Search Results (59)

Non-polio enteroviruses continue to cause numerous epidemics world-wide that range from mild to severe disease, including acute flaccid paralysis, meningitis, severe respiratory infections and encephalitis. Using publicly available data we present a comprehensive global and regional temporal distribution of non-polio enteroviruses, with a focus on highly prevalent genotypes. We found that regional distribution did vary compared to global prevalence where the top prevalent genotypes included CVA6 and EV-A71 in Asia, EV-D68 in North America and CVA13 in Africa, while E-30 was prevalent in Europe, South America and Oceania. In 2020, the COVID-19 pandemic did interrupt non-polio enterovirus detections globally, and cases rebounded in subsequent years, albeit at lower prevalence and with decreased genotype diversity. Environmental surveillance for non-polio enteroviruses does occur and has been used in some regions as an early-warning system; however, further development is needed to effectively supplement potential gaps in clinical surveillance data. Overall, monitoring for non-polio enteroviruses is critical to identify true incidence, improve understanding of genotype circulation, provide an early warning system for emerging/re-emerging genotypes and allow for better outbreak control. Full article

This study explored the distribution and genetic characteristics of respiratory pathogens in outpatients with acute respiratory infections (ARIs) in Yangon, Myanmar, during the 2023 rainy season. Among 267 patients who tested negative for influenza, RSV, and SARS-CoV-2 using rapid diagnostic tests, 84.6% were positive for at least one pathogen according to a multiplex polymerase chain reaction (PCR) assay, the BioFire^® FilmArray^® Respiratory Panel 2.1. The most common viruses detected were rhinovirus/enterovirus (RV/EV) at 37.8%, respiratory syncytial virus (RSV) at 22.4%, and human metapneumovirus (hMPV) at 10.0%. These pathogens co-circulated mainly from July to September, with RV/EV consistently predominant. Symptom comparison among RV/EV-, RSV-, and hMPV-infected patients showed similar clinical features, though fever was more common in hMPV cases. Among RV/EV-positive patients, 59.3% had single infections, while 40.7% experienced co-infections, especially with RSV and adenovirus. Genotyping identified 28 types from five species, primarily RV-A and RV-C, which were genetically diverse. One EV-D68 case was also found, emphasizing its potential risk. This study underscores the genetic diversity and clinical impact of RV/EV and stresses the importance of ongoing molecular surveillance in Myanmar’s post-COVID-19 context to inform effective public health responses. Full article

Background/Objectives: Enterovirus-D68 (EV-D68) and rhinoviruses are major contributors to respiratory illnesses in children, presenting a spectrum of clinical manifestations ranging from asymptomatic cases to severe lower respiratory tract infections. No specific antiviral treatments are currently approved for these viruses. Method: We conducted a comprehensive literature review of antiviral agents investigated for EV-D68 and rhinovirus infections. Results: Several antiviral candidates are under investigation, each targeting distinct stages of the viral replicative cycle. Capsid-binding agents and monoclonal antibodies prevent viral attachment by blocking receptor-virus interactions. Inhibitors of viral replication proteins disrupt polyprotein processing and replication organelle biogenesis by targeting non-structural viral proteins. Host factor inhibitors impair viral attachment, replication organelle formation, or RNA replication by interfering with critical host pathways. Conclusions: While no specific antivirals are yet approved for EV-D68 and rhinovirus infections, emerging therapeutic candidates offer potential avenues for treatment. Continued preclinical and clinical investigation will be essential to validate these approaches and expand the available options for affected patients. Full article

Enterovirus D68 (EV-D68) caused large biennial cyclical outbreaks of respiratory disease and cases of acute flaccid myelitis from 2014 to 2018 in the USA. An anticipated outbreak did not occur in 2020, likely due to non-pharmaceutical interventions targeting the COVID-19 pandemic. A large respiratory disease outbreak occurred again in 2022, but uncertainty remained regarding if circulation of EV-D68 would return to the pre-pandemic patterns. We conducted prospective active surveillance of clinical respiratory specimens from Colorado children for EV-D68 in 2023 and 2024. A subset of residual specimens positive for rhinovirus/enterovirus (RV/EV) were tested for EV-D68 via a validated in-house EV-D68 reverse transcription–PCR assay. During epi weeks 18–44 in 2023, 525 residual specimens positive for RV/EV all tested negative for EV-D68. In 2024, during epi weeks 18–44, 10 (1.8%) of the 546 RV/EV-positive specimens were EV-D68-positive. The EV-D68-positive cases were predominantly young children (median age 4.8 years) receiving treatment with asthma medications. Following the 2022 EV-D68 outbreak, an anticipated outbreak did not occur in 2023. While EV-D68 was detected in 2024, the number of cases was not as significant as in prior outbreak years. Continued surveillance for EV-D68 will be important to understand the future dynamics of EV-D68 circulation and prepare for future outbreaks. Full article

