Enterovirus Infection Research Articles

Respiratory infections and type 1 diabetes: Potential roles in pathogenesis.

Among the environmental factors associated with type 1 diabetes (T1D), viral infections of the gut and pancreas has been investigated most intensely, identifying enterovirus infections as the prime candidate trigger of islet autoimmunity (IA) and T1D development. However, the association between respiratory tract infections (RTI) and IA/T1D is comparatively less known. While there are significant amounts of epidemiological evidence supporting the role of respiratory infections in T1D, there remains a paucity of data characterising infectious agents at the molecular level. This gap in the literature precludes the identification of the specific infectious agents driving the association between RTI and T1D. Furthermore, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on the development of IA/T1D remains undeciphered. Here, we provide a comprehensive overview of the evidence to date, implicating RTIs (viral and non-viral) as potential risk factors for IA/T1D.

Antiviral Activity of trans-Hexenoic Acid against Coxsackievirus B and Enterovirus A71.

Enterovirus infections are life-threatening viral infections which occur mainly among children and are possible causes of viral outbreak. Until now, treatment and management of infections caused by members of the genus Enterovirus largely depended on supportive care, and no antiviral medications are currently approved for the treatment of most of these infections. The urgency of discovering new therapeutic options for the treatment of enterovirus infection is increasing. In the present study, we identified that trans-2-hexenoic acid (THA), a natural product from a dietary source, possesses antiviral activity against coxsackievirus B (CVB) and enterovirus A71 (EV-A71) in a dose-dependent manner. We found that THA possesses antiviral activity at 50% effective concentrations (EC50) of 2.9 μM and 3.21 μM against CVB3 and EV-A71 infections, respectively. The time of addition assay revealed that THA inhibits both CVB3 and EV-A71 replication at the entry stage of infection. Additional results from this study further suggest that THA inhibits viral replication by blocking viral entry. Given that THA has received approval as a food additive, treatment of enterovirus infections with THA might be a safe therapeutic option or could pave the way for semisynthetic manufacturing of more antiviral drugs in the future.

A Neonatal Murine Model for Caprine Enterovirus Infection and the Viral Tissue Tropism.

As the first caprine enterovirus identified from goat herds characterized by severe diarrhea with a high morbidity and mortality rate, the underlying pathogenesis and tissue tropism for CEV-JL14 remains largely unknown. Here, we reported the establishment of a neonatal murine model for caprine enterovirus and the unveiling of the tissue tropism and underlying pathogenesis for CEV-JL14 enterovirus. Susceptible murine strains, the infective dose, the infective routes, viral loads, and tissue tropism for CEV-JL14 infection were determined. The findings showed that ICR mice were susceptible to CEV-JL14 infection via all infection routes. Tissue viral load analysis showed that CEV-JL14 was detected in almost all tissues including the heart, liver, spleen, lung, kidney, intestine, brain, and muscle, with significantly higher viral loads in the heart, liver, lung, kidney, and intestine. These results revealed the pattern of viral load and tropism for CEV-JL14 and provided a model system for elucidating the pathogenesis of CEV-JL14 viruses.

The upregulation of peripheral blood polyamine metabolites spermidine and spermine in children with hand, foot, mouth disease is related to enterovirus 71 capsid protein VP1, but not VP4.

