Search Results (120)

Enterovirus A71 (EVA71) is a major pathogen that causes hand, foot, and mouth disease (HFMD). Although the symptoms of HFMD can be self-limiting, severe meningitis, encephalitis, myocarditis, and acute flaccid paralysis may occur. Upon EVA71 infection, the host cells deploy an intricate network of factors to orchestrate cellular responses and maintain cellular homeostasis. However, the virus has evolved various strategies to avoid unfavorable host restrictions and to establish a productive infection process. As response regimens are correlated with disease symptoms, exploring the interactions between the virus and host contributes to understanding the pathogenesis and underlying mechanisms of infection. In this review, we summarized the recent research progress related to pro-viral factors during EVA71 infection and discussed the underlying mechanisms employed by EVA71 to facilitate virion production. These insights may help identify antiviral therapeutic candidates and support vaccine development. Full article

Background: Enterovirus A71 (EV-A71) is considered as the primary causative agent of hand, foot, and mouth disease (HFMD) in young children, leading to severe neurological complications and contributing to substantial mortalities in recent HFMD outbreaks across Asia. Despite this, there is currently no effective antiviral treatment available for EV-A71. RNA interference (RNAi) is a powerful mechanism of post-transcriptional gene regulation that utilizes small interfering RNA (siRNA) to target and degrade specific RNA sequences. Objectives: The aim of this study was to design various siRNAs targeting EV-A71 genomic regions and evaluate the RNAi efficacy against a novel, previously genetically uncharacterized EV-A71 strain. Methods: A novel EV-A71 strain was first sequenced to design target-specific siRNAs. The viral titers, viral protein expression, cytopathic effects, and cell viability of EV-A71-infected HeLa cells were examined to evaluate the specific viral inhibition by the siRNAs. Results: A substantial reduction in viral titers and viral protein synthesis was observed in EV-A71-infected HeLa cells treated with specific siRNAs targeting the VP4, VP3, 2B, and 3A genes. siRNAs delayed cytopathic effects and increased cell viability of EV-A71-infected HeLa cells. Nonspecific interferon induction caused by siRNAs was not observed in this study. In contrast, replication of coxsackievirus B3, another important member of the Enterovirus genus, remained unaffected. Conclusions: Overall, the findings demonstrate that RNAi targeting genomic regions of EV-A71 VP4, VP3, 2B, or 3A could become a potential strategy for controlling EV-A71 infection, and this promising result can be integrated into future anti-EV-A71 therapy developments. Full article

Background: Hand, foot, and mouth disease (HFMD) typically exhibits spatiotemporal clustering. This study aimed to analyze the spatiotemporal heterogeneity of HFMD in Fujian Province, China, and to identify the associations of air pollutants and socioeconomic factors with the incidence. Methods: Daily reported HFMD case data, daily air pollutant data, and socioeconomic data in Fujian Province from 2014 to 2023 were collected for analysis. A descriptive analysis was used to describe the epidemiological trends of HFMD. Spatial autocorrelation analysis was applied to explore the spatiotemporal clustering characteristics. The associations between risk factors and HFMD incidence were evaluated using the generalized additive model (GAM). Results: HFMD incidence in Fujian has decreased since 2019, and the peak in each year occurred between May and June. Distinct high–high and low–low clustering areas were identified. The cumulative exposure–response curves for SO₂, NO₂, and CO showed a monotonically increasing trend, with relative risks (RRs) < 1 at concentrations lower than the median levels (SO₂ ≈ 4 μg/m³, NO₂ ≈ 16 μg/m³, CO ≈ 1 mg/m³). In contrast, the curves for O₃ and PM_2.5 showed a decreasing trend, with RR < 1 at concentrations above the median levels (O₃ ≈ 55 μg/m³, PM_2.5 ≈ 20 μg/m³). Among socioeconomic factors, only the proportion of the population under 15 years old was found to be associated with HFMD incidence. Conclusions: HFMD incidence in Fujian exhibited distinct spatiotemporal clustering. The incidence was associated with the concentrations of air pollutants. Targeted interventions should be implemented in high-risk areas to mitigate HFMD transmission, with particular attention given to the environmental and demographic factors. Full article