Hand-foot-and-mouth disease (HFMD) caused by Enterovirus 71 (EV71) is highly infectious and can lead to serious neurological complications. This study proposed to evaluate the seroprevalence of EV71 in children of two states of western India by estimating neutralizing antibodies (nAbs) to EV71 genotypes D, G, and C isolated in India, using micro-neutralization assay. Among the serum samples of 612 children tested, 213 (34.80%, 95% CI: 31.00–38.73) and 312 (51.00%, 95% CI: 47.00–55.00) were positive for nAbs to EV71 BrCr and indigenous genotype D, respectively, with a significant rise with age for genotype D. However, compared to other age groups, only 23.2% of children aged 1–5 years showed nAbs to EV71 genotype D with a considerably lower Geometric Mean Titer, indicating the susceptibility of this age group to EV71 infection. Our study confirms the circulation of EV71 in India with relatively high susceptibility of children up to 5 years to EV71 infections. Full article

Background: Gastroparesis, a chronic digestive disorder characterized by delayed gastric emptying, often results from diabetes, post-surgical complications, autoimmune diseases, and neurological disorders. In approximately 50% of cases, the cause is idiopathic gastroparesis (IGD). Recent studies suggest a link between chronic enteroviral infection and persistent gastrointestinal symptoms, including delayed gastric emptying. This study investigates the effects of a silydianin-rich extract from Silybum marianum seeds on enteroviral infections in vitro and the mitigation of delayed gastric emptying in mice. Silydianin, a key bioactive compound known for its liver-protective and antioxidant properties, has not been extensively studied for its impact on enteroviral infections and gastroparesis. Methods: NMR spectroscopy (¹H, ¹³C, DEPT 135 and 2D, and HSQC) and HRMS identified silydianin as the primary compound, with minor flavonolignans. This study assessed the cytotoxicity and antiviral activity of the extract at various stages of the viral life cycle, including virucidal activity, cell protection, and post-infection effects, using neutral red assays in RD cells, with results confirmed by real-time PCR. The viruses studied included coxsackievirus B2, coxsackievirus A10, poliovirus SL-1, and enterovirus EV71. The impact on delayed gastric emptying was evaluated in a mouse model using doses of 100 and 200 mg/kg compared to a control group receiving physiological saline. Results: The silydianin-rich extract showed consistent antiviral activity, with the highest selectivity index (SI) for EV71 (4.08) during virucidal activity. It provided moderate cell protection, with EC₅₀ values ranging from 120.88 to 186.10 µg/mL and SI values from 2.20 to 3.39. Post-infection treatment showed varying efficacy, with coxsackie A10 demonstrating the highest SI (3.90). In vivo, the extract at 200 mg/kg significantly improved gastric emptying to 96.47% and slightly increased gastrointestinal transit from 50.33% to 61.46%. Conclusions: These results suggest that silydianin may be effective for treating enteroviral infections and enhancing intestinal function, making it a promising candidate for gastroparesis treatment and warranting further research. Full article

Enterovirus D68 (EV-D68) is a leading cause of acute respiratory disease outbreaks, especially among children. EV-D68 infections can rapidly progress to severe clinical complications and potentially fatal outcomes. In Brazil, no diagnostic or genomic surveillance of this virus is currently performed. Between July and September 2023, cases of acute EV-D68 infection were identified among pediatric patients in several municipalities within the State of Alagoas, Northeast Brazil. Infections were confirmed by RT-qPCR using nasopharyngeal samples, and the complete EV-D68 genomes were sequenced and analyzed through phylogenetic inference. EV-D68 RNA was identified in four children aged 1–9 years from four geographically distinct municipalities in Alagoas. All infections were associated with lower respiratory tract symptoms, including dyspnea and wheezing; however, no fatalities were reported. Complete genomic sequencing revealed that the samples belonged to genotype B, subgenotype B3. This is the first study to report complete genomic data on EV-D68 infections from Brazil and South America. Enhanced genomic surveillance and focused EV-D68 diagnosis are critical to better understanding and managing the regional and national dissemination of this virus. Full article