Hand, foot, and mouth disease (HFMD) is a common viral childhood illness caused most commonly by enterovirus 71 (EV71) and coxsackievirus A16. The pathogenesis of EV71 has been extensively studied, and the regulation of the host immune response is suspected to aggravate the serious complications induced by EV71. Our previous research showed that EV71 infection significantly increased the release of circulating interleukin (IL)-6, IL-10, IL-13, and IL-27. Notably, these cytokines are related to the EV71 infection risk and clinical stage. Polyamines are compounds that are ubiquitous in mammalian cells and play a key role in various cellular processes. Several studies have shown that targeting polyamine metabolic pathways can reduce infections caused by viruses. However, the significance of polyamine metabolism in EV71 infection remains largely unknown. Serum samples from 82 children with HFMD and 70 healthy volunteers (HVs) were collected to determine the polyamine metabolites spermidine (SPD) and spermine (SPM), and IL-6 levels. In addition, peripheral blood mononuclear cells (PBMCs) were treated with EV71 viral protein 1 (VP1) and EV71 VP4, and the cells and supernatant were then collected to analyze the expression of polyamine metabolism-related enzymes by western blot. The data were analyzed using GraphPad Prism 7.0 software (USA). The serum polyamine metabolites SPD and SPM were elevated in the HFMD patients, especially in the EV71-infected children. Further, a positive correlation was found between serum SPD and IL-6 levels in the EV71-infected children. We also found that the upregulation of peripheral blood polyamine metabolites in the EV71-infected HFMD children was related to EV71 capsid protein VP1, but not VP4. VP1 may promote the expression of polyamine metabolism-related enzymes and promote the production of polyamine metabolites, thereby upregulating the SPD/nuclear factor kappa B/IL-6 signaling pathway. However, VP4 has the opposite effect in this process. Our results suggest that EV71 capsid protein may regulate the polyamine metabolic pathways of infected cells in a variety of ways. This study provides insights into the mechanism of EV71 infection and polyamine metabolism and has good reference value for the development of EV71 vaccine.

Antiviral activity of the HSP90 inhibitor VER-50589 against enterovirus 71

Enterovirus 71 (EV71) is the major pathogen responsible for hand, foot, and mouth disease (HFMD) outbreaks; to date, there is no specific anti-EV71 agent. HSP90 is a crucial host factor for the viral life cycle and an ideal therapeutic target for limiting viral proliferation. However, the specific role of HSP90 in EV71-related signaling pathways and anti-EV71 agents targeting HSP90 remains unclear. This study aimed to verify the role of HSP90 in signaling pathways involved in EV71 replication and investigate the antiviral effects of a small molecule of VER-50589, a potent HSP90 inhibitor, against EV71 both in vitro and in vivo. Viral plaque assay, western blotting, and qPCR results showed that VER-50589 diminished the plaque formation induced by EV71 and inhibited EV71 mRNA and protein synthesis. A single daily dose of VER-50589 treatment significantly improved the survival rate of EV71-infected mice (p < 0.005). Interestingly, VER-50589 also exhibits activities against a series of human enteroviruses, including Coxsackievirus B3 (CVB3), Coxsackievirus B4-5 (CVB4-5), Coxsackievirus B4-7 (CVB4-7), and Echovirus 11 (Echo11). EV71 infection activated the AKT and ERK signaling pathways, and phosphorylation of AKT and RAF/MEK/ERK was weakened by VER-50589 administration. Thus, VER-50589 exhibits robust antiviral activity by inhibiting HSP90 and mediating the AKT and RAF/MEK/ERK signaling pathways. Considering that there are no effective antivirals or vaccines for the prevention and cure of HFMD in a clinical setting, the development of an anti-EV71 agent would be a straightforward and feasible therapeutic approach.

The Need for a Vaccine Against Hand, Foot, and Mouth Disease in Malaysia

Hand, foot, and mouth disease (HFMD) is a contagious viral infection, which commonly affects young children under five years of age (Yu et al., 2019). HFMD is caused by serotypes of the Enterovirus A species, particularly enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), in the genus Enterovirus (Takahashi et al., 2016). Symptoms of HFMD usually include fever, sore throat and maculopapular or vesicular rashes on hands, feet and mouth, which resolve spontaneously. On the other hand, severe HFMD, which is often associated with EV71 infection, can lead to life-threatening cardiopulmonary and neurologic complications (Xu et al., 2015).

Species spectrum of nonpolio enteroviruses in KhMAO–Yugra during the prepandemic and pandemic periods

