly with uv-light inactivated EV70 isolate J670/71. Neutralizing activity against EV70 was quantified in serum and tear samples and the immunoglobulin (Ig) classes of the neutralizing activity in serum identified by sucrose gradient ultra-centrifugation. Adjuvant muramyl dipeptide (MDP) was applied topically to assess the role of ocular inflammation on levels of neutralizing antibody, proteins and Ig in tears. The protective effects of human and rabbit sera and interferon-alpha (IFN-alpha) against EV70 were compared in human conjunctival and lens cells. RESULTS: Sera collected at 6 and 13 d contained 19S IgM anti-EV70 neutralizing antibody, while serum collected 21 d post injection contained 19S IgM and 7S IgG anti-EV70 neutralizing antibody. Low titers of anti-EV70 activity (< or =30 U/ml) were detected in tears of seropositive rabbits. MDP induction of conjunctivitis in seropositive rabbits increased tear IgG concentration (3-fold) and anti-EV70 neutralizing antibody titers (> or =10-fold). The protective effect of the rabbit and human sera against EV70 infection in conjunctival, but not lens epithelial cells, was enhanced by the addition of IFN-alpha. CONCLUSIONS: Immunization with uv-light inactivated EV70 elicits a classical humoral immune response in rabbits. The protective activity of serum in EV70-infected human conjunctival cells, but not lens cells, was increased by IFN-alpha. Adjuvant MDP-induced conjunctivitis, increased blood-conjunctival barrier (BCB) permeability and anti-EV70 neutralizing activity in tear of seropositive rabbits. The results suggest immunization with inactivated EV70 could provide systemic as well as ocular protection during natural EV70 infection.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2005

Enterovirus 70 binds to different glycoconjugates containing alpha2,3-linked sialic acid on different cell lines.

Enterovirus 70 (EV70), the causative agent of acute hemorrhagic conjunctivitis, exhibits a restricted tropism for conjunctival and corneal cells in vivo but infects a wide spectrum of mammalian cells in culture. Previously, we demonstrated that human CD55 is a receptor for EV70 on HeLa cells but that EV70 also binds to sialic acid-containing receptors on a variety of other human cell lines. Virus recognition of sialic acid attached to underlying glycans by a particular glycosidic linkage may contribute to host range, tissue tropism, and pathogenesis. Therefore, we tested the possibility that EV70 binds to alpha2,3-linked sialic acid, like other viruses associated with ocular infections. Through the use of linkage-specific sialidases, sialyltransferases, and lectins, we show that EV70 recognizes alpha2,3-linked sialic acid on human corneal epithelial cells and on U-937 cells. Virus attachment to both cell lines is CD55 independent and sensitive to benzyl N-acetyl-alpha-D-galactosaminide, an inhibitor of O-linked glycosylation. Virus binding to corneal cells, but not U-937 cells, is inhibited by proteinase K, but not by phosphatidylinositol-specific phospholipase C treatment. These results are consistent with the idea that a major EV70 receptor on corneal epithelial cells is an O-glycosylated, non-glycosyl phosphatidylinositol-anchored membrane glycoprotein containing alpha2,3-linked sialic acid, while sialylated receptors on U-937 cells are not proteinaceous.

Animals↗
PubMed2004

Enterovirus 68 is associated with respiratory illness and shares biological features with both the enteroviruses and the rhinoviruses.