Enterovirus 68 (EV-D68) is a non-enveloped virus with a positive-sense single-stranded RNA genome that causes respiratory diseases and acute flaccid myelitis, posing significant threats to human health. However, an effective vaccine remains undeveloped. SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent enzyme, plays a key role in cellular metabolism, but its interaction with NAD+ during viral infections is not well understood. In this study, through a metabolomics analysis, we demonstrate that EV-D68 infection influences cellular metabolism. Additionally, we show that NAD+ inhibits EV-D68 infection both in vivo and in vitro. EV-D68 reduces cellular NAD+ levels by regulating the expression of enzymes involved in NAD+ consumption and synthesis. Moreover, the infection increases the expression of sirtuin 1 (SIRT1), which inhibits EV-D68 replication in turn. Mechanistically, SIRT1 suppresses EV-D68 5′UTR-mediated translation, and the antiviral effect of SIRT1 on EV-D68 replication is enhanced by NAD+. Collectively, our findings highlight the critical role of NAD+ metabolism in EV-D68 infection and reveal the antiviral potential of SIRT1, providing valuable insights for the development of antiviral strategies. Full article

Background: The impact of respiratory viral infections associated with Kawasaki Disease (KD) cases on KD’s clinical presentation and initial response to treatment has not been clearly determined. Objective: This study aimed to evaluate respiratory viral infections using FilmArray Respiratory Panel (FARP) testing and analyze the effect of the concurrent presence of pathogens on clinical presentations of KD. Methods: Between January 2021 and June 2023, we conducted a retrospective, single-center observational study of 105 Japanese children with KD. KD was diagnosed and treated according to RAISE study guidelines, and the cases’ clinical information was assessed. FARP testing was performed in 71 out of 105 KD cases with fever and/or respiratory symptoms. Results: In 38 (53.5%) out of 71 cases, at least one virus was detected. The FARP-positive cases tended to have a higher frequency of Kobayashi scores (K-scores) ≥ 5 than the negative cases (42.1% vs. 21.2%), and lower initial treatment failure (7.89% vs. 21.2%). The most common virus detected was rhino/enterovirus (RV/EV: 27 cases), followed by seven cases of respiratory syncytial virus (RSV). RV/EV-positive KD cases did not differ significantly in their clinical data or the frequency of K-scores ≥ 5, and RSV-positive cases showed significantly elevated liver enzyme (AST:59 U/L (43.5–150.5) vs. 35 U/L (27–41), ALT:40 U/L (28.5–244.5) vs. 18 U/L (14–27)) and CRP levels (12 mg/dL (7.3–14.2) vs. 6.5 mg/dL (4.1–8.5)), and an increased frequency of K-scores ≥ 5 (71.4% vs. 21.2%) compared to FARP-negative cases. KD cases that were also RSV-positive or RV/EV-positive showed favorable responses to initial treatments. Conclusions: Concurrent respiratory virus infection could affect the clinical manifestation and initial treatment response of KD. Full article

Enterovirus-D68 (EV68) continues to present as a global health issue causing respiratory illness and outbreaks associated with long-lasting neurological disease, with no antivirals or specific treatment options. The development of antiviral therapeutics, such as small-molecule inhibitors that target conserved proteins like the enteroviral 3C protease, remains to be achieved. While various 3C inhibitors have been investigated, their design does not consider the potential emergence of drug resistance mutations. For other antivirals where resistance has been a challenge, we have demonstrated that the likelihood of resistance can be minimized by designing inhibitors that leverage the evolutionary constraints of the target. Here, we characterize a series of 3C inhibitors against EV68-3C protease through enzyme inhibition, protein crystallography, and structural analysis. We have determined and analyzed three high-resolution inhibitor-bound crystal structures of EV68-3C protease, which revealed possible sites of resistance mutations, a key structural water molecule conserved during ligand binding, and the conformational flexibility of the catalytic histidine H40. This structural analysis combined with enzymatic assays provides insights for the rational design of inhibitors that are robust against resistance toward developing antiviral treatments for EV68 infections. Full article

Four previously undescribed pentacyclic triterpenoid saponins, pannosides F–I (1–4), were isolated from the halophyte Aster tripolium L. (Tripolium pannonicum), and their chemical structures were elucidated using 1D and 2D NMR spectroscopy and mass spectrometry. Comprehensive structural analysis revealed the presence of distinct aglycone and glycosidic moieties, along with complex acylation patterns. The acyl chains of pannosides, 3-hydroxybutyrate (3-HB) residues, were derivatized with (S)- and (R)- phenylglycine methyl ester to resolve the absolute configurations of the chiral centers in 3-HB. Then, the acyl chain-containing saponins, pannosides were evaluated for their antiviral activities against enterovirus A71 (EV71), coxsackievirus B3 (CVB3), and rhinovirus 1B (HRV1B). Pannosides exhibited antiviral activities against HRV1B, EV71, and CVB3. These findings suggest that saponins from A. tripolium exhibit potential antiviral activities and could be further explored for their therapeutic applications. Full article