BACKGROUND: The characteristics of the regional features of the etiological structure of nonpolio enterovirus infection before and during the coronavirus disease 2019 (COVID-19) pandemic were evaluated.&#x0D; AIM: To assess the monitoring of the etiologies of enterovirus infection in the prepandemic and pandemic periods.&#x0D; MATERIALS AND METHODS: Data from the forms of statistical observation for 20132022 and the results of molecular genetic studies of nonpolio EVI were used.&#x0D; RESULTS: The dynamics of the incidence of enterovirus infection in the KhantyMansi Autonomous Okrug before the COVID-19 pandemic was characterized by high activity levels of the epidemic process, exceeding the average for the Russian Federation by 56 times. The urban population, with a predominance of children aged 6 years, mainly contributed to the total incidence of enterovirus infection. During the period with the highest incidence rates in 2017 and 2019, Coxsackie A6 viruses in combination with ECHO30, Coxsackie A9 dominated, and during the period of their decline, the proportion of enterovirus A71, Coxsackie A16 increased. During the pandemic, the calculated trends of dynamics for 2022 were confirmed for dominant viruses and enterovirus A71. In the same year, Coxsackie B2 and ECHO6 viruses were increasingly identified, which were previously circulated irregularly and in isolated cases. The prevalence of CV-A6 in the epidemic process was accompanied by clinical manifestations of infection, mainly as enterovirus vesicular stomatitis, with a high frequency of ECHO30, computer cases were recorded in most cases.&#x0D; CONCLUSION: Based on the results of monitoring the etiological structure of nonpoliomyelitis enterovirus infection in the prepandemic period, a further increase in morbidity in enterovirus infection is predicted in the KhantyMansi Autonomous Okrug. Genotyping of the detected strains makes it possible to determine the spectrum of enterovirus strains endemic to the territory and predict their prevalence, which is necessary to prevent the spread of enterovirus infection and ensure sanitary and epidemiological well-being in the region.

Profiling of peripheral blood B-cell transcriptome in children who developed coeliac disease in a prospective study

BackgroundIn coeliac disease (CoD), the role of B-cells has mainly been considered to be production of antibodies. The functional role of B-cells has not been analysed extensively in CoD. MethodsWe conducted a study to characterize gene expression in B-cells from children developing CoD early in life using samples collected before and at the diagnosis of the disease. Blood samples were collected from children at risk at 12, 18, 24 and 36 months of age. RNA from peripheral blood CD19+ cells was sequenced and differential gene expression was analysed using R package Limma. FindingsOverall, we found one gene, HNRNPL, modestly downregulated in all patients (logFC −0·7; q = 0·09), and several others downregulated in those diagnosed with CoD already by the age of 2 years. InterpretationThe data highlight the role of B-cells in CoD development. The role of HNRPL in suppressing enteroviral replication suggests that the predisposing factor for both CoD and enteroviral infections is the low level of HNRNPL expression. FundingEU FP7 grant no. 202063, EU Regional Developmental Fund and research grant PRG712, The Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) 2012–2017, grant no. 250114) and, AoF Personalized Medicine Program (grant no. 292482), AoF grants 292335, 294337, 319280, 31444, 319280, 329277, 331790) and grants from the Sigrid Jusélius Foundation (SJF).

Virus induced dysbiosis promotes type 1 diabetes onset.

Autoimmune disorders are complex diseases of unclear etiology, although evidence suggests that the convergence of genetic susceptibility and environmental factors are critical. In type 1 diabetes (T1D), enterovirus infection and disruption of the intestinal microbiota are two environmental factors that have been independently associated with T1D onset in both humans and animal models. However, the possible interaction between viral infection and the intestinal microbiota remains unknown. Here, we demonstrate that Coxsackievirus B4 (CVB4), an enterovirus that accelerates T1D onset in non-obese diabetic (NOD) mice, induced restructuring of the intestinal microbiome prior to T1D onset. Microbiome restructuring was associated with an eroded mucosal barrier, bacterial translocation to the pancreatic lymph node, and increased circulating and intestinal commensal-reactive antibodies. The CVB4-induced change in community composition was strikingly similar to that of uninfected NOD mice that spontaneously developed diabetes, implying a mutual "diabetogenic" microbiome. Notably, members of the Bifidobacteria and Akkermansia genera emerged as conspicuous members of this diabetogenic microbiome, implicating these taxa, among others, in diabetes onset. Further, fecal microbiome transfer (FMT) of the diabetogenic microbiota from CVB4-infected mice enhanced T1D susceptibility and led to diminished expression of the short chain fatty acid receptor GPR43 and fewer IL-10-expressing regulatory CD4+ T cells in the intestine of naïve NOD recipients. These findings support an overlap in known environmental risk factors of T1D, and suggest that microbiome disruption and impaired intestinal homeostasis contribute to CVB-enhanced autoreactivity and T1D.