Enterovirus (EV) 68 was originally isolated in California in 1962 from four children with respiratory illness. Since that time, reports of EV68 isolation have been very uncommon. Between 1989 and 2003, 12 additional EV68 clinical isolates were identified and characterized, all of which were obtained from respiratory specimens of patients with respiratory tract illnesses. No EV68 isolates from enteric specimens have been identified from these same laboratories. These recent isolates, as well as the original California strains and human rhinovirus (HRV) 87 (recently shown to be an isolate of EV68 and distinct from the other human rhinoviruses), were compared by partial nucleotide sequencing in three genomic regions (partial sequencing of the 5'-non-translated region and 3D polymerase gene, and complete sequencing of the VP1 capsid gene). The EV68 isolates, including HRV87, were monophyletic in all three regions of the genome. EV68 isolates and HRV87 grew poorly at 37 degrees C relative to growth at 33 degrees C and their titres were reduced by incubation at pH 3.0, whereas the control enterovirus, echovirus 11, grew equally well at 33 and 37 degrees C and its titre was not affected by treatment at pH 3.0. Acid lability and a lower optimum growth temperature are characteristic features of the human rhinoviruses. It is concluded that EV68 is primarily an agent of respiratory disease and that it shares important biological and molecular properties with both the enteroviruses and the rhinoviruses.

Adult↗
PubMed2005

Immunogenicity of enterovirus 70 capsid protein VP1 and its non-overlapping N- and C-terminal fragments.

Currently no practical treatment method or effective virus vaccine is available for acute hemorrhagic conjunctivitis (AHC) caused by enterovirus 70 (EV70). Antibodies to UV-inactivated EV70 (J670/71 epidemic isolate) and to the inclusion bodies of recombinant proteins of full-length EV70 VP1 (GST-VP1m), its non-overlapping terminal fragments N138 (1-138 aa) and C170 (141-310 aa) (or GST-N138m and GST-C170) were developed in rabbits. The anti-EV70 neutralizing activities of the rabbit sera were determined by standard neutralization assays. The antibodies to UV-inactivated EV70, were immuno-reactive with EV70 capsid proteins VP1 and VP3 of four EV70 epidemic isolates (KW/97, T260/74, J670/71 and AE/72) in Western-blot analysis, and immunoprecipitated the capsid proteins VP1 and VP3 from the cell lysates of virus-infected human Chang's conjunctival (HCC) cells. The antibodies to GST-VP1m, GST-N138m and GST-C170, immunoprecipitated only the VP1 proteins of the four EV70 isolates. Anti-EV70 J670/71 antibodies and the antibodies to the three recombinant VP1 proteins were all capable of immunoprecipitating EV70 whole-virus of the four EV70 epidemic isolates grown in HCC cells. The anti-EV70 virion antibodies neutralized EV70 isolates with titers of 6000-10,000 units/ml while the antibodies to GST-VP1m, GST-N138m or GST-C170 neutralized EV70 isolates with titers of 20-320units/ml. The results suggest that (a) immunization with bacterially produced recombinant EV70 VP1 and its non-overlapping N- and C-terminal fragments, was capable of eliciting EV70-neutralizing antibodies; (b) the neutralization titers of antibodies to the recombinant VP1 proteins were lower than that of antibodies to the UV-inactivated EV70 virions; and (c) the non-overlapping N138 and C170 fragments of EV70 VP1 both harbor independent anti-EV70 neutralization antigenic sites.

Antibodies, Viral↗
PubMed2005

Management of subconjunctival haematoma by tissue plasminogen activator.

A patient with subconjunctival haematoma related to enterovirus 70 who was treated with tissue plasminogen activator (tPA) is reported. A 46-year-old man developed a severe subconjunctival haematoma and discharge in the left eye. Investigations, including coagulation tests, showed no abnormalities apart from a high-serum antibody titre for enterovirus 70. The polymerase chain reaction demonstrated enterovirus 70 DNA in resected conjunctival tissue, leading to a diagnosis of acute haemorrhagic conjunctivitis. The left eye was treated with a single subconjunctival injection of tPA (16 000 IU) and the subconjunctival haematoma resolved completely after 3 days. Severe subconjunctival haematoma can occur in patients with acute haemorrhagic conjunctivitis due to enterovirus 70. Subconjunctival injection of tPA may be useful for the treatment of severe subconjunctival haematoma.