Enteroviruses have been a historical concern since the identification of polioviruses in humans. Wild polioviruses have almost been eliminated, while multiple species of non-polio enteroviruses and their variants co-circulate annually. To date, at least 116 types have been found in humans and are grouped into the species Enterovirus A–D and Rhinovirus A–C. However, there are few available antiviral drugs, especially with a universal pharmaceutical effect. Here, we demonstrate that peptide P25 from EV-D68 has broad antiviral activity against EV A–D enteroviruses in vitro. P25, derived from the HI loop and β-I sheet of VP1, operates through a conserved hydrophilic motif -R---K-K--K- and the hydrophobic F near the N-terminus. It could prevent viral infection of EV-A71 by competing for the heparan sulfate (HS) receptor, binding and stabilizing virions by suppressing the release of the viral genome. P25 also inhibited the generation of infectious viral particles by reducing viral protein synthesis. The molecular docking revealed that P25 might bind to the pocket opening area, a potential target for broad-spectrum antivirals. Our findings implicate the multiple antiviral effects of peptide P25, including blocking viral binding to the HS receptor, impeding viral genome release, and reducing progeny particles, which could be a novel universal anti-enterovirus drug candidate. Full article

Some respiratory viruses, such as Human Rhinovirus, SARS-CoV-2, and Enterovirus D-68 (EV-D68), share the feature of hijacking host lipids in order to generate specialised replication organelles (ROs) with unique lipid compositions to enable viral replication. We have recently uncovered a novel non-canonical function of the stimulator of interferon genes (STING) pathway, as a critical factor in the formation of ROs in response to HRV infection. The STING pathway is the main DNA virus sensing system of the innate immune system controlling the type I IFN machinery. Although it is well-characterised as part of the DNA sensor machinery, the STING function in RNA viral infections is largely unexplored. In the current study, we investigated whether other RO-forming RNA viruses, such as EV-D68 and SARS-CoV-2, can also utilise STING for their replication. Using genetic and pharmacological inhibition, we demonstrate that STING is hijacked by these viruses and is utilised as part of the viral replication machinery. STING also co-localises with glycolytic enzymes needed to fuel the energy for replication. The inhibition of STING leads to the modulation of glucose metabolism in EV-D68-infected cells, suggesting that it might also manipulate immunometabolism. Therefore, for RO-generating RNA viruses, STING seems to have non-canonical functions in membrane lipid re-modelling, and the formation of replication vesicles, as well as immunometabolism. Full article

Enterovirus-D68 (EV68) has emerged as a global health concern over the last decade with severe symptomatic infections resulting in long-lasting neurological deficits and death. Unfortunately, there are currently no FDA-approved antiviral drugs for EV68 or any other non-polio enterovirus. One particularly attractive class of potential drugs are small molecules inhibitors, which can target the conserved active site of EV68-3C protease. For other viral proteases, we have demonstrated that the emergence of drug resistance can be minimized by designing inhibitors that leverage the evolutionary constraints of substrate specificity. However, the structural characterization of EV68-3C protease bound to its substrates has been lacking. Here, we have determined the substrate specificity of EV68-3C protease through molecular modeling, molecular dynamics (MD) simulations, and co-crystal structures. Molecular models enabled us to successfully characterize the conserved hydrogen-bond networks between EV68-3C protease and the peptides corresponding to the viral cleavage sites. In addition, co-crystal structures we determined have revealed substrate-induced conformational changes of the protease which involved new interactions, primarily surrounding the S1 pocket. We calculated the substrate envelope, the three-dimensional consensus volume occupied by the substrates within the active site. With the elucidation of the EV68-3C protease substrate envelope, we evaluated how 3C protease inhibitors, AG7088 and SG-85, fit within the active site to predict potential resistance mutations. Full article

Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease in infants and children with potential for fatal complications such as encephalitis and acute flaccid myelitis. This study examined the long-term immunity conferred by EV71vac, an inactivated EV-A71 vaccine adjuvanted with aluminum phosphate, in children from the age of 2 months to <6 years, for up to 5 years after the first immunization. A total of 227 participants between 2 months and <6 years of age who had previously received either EV71vac or placebo in the phase two clinical study were enrolled. Subjects were divided into age groups: 2 years to <6 years (Group 2b), 6 months to <2 years (Group 2c), and 2 months to <6 months (Group 2d). At Year 5, the neutralizing antibody titers against the B4 subgenotype remained high at 621.38 to 978.20, 841.40 to 1159.93, and 477.71 to 745.07 for Groups 2b, 2c, and 2d, respectively. Cross-neutralizing titers at Year 5 remained high against B5 and C4a subgenotypes, respectively. No long-term safety issues were reported. Our study provides novel insights into the long-term immunity conferred by EV71vac in children aged from two months to six years, particularly in those who received EV71vac between two and six months of age. Full article