PLX8394, a RAF inhibitor, inhibits enterovirus 71 replication by blocking RAF/MEK/ERK signaling

Enterovirus 71 (EV71) poses a serious threat to human health, with scattered outbreaks worldwide. There are several vaccines against a few EV71 strains but no efficient drug for the treatment of EV71 infection. Therefore, it is urgent and of significance to develop anti-EV71 drugs. Here, we found that PLX8394, a RAF inhibitor, possesses high antiviral activity against EV71 in vitro, being superior to the traditional clinical drug ribavirin. Moreover, PLX8394 exhibits broad-spectrum antiviral activity against enteroviruses. Notably, in a suckling mouse model, PLX8394 provided a 70% protection rate for EV71-infected mice, reduced the viral load in liver and heart tissues, and relieved the inflammatory response. A mechanistic study showed that PLX8394 inhibited EV71 by suppressing the RAF/MEK/ERK signaling pathway. Thus, PLX8394 lays a foundation for the development of new drugs against EV71.

Local immune dysregulation and subsequent inflammatory response contribute to pulmonary edema caused by Enterovirus infection in mice.

Pulmonary edema that comes on suddenly is the leading cause of mortality in hand-foot-and-mouth disease (HFMD) patients; however, its pathogenesis is still largely unclear. A range of research suggest immunopathogenesis during the occurrence of pulmonary edema in severe HFMD patients. Herein, to investigate the potential mechanism of immune dysregulation in the development of pulmonary edema upon Enterovirus (EV) infection, we established mouse infection models for Enteroviruses (EVs) including Coxsackievirus (CV) A6, Enterovirus A71 (EVA71), and CVA2 exhibiting a high incidence of pulmonary edema. We found that EVs infection induced an immune system disorder by reducing the numbers of pulmonary and circulatory T cells, B cells, macrophages, and monocytes and increasing the numbers of lung neutrophils, myeloid-derived suppressor cells (MDSCs), and activated T cells. In addition, the concentrations of C-X-C motif chemokine ligand 1 (CXCL-1), tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin 6 were increased in EV-infected lungs. Moreover, we found that EVs replication in mice lungs lead to apoptosis of lung cells and degradation of tight junction proteins. In conclusion, EVs infection likely triggered a complexed immune defense mechanism and caused dysregulation of innate immune cells (MDSCs, neutrophils, monocytes, and macrophages) and adaptive cellular immunity (B cells, T cells). This dysregulation increased the release of cytokines and other inflammatory factors from activated immune-related cells and caused lung barrier damage and pulmonary edema.

Relevance of enteroviruses in neonatal meningitis

IntroductionEnterovirus (EV) infections are the most frequent infections in the neonatal period and in many cases lead to hospital admission of the newborn (NB).The aim of this study was to determine the incidence of EV in the etiology of neonatal meningitis and to define the clinical characteristics of newborns with EV meningitis. Material and methodRetrospective observational cohort study. Including 91 NBs with meningitis and gestational age greater than 34 weeks gestational age (GA) attended in our center over a period of 16 years. ResultsThe percentage of NBs with EV meningitis was higher than that of NBs with bacterial meningitis (BM) and accounted for 78% (n=71). Half of the NBs with EV infection had a history of epidemic environment among their caregivers. Fever was present in 96% of cases as a clinical sign and, in general, sensory disturbances represented the main neurological alterations. Antibiotics (ATB) were given to 71.4% of patients with EV infection.Detection of EV in CSF samples showed a high sensitivity for the diagnosis of EV meningitis. The most frequently implicated EV types were echovirus 11, coxsackievirus B5, echovirus 18, 25 and 7. ConclusionsThe results of this series show that enterovirus infection is a common cause of neonatal meningitis. These data underline the importance of rapid EV testing of infants with suspected meningitis. This allows early diagnosis and reduces antibiotic treatment, hospitalization time and related costs.

Experimental animal models for development of human enterovirus vaccine.