Conjunctivitis, Acute Hemorrhagic↗
PubMed2003

Enterovirus 71 infection induces apoptosis in Vero cells.

The effects of Enterovirus 71 (HEV71) infection on African green monkey kidney cells (Vero) were investigated. It was found that the infected cells showed progressive cellular morphological changes characteristic in apoptotic cells within 10 hours post-infection. The number of apoptotic cells correlated significantly with the number of HEV71 antigen positive cells when cells were labeled using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) and stained for HEV71 antigen. Approximately 11, 26, 45 and 50% of the infected cells were apoptotic at 12, 24, 48 and 72 hours post-infection, respectively. Internucleosomal DNA fragmentation, characteristic in the late stage of apoptosis was noted beginning on day 2 post-infection. The DNA fragmentation, however, was absent in cells treated with the heat- and ultraviolet light-inactivated virus inocula. These results demonstrate the capacity of HEV71 to induce apoptosis in the infected cells. The induction, however, requires high level of HEV71 infectivity and the presence of live virus particles, suggesting the need for the presence of specific viral proteins for apoptosis to occur.

Animals↗
PubMed2025

Outbreak of Enterovirus D68 in Young Children, Brescia, Italy, August to November 2024.

Enterovirus D68 (EV-D68) is responsible for a plethora of clinical manifestations ranging from asymptomatic infections to severe respiratory symptoms and neurological disorders. EV-D68 was first detected in children with pneumonia in 1962 and, from then, only sporadic cases were reported until 2014, when outbreaks were notified across the world. After the withdrawal of preventive measures against SARS-CoV-2, a significant increase in EV-D68 infections has been reported in 2021-2022. A surveillance program to evaluate the incidence of enterovirus/rhinovirus (EV/RV) infections was implemented at the Brescia Civic Hospital, Italy. Fifty-five EV/RV-positive respiratory samples, belonging to pediatric patients, were subjected to NGS. We observed that 61.8% of samples were positive for EV, with EV-D68 as the most prevalent genotype predominantly detected between August and November 2024. Phylogenetic analysis revealed that EV-D68 sequences formed two monophyletic clades corresponding to the A2 and B3 lineages, highlighting their recent introduction in Italy. Interestingly, 40% of pediatric EV-D68 infections were detected with at least one other EV/RV. Our study highlights the crucial role played by genomic surveillance of respiratory infections to monitor the circulation of emerging and re-emerging viruses, as well as their evolution. This will be fundamental to enable prompt intervention strategies.

Humans↗
PubMed2004

Binding to decay-accelerating factor is not required for infection of human leukocyte cell lines by enterovirus 70.

Enterovirus 70 (EV70) is one of several human enteroviruses that exhibit a propensity for infecting the central nervous system (CNS). The mechanisms by which neurotropic enteroviruses gain access to and invade the CNS are poorly understood. One possibility is that circulating leukocytes become infected and carry neurotropic enteroviruses to the CNS. We examined the ability of EV70 to infect cell lines derived from lymphoid, myeloid, and monocytic lineages. Most leukocyte cell lines tested bound radiolabeled EV70 and were permissive for EV70 replication, suggesting that EV70, in contrast to other enteroviruses, has an in vitro tropism that includes lymphoid, monocytic, and myeloid cell lines. For some of the cell lines, virus binding and infection correlated with surface expression of decay-accelerating factor (DAF), an attachment protein for EV70 on HeLa cells. However, EV70 also adsorbed to and infected cell lines that expressed little or no DAF. In contrast to what was observed for HeLa cells, neither DAF-specific monoclonal antibodies nor phosphatidylinositol-specific phospholipase C treatment inhibited EV70 binding to permissive leukocyte cell lines, and antibody blockade of DAF had little or no effect on EV70 replication. We also found that neither the human coxsackievirus-adenovirus receptor nor intercellular cell adhesion molecule 1, which mediate the entry of coxsackie B viruses and coxsackievirus A21, respectively, functions as a receptor for EV70. EV70 binding to all cell lines was sensitive to sialidase treatment and to inhibition of O glycosylation by benzyl N-acetyl-alpha-D-galactosaminide. Taken together, these results suggest that a sialylated molecule(s) other than DAF serves as a receptor for EV70 on permissive human leukocyte cell lines.