Background: Hand, foot, and mouth disease (HFMD) is a frequently self-limited viral infectious disease that affects children and has no specific antiviral treatment option. There has been increasing interest in bee products in recent years, and propolis has come to the fore due to its impressive therapeutic and protective effects. Although previous studies have shown the inhibitory effect of propolis against enteroviruses (EVs), there are no clinical data regarding its use in combatting HFMD. This prospective multicenter randomized clinical study aimed to evaluate the effect of administering propolis to children with HFMD. Methods: This study analyzed 183 children with HFMD. All children were assessed for eligibility and diagnosed with HFMD by a child health and disease specialist after presenting with symptoms of either fever, enanthem, or exanthems that had begun within the last 48 h. The patients were randomly assigned to the group receiving Anatolian propolis (n = 87) or that receiving no supplement—the control group (n = 96)—in addition to receiving symptomatic therapy as decided by the physician. The duration of the patient’s complaints, the distribution of the lesions on their body, and their fever status were recorded on admission. Parents were asked to rate the severity of their child’s restlessness, inappetence, and sleeplessness on a scale of 0–10 at their initial, second (at 48th hour), and third (after 5–7 days) visits to the hospital. The primary data analysis methods included the Kolmogorov–Smirnov test for normality and non-parametric tests such as the Kruskal–Wallis and Mann–Whitney U tests, which were used for group comparisons. Results: The median age of the patients was 28 months (range: 12–112), and the male-to-female ratio was 1:1. Most patients (62.8%) had no history of a household contact with HFMD. Intraoral lesions were present in 92.3% of patients, and 47.5% received the propolis treatment while 53.5% were in the control group. There was a significant difference between the groups in terms of their complaint scores during their second (p = 0.028) and third (p < 0.001) visits to the hospital. In addition, the mean duration of the illness in the propolis group (7.45 days) was significantly lower than that in the control group (8.58 days) (p < 0.001). No adverse effects were observed. Conclusions: Propolis has been shown to facilitate symptomatic relief and reduce the duration of the disease in children with HFMD. To better assess the efficacy of this product, which can be used safely in children, future studies supported by virological analyses are required. Full article

Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD), leading to a serious health threat to young children. Probiotics are effective at treating or preventing gastrointestinal infections, especially viral infections. Probiotics against EV71 are mainly traditional lactic acid-producing bacteria, and most of them have been proven to be effective only in vitro. Here, we report that the marine bacterium Paraliobacillus zengyii X-1125 (P. zengyii) has promising anti-EV71 activity. The antiviral effect of P. zengyii against EV71 was assessed in different cell lines, and the viral RNA levels and titers were obviously reduced after treatment with P. zengyii. Furthermore, we established an EV71-infected mouse model to evaluate its antiviral efficacy in vivo. The oral administration of P. zengyii significantly decreased the viral loads in the hindlimb muscles, spleens, and ileums. Further research revealed that P. zengyii enhances the expression of type I interferon (IFN-I) in EV71-infected cells. Similarly, transcriptome analysis indicated that the expression of interferon-stimulated genes (ISGs) in EV71-infected mice significantly increased after P. zengyii treatment. Taken together, the results of this study indicated that P. zengyii markedly reduces EV71 infection by regulating the IFN response both in vivo and in vitro, providing a potential means to work against EV71 infection. Full article

Background/Objectives: Enterovirus 71 (EV71) and coxsackieviruses A16 (CA16), A10 (CA10), and A6 (CA6) are the primary pathogens that cause hand, foot, and mouth disease (HFMD). Currently, many manufacturers are developing bivalent, trivalent, and tetravalent vaccines that target these antigens. Cell-based neutralization assay (CBNA), the gold standard for detecting neutralizing antibodies (NtAbs), which are used as indicators of HFMD vaccine efficacy, has several limitations. We aimed to develop a novel assay for detecting NtAbs against a quadrivalent HFMD vaccine. Methods: We developed a four-color pseudovirus-based neutralization assay (PBNA), utilizing fluorescent reporter genes, to rapidly evaluate neutralizing antibodies against EV71, CA16, CA10, and CA6 in multivalent vaccines and compared it with CBNA. Results: PBNA could rapidly and simultaneously detect NtAbs against the four serotypes and required lesser amounts of sera compared to CBNA. A good consistency in determining NtAb titers was observed for PBNA and CBNA. Conclusions: PBNA provides a robust tool for evaluating the efficacy of multivalent HFMD vaccines and conducting seroepidemiological studies. Full article

Hand, Foot, and Mouth Disease (HFMD) is a viral illness caused by enterovirus infections. While the introduction of the enterovirus 71 (EV71) vaccine has significantly reduced the number of EV71-related cases, the continued spread of Coxsackievirus A16 (CVA16) remains a major public health threat. Previous studies have shown that human SCARB2 (hSCARB2) knock-in (KI) mice, generated using embryonic stem cell (ESC) technology, are susceptible to CVA16. However, these models have failed to reproduce the clinical pathology and neurotoxicity after CVA16 infection. Therefore, there is an urgent need for a more reliable and effective animal model to study CVA16. In this study, we successfully created a hSCARB2 KI mouse model targeting the ROSA26 locus using CRISPR/Cas9 gene editing technology. The application of CRISPR/Cas9 enabled stable and widespread expression of hSCARB2 in the model. After infection, the KI mice exhibited a clinical pathology that closely mimics human infection, with prominent limb weakness and paralysis. The virus was detectable in multiple major organs of the mice, with peak viral load observed on day 7 post-infection, gradually clearing thereafter. Further analysis revealed widespread neuronal necrosis and infiltration of inflammatory cells in the brain and spinal cord of the KI mice. Additionally, significant activation of astrocytes (GFAP-positive) and microglia (IBA1-positive) was observed in the brain, suggesting that CVA16 infection may induce limb paralysis by attacking neuronal cells. Overall, this model effectively replicates the neuropathological changes induced by CVA16 infection and provides a potential experimental platform for studying CVA16-associated pathogenesis and neurotoxicity. 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