Enterovirus infections induce infectious diseases in young children, such as hand, foot, and mouth disease which is characterized by highly contagious rashes or blisters around the hands, feet, buttocks, and mouth. This predominantly arises from enterovirus A71 or coxsackievirus A16 infections and in severe cases, they can lead to encephalitis, paralysis, pulmonary edema, or even fatality, representing a global health threat. Due to the absence of effective therapeutic strategies for these infections, various experimental animal models are being investigated for the development of vaccines. During the early stages of research on enterovirus infections, non-human primate infections exhibited symptoms like those in humans, leading to their utilization as model animals. However, due to economic and ethical considerations, their current usage is limited. While enterovirus infections do not readily occur in mice, an infection model with mouse-adapted strain in neonatal mice has been employed. Cellular receptors have been identified in human cells, and genetically modified mice expressing these receptors have been used. Most recently, the utilization of Mongolian gerbil model is actively being considered and should be pursued for further animal model development. So, herein, we provide a summarized overview of the current portfolio of available enterovirus infection models, emphasizing their respective advantages and limitations.

Вспышка парвовирусной инфекции B19 у детей в республике Саха (Якутия)

Parvovirus infection B19 is widespread all over the world and causes a wide range of clinical manifestations, ranging from a mild course of the disease with manifestations of infectious erythema in immunocompetent patients, severe cytopenia in immunocompromised patients and causing difficulties in diagnosis. Objective. To present the description of an outbreak of parvovirus infection with the atypical duration in children in the Republic of Sakha (Yakutia). Results. Since April 10, 2023, 47 cases of parvovirus infection have been registered in the Republic of Sakha (Yakutia) in children aged 8–17 from an educational institution of around-the-clock stay. Considering that clinically the disease in 100% of cases was characterized only by the presence of exanthema without fever and symptoms of intoxication, in the first cases the symptoms of the disease were regarded as manifestations of allergic dermatitis. After an increase in the number of cases, differential diagnosis was carried out between measles, rubella and enterovirus infection. And only at the stage of obtaining negative results for these diseases, parvovirus infection was included in the examination plan. The diagnosis of "parvovirus infection" was confirmed in the laboratory by the detection of parvovirus B19 DNA in oropharyngeal smears, as well as by the serology test of blood serum with the detection of IgM to parvovirus B19. Conclusion. Given the variety of clinical manifestations of parvovirus infection, it is necessary to increase the alertness of specialists regarding the features of clinical manifestations of infection and its early diagnosis. Key words: parvovirus infection, outbreak, children

Enterovirus infection and its relationship with neurodegenerative diseases

Neurodegenerative diseases (NDs) are increasingly common, especially in populations with higher life expectancies. They are associated mainly with protein metabolism and structure changes, leading to neuronal cell death. Viral infections affect these cellular processes and may be involved in the etiology of several neurological illnesses, particularly NDs. Enteroviruses (EVs) frequently infect the central nervous system (CNS), causing neurological disease. Inflammation, disruption of the host autophagy machinery, and deregulation and accumulation/misfolding of proteins are the main alterations observed after infection by an EV. In this perspective, we discuss the most recent findings on the subject, examining the possible role of EVs in the development of NDs, and shedding light on the putative role played by these viruses in developing NDs.

МОНИТОРИНГ ЦИРКУЛИРУЮЩИХ НЕПОЛИОМИЕЛИТНЫХ ЭНТЕРОВИРУСОВ КАК ИНСТРУМЕНТ КОНТРОЛЯ И ПРОГНОЗА ЭПИДЕМИОЛОГИЧЕСКОЙ СИТУАЦИИ ПО ЭНТЕРОВИРУСНОЙ ИНФЕКЦИИ В РЕСПУБЛИКЕ БЕЛАРУСЬ

More than 100 serotypes of non-polio enteroviruses (NPEV) that are pathogenic for humans can cause deseases of different manifestations and severity, being a serious health problem in many countries of the world, including the Republic of Belarus. In this regard, monitoring the causative agents of enterovirus infections (EVI) circulating in the country aiming of early new sero- and genotypes detection has much of significance. This work is dedicated to the analysis of NPEV monitoring results concerning their circulation in the territory of the Republic of Belarus in 2021–2022, data on their spectrum, molecular genetics and molecular epidemiological characteristics of the serotypes, as well as on the registered signs of the incidence of EVI. It was found that NPEV that circulated in the country in 2021–2022 were Coxsackie B3, Coxsackie B5, Coxsackie A9, ECHO 7, ECHO 30 and HEV B80 viruses. The group of Coxsackie B viruses prevailed (57,1%) with the dominance of the Coxsackie B3 serotype (35,7%). Coxsackie B5 and ECHO 30 viruses, which have a high epidemic potential, were manifested by genotypes that were actively circulating in the country in the previous years. It is shown that 2022 was the year of the rise in the incidence of EVI. At the time, the prerequisites for sharp NPEV sirculation increase are unlikely though not impossible in case of new sero- or genotypes of NPEV being found.