Animals↗
PubMed2026

Genomic surveillance of enterovirus D68 circulating in 2025 reveals the emergence of a novel A2/B3 recombinant lineage.

Enterovirus D68 (EV-D68) has re-emerged over the past decade as a significant respiratory pathogen associated with severe respiratory disease and acute flaccid myelitis. Its circulation has typically followed a biennial pattern, with predominance in late summer and early fall, a pattern that was temporarily disrupted during the COVID-19 pandemic. Surveillance in 2025 revealed off-season circulation of EV-D68. This study describes the genomic characteristics of the 2025 EV-D68 viruses and the clinical features of affected patients. Between May and December 2025, remnant respiratory specimens positive for rhinovirus/enterovirus were screened for EV-D68 and subjected to whole-genome sequencing. Phylogenetic analyses were performed using maximum-likelihood methods. Recombination was assessed using subgenomic phylogenies, SimPlot similarity and BootScan analyses, and read-level inspection. Among 1,321 patients tested, 147 (11.1%) were EV-D68-positive, and 119 (81.0%) yielded complete genomes. EV-D68 positivity increased in July 2025, peaked in August (~21%), and remained elevated through September and October, exceeding levels observed in 2024. Patients had a median age of 36 years, with infections disproportionately affecting older adults. Phylogenetic analysis demonstrated exclusive circulation of subclade A2. Five genomes formed a distinct recombinant lineage (A2-Re). Subgenomic phylogenies showed clustering with A2 viruses in the P1 region and with B3 viruses in the P2-P3 regions. SimPlot and BootScan analyses identified a recombination breakpoint near the 2A/2B junction (~nt 3,700). The recombinant lineage was associated with temporally clustered cases in September-October. These findings demonstrate recombination between distinct EV-D68 subclades and underscore the importance of whole-genome surveillance for accurate viral characterization. Continued genomic monitoring is essential for detecting emerging variants with potential implications for transmissibility, pathogenicity, and public health preparedness.IMPORTANCEThis study highlights an increased off-season circulation of Enterovirus D68 (EV-D68) and a higher burden of disease in adults in 2025. The identification of a novel A2-B3 recombinant lineage provides evidence of ongoing viral evolution through recombination, a mechanism that may alter transmissibility, virulence, or immune responses. Detection of this lineage in temporally clustered cases suggests local transmission and underscores the potential for rapid spread of newly emerged variants. These findings emphasize the limitations of partial genomic approaches and the critical role of whole-genome sequencing in accurately characterizing circulating strains and identifying recombination events. Enhanced genomic surveillance is essential to detect emerging variants in real time, inform diagnostic assay performance, and support public health responses. Continued monitoring of EV-D68 evolution will be important for anticipating changes in disease burden, guiding clinical awareness, and strengthening preparedness for future outbreaks.

Humans↗
PubMed2025

EV-D68 cleaves LARP1 and PABPC1 by 3Cpro to redirect host mRNA translation machinery toward its genomic RNA.