Hand, Foot, and Mouth Disease (HFMD) predominantly affects children under the age of five and remains a significant public health concern in the Asia-Pacific region. HFMD outbreaks are closely linked to seasonal changes and meteorological factors, particularly in tropical and subtropical areas. In Thailand, a total of 657,570 HFMD cases were reported between 2011 and 2022 (12 years). This study aimed to identify the high- and low-risk HFMD outbreak areas using machine learning models: Logistic Regression (LR), Support Vector Machine (SVM), Decision Tree (DT), Random Forests (RF), Gradient Boosting Machine (GBM), and Extreme Gradient Boosting (XGBoost). Our findings showed that the XGBoost model outperformed the other models in predicting unseen data and defining the best model. The best model can be used to detect high-risk outbreak areas and to explore the relationship between meteorological factors and HFMD outbreaks. The results highlighted the seasonal distribution of high-risk HFMD outbreak months across different provinces in Thailand, with average maximum temperature, average rainfall, and average vapor pressure identified as the most influential factors. Furthermore, the best model was used to analyze HFMD outbreaks during the COVID-19 pandemic, showing a notable reduction in high-risk outbreak months and areas, likely due to the control measures implemented during this period. Overall, our model shows great potential as a tool for warnings, providing useful insights to help public health officials reduce the impact of HFMD outbreaks. Full article

Background: In 2024, mainland China witnessed a significant upsurge in Hand, Foot, and Mouth Disease (HFMD) cases. Coxsackievirus A16 (CVA16) is one of the primary causative agents of HFMD. Long-term monitoring of theCVA16 infection rate and genotype changes is crucial for the prevention and control of HFMD. Methods: A total of 40,673 clinical specimens were collected from suspected HFMD cases in Guangdong province from 2018 to 2024, including rectal swabs (n = 27,954), throat swabs (n = 6791), stool (n = 5923), cerebrospinal fluid (n = 3), and herpes fluid (n = 2). A total of 24,410 samples were detected as EV-positive and further typed by RT-PCR. A total of 872 CVA16-positive samples were isolated and further sequenced to obtain the full-length VP1 sequence. Phylogenetic analysis was performed based on viral protein 1 gene (VP1). Results: In the first 25 weeks of 2024, reported cases of HFMD were 1.36 times higher than the mean rates of 2023. In 2024, CVA16 predominated at 75.42%, contrasting with the past etiological pattern in which the CVA6 was predominant with the detection rate ranging from 32.85 to 77.61% from 2019 to 2023. Phylogenetic analysis based on the VP1 gene revealed that the B1a and B1b subtypes co-circulated in Guangdong from 2018 to 2022. The B1c outbreak clade, detected in Guangdong in 2023, constituted 68.24% of the 148 strains of CVA16 collected in 2024, suggesting a subtype shift in the CVA16 virus. There were three specific amino acid variations (P3S, I235V, and T240A) in the VP1 sequence of B1c. Conclusions: The new emergence of the CVA16 B1c outbreak clade in Guangdong during 2023–2024 highlights the necessity for the enhanced surveillance of the virus evolution epidemiological dynamic in this region. Furthermore, it is imperative to closely monitor the etiological pattern changes in Hand, Foot, and Mouth Disease (HFMD) in other regions as well. Such vigilance will be instrumental in guiding future vaccination strategies for HFMD. Full article

Hand, foot, and mouth disease (HFMD) represents an emerging health concern whose main causative agents are Coxsackievirus A6 (CVA6) and enterovirus A71 (EV71). The lack of a CVA6 vaccine and the rise of new HFMD-causing strains due to the containment of established HFMD-causing viruses necessitates the search for alternative vaccine technologies, including virus-like particle (VLP) vaccine candidates. While studies have demonstrated that production of enterovirus-like particles in various organisms can be achieved by expression of the viral P1 structural proteins and the 3CD protease, optimization based on the interplay between the three most commonly altered infection parameters (multiplicity of infection (MOI), viable cell density at the time of infection (VCD), and the infection period) is often not investigated. To address this challenge, we have performed Design of Experiments (DoE) to optimize the production of CVA6 and EV71 VLPs. Our results indicate that CVA6 VLP production peaks at high MOI, high VCD, and long infection periods. Our subsequent downstream purification processes yielded 38 mg and 158 mg of purified CVA6 and EV71 VLPs from 1 L crude harvest, respectively. This translates into thousands of potential vaccine doses and highlights the economic potential of enterovirus-like particles for vaccine purposes. Full article