Comparison of Throat and Nasopharyngeal Swabs for the Molecular Detection of Enterovirus in Pediatric Patients.

Enterovirus infections frequently occur in children worldwide. Molecular assays are widely used to detect enterovirus. Nasopharyngeal swabs (NPS) and throat swabs (TS) are common specimen types used in clinical practice. Here, the reliability of TS for detecting enterovirus in pediatric patients was compared with that of NPS using real-time reverse transcription polymerase chain reaction (RT-rPCR). Results obtained using the Allplex Respiratory Panel 2 (Seegene, Korea) for NPS (NPS-RP) and Accu-Power EV Real-time RT-PCR (Bioneer, Korea) for TS (TS-EV), which were performed simultaneously between September 2017 to March 2020, were initially compared. Cross examination (Allplex Respiratory Panel 2 assay using TS and AccuPower EV assay with NPS) was performed for specimens collected between July 2019 to March 2020 to evaluate the performance of the enterovirus assays based on each specimen type. Among the 742 case results of initial tests, 597 cases (80.5%) tested negative in both assays, and 91 cases (12.6%) tested positive in both assays. Fifty-four discrepant results were observed: 39 cases (5.3%) tested positive in TS-EV and negative in NPS-RP, and 15 cases (2.0%) tested positive in NPS-RP and negative in TS-EV. The overall percent agreement was 92.7%. In the 99 cases cross examined, overall percent agreements were 98.0%, 94.9%, 92.9%, and 89.9% for TS-EV vs. TS-RP, NPS-RP vs. NPS-EV, TS-EV vs. NPS-EV, and NPS-RP vs. TS-RP, respectively. TS yields a high agreement rate with NPS in detecting enterovirus, regardless of single-plex or multiplex RT-rPCR assays. Thus, TS could be a good alternative specimen in pediatric patients who are reluctant to NPS sampling.

ML390 inhibits enterovirus 71 replication by targeting de novo pyrimidine biosynthesis pathway

Enterovirus 71 (EV71), a small, single-stranded, positive-sense RNA virus belonging to the enterovirus genus in the family Picornaviridae, causes hand, foot, and mouth disease. Although EV71 seriously threatens to public health, no effective antiviral drugs are available for treating this disease. In this study, we found that ML390, a dihydroorotate dehydrogenase inhibitor, has potential anti-EV71 activity. ML390 dose-dependently inhibited EV71 replication with IC50 and selectivity index values of 0.06601 μM and 156.5, respectively. Supplementation with the downstream product orotate significantly suppressed the ability of ML390 to inhibit EV71 replication. Moreover, an adequate supply of exogenous uridine and cytosine suppressed the anti-EV71 activity of ML390. Thus, the antiviral activity of ML390 is mediated by the inhibition of the pyrimidine synthesis pathway. In an EV71-infected mouse model, ML390 reduced the load of EV71 in the brain, liver, heart, spleen, front legs, and hind legs, and significantly increased the survival rate of the mice infected by EV71. ML390 shows potential for the treatment of hand, foot, and mouth disease caused by EV71 infection.

Targeting 7-dehydrocholesterol reductase against EV-A71 replication by upregulating interferon response