Enterovirus D68 (EV-D68) is an emerging pathogen associated with severe respiratory diseases and neurological complications, such as acute flaccid myelitis. EV-D68 has developed sophisticated mechanisms to hijack host translation machinery, facilitating its replication and impairing host mRNA translation. In this study, we demonstrate that EV-D68 cleaves La-related protein 1 (LARP1) and poly(A)-binding protein cytoplasmic 1 (PABPC1) through its proteases 3Cpro and 2Apro. Our results indicate that overexpressing LARP1 and PABPC1 significantly inhibits EV-D68 replication and reduces the virus-mediated suppression of host translation. While both LARP1 and PABPC1 regulate translation, they exert antiviral effects through distinct mechanisms. We found that LARP1 interacts with the 5'UTR of EV-D68 RNA through its LAM domain, and this interaction is crucial for its antiviral function. LARP1 translation modulation is also influenced by the mTOR and CDK1 signaling pathways. Viral infection inhibits mTOR and CDK1 phosphorylation, which enhances LARP1's binding to viral RNA and inhibits viral translation. To counteract this inhibition, EV-D68 cleaves LARP1 through 3Cpro, thereby promoting efficient viral translation. We also investigated other enteroviruses, such as EV-A71 and CV-A16, which similarly target LARP1 and PABPC1, indicating a conserved mechanism across enteroviruses. Our findings offer new insights into how EV-D68 manipulates host translation and highlight the potential of targeting LARP1 and PABPC1 for antiviral interventions.

Humans↗
PubMed2002

Genetic clustering of all 102 human rhinovirus prototype strains: serotype 87 is close to human enterovirus 70.

Human rhinoviruses (HRV), common agents of respiratory infections, comprise 102 designated serotypes. The genetic relationships of HRV prototype strains and the possibility of using genetic identification of a given HRV field strain were studied. Genomic sequences in the VP4/VP2 region were obtained from all 102 prototype strains. Phylogenetic analysis included 61 recently isolated Finnish field strains. Seventy-six out of the 102 prototype strains clustered in the HRV genetic group A and 25 in group B. Serotype 87 clustered separately and together with human enterovirus 70. The 'percentage' interserotypic differences were generally similar to those between different enterovirus serotypes, but for six pairs of HRV serotypes they were less than 10%. The maximum variation in genetic group A was 41% at the nucleotide level and 28% at the amino acid level, and in genetic group B 34% and 20%, respectively. Judging from the observed interserotypic differences, the 61 Finnish field isolates might represent as many as 19 different serotypes. One cluster of the field strains did not directly associate with any of the prototype strains and might represent a new serotype. However, larger numbers of field isolates of known serotype need to be characterized, possibly also in the VP1 region, to evaluate the feasibility of genetic typing of HRV strains.

Capsid↗
PubMed2002

Human rhinovirus 87 and enterovirus 68 represent a unique serotype with rhinovirus and enterovirus features.

It has recently been reported that all but one of the 102 known serotypes of the genus Rhinovirus segregate into two genetic clusters (C. Savolainen, S. Blomqvist, M. N. Mulders, and T. Hovi, J. Gen. Virol. 83:333-340, 2002). The only exception is human rhinovirus 87 (HRV87). Here we demonstrate that HRV87 is genetically and antigenically highly similar to enterovirus 68 (EV68) and is related to EV70, the other member of human enterovirus group D. The partial nucleotide sequences of the 5' untranslated region, capsid regions VP4/VP2 and VP1, and the 3D RNA polymerase gene of the HRV87 prototype strain F02-3607 Corn showed 97.3, 97.8, 95.2, and 95.9% identity to the corresponding regions of EV68 prototype strain Fermon. The amino acid identities were 100 and 98.1% for the products of the two capsid regions and 97.9% for 3D RNA polymerase. Antigenic cross-reaction between HRV87 and EV68 was indicated by microneutralization with monotypic antisera. Phylogenetic analysis showed definite clustering of HRV87 and EV68 with EV70 for all sequences examined. Both HRV87 and EV68 were shown to be acid sensitive by two different assays, while EV70 was acid resistant, which is typical of enteroviruses. The cytopathic effect induced by HRV87 or EV68 was inhibited by monoclonal antibodies to the decay-accelerating factor known to be the receptor of EV70. We conclude that HRV87 and EV68 are strains of the same picornavirus serotype presenting features of both rhinoviruses and enteroviruses.

Amino Acid Sequence↗