Enterovirus 71 (EV71) is a common pathogen responsible for hand, foot, and mouth disease (HFMD), leading to severe neurological complications and even death. However, the mechanisms underlying severe EV71-induced disease remain unclear, and no effective specific treatments are available. In this study, we successfully infected mice of different ages using a mouse-adapted EV71 strain, resulting in disease and mortality. We compared immune system responses between infected and uninfected mice of different ages to identify key pathogenic targets during EV71 infection. Our findings revealed that the level of Group 3 Innate Lymphoid Cells (ILC3s) in mice negatively correlated with the severity of disease induced by EV71 infection. We conducted anti-ILC3 cytokine injections and cytokine neutralizing antibody experiments on 14-day-old EV71-infected mice. The results showed that the cytokine IL-17 secreted by ILC3 cells had a mild protective effect, while IL-22 promoted inflammatory responses. Our research demonstrates that ILC3 cells play a dual role in EV71 infection. These findings not only clarify key immune factors in the progression of EV71-induced disease but also provide a promising approach for the early diagnosis and treatment of severe EV71 infections. Full article

Dermatological vaccines have emerged as critical tools in preventing and managing a wide spectrum of skin conditions ranging from infectious diseases to malignancies. By synthesizing evidence from existing literature, this review aims to comprehensively evaluate the efficacy, safety, and immunogenicity of vaccines used in dermatology, including both approved vaccines and those currently being researched. Vaccines discussed in this paper include those targeting dermatoses and malignancies (e.g., acne vulgaris, atopic dermatitis, and melanoma); infectious diseases (e.g., human papillomavirus (HPV); varicella zoster virus (VZV); herpes zoster (HZ); warts; smallpox; mpox (monkeypox); hand, foot, and mouth disease (HFMD); candidiasis and Group B Streptococcus (GBS); and neglected tropical diseases (e.g., Buruli ulcer, leprosy, and leishmaniasis). Through this review, we aim to provide a detailed understanding of the role of vaccines in dermatology, identify knowledge gaps, and propose areas for future research. Full article

The impact of vaccination on the dynamics of hand, foot, and mouth disease (HFMD) transmission is explored in this paper, considering a fractional-order derivative system of equations. This model provides vaccination strategies and characterizes local and global stability using Lyapunov functions. This work computes the basic reproduction number ($R_0$) to represent the endemic and epidemic scenarios. Additionally, sensitivity analysis was performed to identify the most critical parameters responsible for the disease dissemination. Our results indicate that vaccination plays a crucial role in controlling HFMD, significantly reducing its prevalence. These findings align with existing research, supporting the importance of effective vaccination strategies and public health interventions against HFMD. The fractional-order model captures the memory effect in infectious disease dynamics, providing further insight into modeling HFMD transmission compared to a traditional integer-order model. The results would contribute to effective vaccination strategies and public health interventions against HFMD. Full article

Coxsackievirus A6 (CVA6) has become increasingly clinically relevant as a cause of Hand, Foot and Mouth Disease (HFMD) globally since 2008. However, most laboratories do not routinely determine the enteroviral type of positive samples. The non-pharmaceutical measures introduced to curb transmission during the COVID-19 pandemic may also have perturbed CVA6 epidemiology. We thus aimed to determine the prevalence, clinical presentation and genetic relationship of CVA6 across three complete epidemic seasons: one pre-SARS-CoV-2 emergence and two post-SARS-CoV-2 emergence in our regional healthcare setting. Surplus diagnostic nucleic acid from diagnosed enteroviral positives diagnosed between September and December of 2018 and between May 2021 and April of 2023 was subject to VP1 gene sequencing to determine the CVA6 cases and interrogate their phylogenetic relationship. The confirmed CVA6 cases were also retrospectively clinically audited. CVA6 infections were identified in 33 and 69 individuals pre- and post-pandemic, respectively, with cases peaking in November of 2018 and 2022, but in October of 2021. HFMD was the primary diagnosis in 85.5% of the post-pandemic cases, but only 69.7% of the pre-pandemic cases, where respiratory and neurological symptoms (45.5% and 12.1%, respectively) were significantly elevated. A complete VP1 sequence was retrieved for 94% of the CVA6 cases, revealing that studied infections were genetically diverse and suggestive of multiple local and international transmission chains. CVA6 presented a significant clinical burden in our regional U.K. hospital setting both pre- and post-pandemic and was subject to dynamic clinical and genetic epidemiology. Full article