Recent studies have shown a close link between viral infections and cholesterol metabolism. Here, we reported that 7-dehydrocholesterol reductase (DHCR7), a terminal enzyme for catalyzing cholesterol synthesis in the Kandutsch-Russell pathway, is harnessed by enterovirus A71 (EV-A71) benefitting for its replication. Overexpression of DHCR7 resulted in upregulating of EV-A71 replication, while the S14A mutation, which reduces DHCR7 enzyme activity, has no effect on EV-A71 replication. Knockdown of DHCR7 expression with small interfering RNA (siRNA) or enzyme activity inhibition with pharmacological inhibitor AY9944 could significantly inhibit EV-A71 replication. Adding cholesterol to DHCR7 knockdown cells or AY9944-treated cells could rescue EV-A71 replication. More importantly, prophylactic administration of AY9944 effectively protected mice from lethal EV-A71 infection. In addition, the natural cholesterol precursor 7-dehydrocholesterol (7-DHC), which is converted to cholesterol by DHCR7, has a similar effect against EV-A71 infection. Mechanistically, AY9944 or 7-DHC treatment can specifically promote IRF3 phosphorylation to activate interferon response. Moreover, AY9944 effectively cleared coxsackievirus B3 (CVB3) and coxsackievirus A16 (CVA16) infections in vitro. In conclusion, pharmacological modulation of DHCR7 might provide a chance for treatment of enterovirus infection, including EV-A71.

1459. Prevalence of Enterovirus and Parechovirus in Children with Acute Gastroenteritis and in Healthy Controls over a 7-year Period; 2011-2018

Abstract Background As of 2017 (WHO, 2017), diarrheal disease ranked second as a cause of worldwide mortality for children under five years of age. Approximately 50-70% of acute gastroenteritis (AGE) is viral in etiology, with commonly detected viruses including norovirus, rotavirus, and adenovirus. However, the epidemiology of less commonly detected viruses, specifically enterovirus (EV) and parechovirus A (PeV-A), associated AGE in the United States is not well described. The purpose of our study was to determine the prevalence of EV and PeV-A in children with AGE vs. healthy controls (HC) over a 7-year period. Methods From December 2011 – November 2018, we screened stool samples from children less than 18 years of age prospectively enrolled in Children’s Mercy-Kansas City’s (CM-KC) site for the CDC’s New Vaccine Surveillance Network; 3005 samples from subjects presenting with AGE and 1097 from HC. Samples from 2011 – 2016 (AGE: 2453; HC:752) and 2017 – 2018 (AGE:552; HC:344) were tested at CDC and CM-KC respectively by a real-time-PCR assay using specific EV and PeV-A primers targeting the highly conserved 5’ untranslated region. Demographic data were collected from EMR. Results Among 3005 AGE samples, EV was detected in 12.5% (n=386/3004), and PeV-A in 10.3% (n=252/3005). Among 1097 HC samples, EV was detected in 9.0% (99/1096), and PeV-A in 11.9% (130/1097). In 2014-2015 EV detection in AGE was highest (17.9%) among all years and significantly higher (p=0.004) than in HC samples (9.1%), whereas PeV-A detection in AGE was 9.5% vs. 15.6% in HC samples, p=0.008 (Table 1). Co-infections with EV and PeV-A were seen in 55 AGE and 21 HC. Most EV detections (45.1%) were in 1- to 2-year-olds, whereas PeV-A detections (47.3%) were in children &amp;lt; 1 year old (Table 2). Both EV (58.3%) and PeV-A (48.4%) detections were significantly more frequent in male children (p=0.006). The highest frequency of EV detections was in summer to fall months, and for PeV-A in late summer through early winter. Conclusion We report a higher prevalence of EV infections in AGE, and PeV-A infections in HC during 2011 to 2018, plus their seasonal and age distributions. Although our data do not currently demonstrate an association between detection of EV or PeV-A types and AGE, additional data could provide more clarity into a potential association. Disclosures Brian R. Lee, PhD, MPH, CDC: Grant/Research Support|Merck: Grant/Research Support Christopher J Harrison, MD, Astellas: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|Pediatric news: Honoraria|Pfizer: Grant/Research Support Mary E. Moffatt, M.D., Becton and Dickinson and Company: Stocks/Bonds|Biogen: Stocks/Bonds|Coloplast B: Stocks/Bonds|Express Scripts: Stocks/Bonds|Novo Nordisk A/S Spons ADR: Stocks/Bonds|Novo Nordisk A/S-B: Stocks/Bonds|Steris PLC: Stocks/Bonds|Stryker Corp: Stocks/Bonds|Thermo Fisher Scientific: Stocks/Bonds Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, F(AAM), BioFire: Grant/Research Support|Luminex: Grant/Research Support.