Echovirus Infection Research Articles

Echovirus induces autophagy to promote viral replication via regulating mTOR/ULK1 signaling pathway.

Among enteroviruses, echovirus can cause severe illnesses in neonates or infants, with high morbidity and mortality. Autophagy, a central component of host defense mechanisms, can function against diverse infections. In the present study, we investigated the interplay between echovirus and autophagy. We demonstrated that echovirus infection increases LC3-II expression dose-dependently, accompanied by an increased intracellular LC3 puncta level. In addition, echovirus infection induces the formation of autophagosome. These results suggest that echovirus infection induces autophagy machinery. Furthermore, phosphorylated mTOR and ULK1 were both decreased upon echovirus infection. In contrast, both levels of the vacuolar protein sorting 34 (VPS34) and Beclin-1, the downstream molecules which play essential roles in promoting the formation of autophagic vesicles, increased upon virus infection. These results imply that the signaling pathways involved in autophagosome formation were activated by echovirus infection. Moreover, induction of autophagy promotes echovirus replication and viral protein VP1 expression, while inhibition of autophagy impairs VP1 expression. Our findings suggest that autophagy can be induced by echovirus infection via regulating mTOR/ULK1 signaling pathway and exhibits a proviral function, revealing the potential role of autophagy in echovirus infection.

Therapeutics for fulminant hepatitis caused by enteroviruses in neonates.

Neonatal infection with nonpolio enteroviruses (EVs) causes nonspecific febrile illnesses and even life-threatening multiorgan failure. Hepatitis, which often results in hepatic necrosis followed by disseminated intravascular coagulopathy, is one of the most severe and frequent fatal neonatal EV infection complications. Coxsackievirus B (CVB) 1-5 and many echoviruses have been most commonly identified. Neonatal EV infection treatment has usually involved initial supportive care. Studies for CVB and echovirus infection treatments were developed for more than thirty years. Intravenous immunoglobulin and pleconaril therapy was performed in some clinical trials. Additionally, other studies demonstrated antiviral and/or anti-inflammatory pathogenesis mechanisms of neonatal EV hepatitis in in vitro or in vivo models. These treatments represented promising options for the clinical practice of neonatal EV hepatitis. However, further investigation is needed to elucidate the whole therapeutic potential and safety problems.

Evaluation of Demographic Characteristics and Biochemical Parameters with Echovirus Infection in Children at Thi-Qar Province/Iraq

The current study was conducted in Thi-Qar province, with One hundred blood specimens were collected from patients in Mohammed Al-Mousawi Hospital for Children (ages between 2 days - 3 years, males and females), at the period between November 2021 to February 2022.This study aimed to revealed the relationship between different characteristics (sex, age and clinical symptoms) with viral infections , and diagnosis by WBC COUNT, platelet and C-reactive protein for each patients. Based on the results recorded among 100 children have different disease, but only, 9% of patients were infected with the Echovirus, and 91% were negative for viral infection, the results also noted a significant difference in viral prevalence in children at p. value < 0.05. Results also noted a non-significant difference according to children’ gender at p. value < 0.05. Most children infected with Echovirus was in 6-8 and 8-10 month 25%, while the age groups (3day-< 2 month), (2 - < 4 month), (12 - < 14 month), and (14 - < 16 month), were non-infected with Echovirus. The results also noted a significant difference according to age groups at p. value < 0.05. The results of present study showed that CRP and WBC count were increase, while the platelet count was low or normal in children

Non-hepatotropic viral hepatitis and its causative pathogens: The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology.

Non-hepatotropic viral hepatitis and its causative pathogens: The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology.

An In Vivo Model of Echovirus-Induced Meningitis Defines the Differential Roles of Type I and Type III Interferon Signaling in Central Nervous System Infection.

Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae and death, particularly in neonates. However, the mechanisms by which these viruses induce meningeal inflammation are poorly understood, owing at least in part to the lack of in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we developed an in vivo neonatal mouse model that recapitulates key aspects of echovirus-induced meningitis. We show that expression of the human homologue of the primary echovirus receptor, the neonatal Fc receptor (FcRn), is not sufficient for infection of the brains of neonatal mice. However, ablation of type I, but not III, interferon (IFN) signaling in mice expressing human FcRn permitted high levels of echovirus replication in the brain, with corresponding clinical symptoms, including delayed motor skills and hind-limb weakness. Using this model, we defined the immunological response of the brain to echovirus infection and identified key cytokines, such as granulocyte colony-stimulating factor (G-CSF) and interleukin 6 (IL-6), that were induced by this infection. Lastly, we showed that echoviruses specifically replicate in the leptomeninges, where they induce profound inflammation and cell death. Together, this work establishes an in vivo model of aseptic meningitis associated with echovirus infections that delineates the differential roles of type I and type III IFNs in echovirus-associated neuronal disease and defines the specificity of echoviral infections within the meninges. IMPORTANCE Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae or even death. The mechanisms by which echoviruses infect the brain are poorly understood, largely owing to the lack of robust in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we establish a neonatal mouse model of echovirus-induced aseptic meningitis and show that expression of the human homologue of the FcRn, the primary receptor for echoviruses, and ablation of type I IFN signaling are required to recapitulate echovirus-induced meningitis and clinical disease. These findings provide key insights into the host factors that control echovirus-induced meningitis and a model that could be used to test anti-echovirus therapeutics.

Enterovirus Replication and Dissemination Are Differentially Controlled by Type I and III Interferons in the Gastrointestinal Tract

ABSTRACTEnteroviruses are among the most common viral infectious agents of humans and cause a broad spectrum of mild-to-severe illness. Enteroviruses are transmitted primarily by the fecal-oral route, but the events associated with their intestinal replication in vivo are poorly defined. Here, we developed a neonatal mouse model of enterovirus infection by the enteral route using echovirus 5 and used this model to define the differential roles of type I and III interferons (IFNs) in enterovirus replication in the intestinal epithelium and subsequent dissemination to secondary tissues. We show that human neonatal Fc receptor (FcRn), the primary receptor for echoviruses, is essential for intestinal infection by the enteral route and that type I IFNs control dissemination to secondary sites, including the liver. In contrast, type III IFNs limit echovirus infection in the intestinal epithelium, and mice lacking this pathway exhibit extended epithelial replication. Finally, we show that echovirus infection in the small intestine is cell type specific and occurs exclusively in enterocytes. These studies define the type-specific roles of IFNs in enterovirus infection of the gastrointestinal (GI) tract and the cellular tropism of echovirus replication in the intestinal epithelium.

Annual trends in adverse events following mumps vaccination in Japan: A retrospective study

BackgroundIn Japan, a monovalent mumps vaccine is provided on a voluntary basis. Due to public concerns over post-vaccination aseptic meningitis, the vaccination coverage is not high enough. The present study investigated the incidence of adverse events, including aseptic meningitis, after Torii strain–derived mumps vaccination. MethodsThis retrospective, observational study used data collected by a vaccine manufacturer regarding adverse events following mumps vaccinations at medical institutions between 1992 and 2018. In addition, the number of Torii strain–derived mumps vaccines shipped each year was obtained. The incidence (per 100,000 doses) and 95% confidence intervals (CIs) were calculated for all adverse events and each adverse event, categorized as aseptic meningitis, encephalitis, mumps, mumps complications, and others. ResultsDuring the study period, 8,262,121 mumps vaccine doses were shipped, and 688 subjects reported adverse events. The incidence for all adverse events (per 100,000 doses) was 8.33, and the incidence was 4.19 for aseptic meningitis, 0.33 for encephalitis, 0.80 for mumps, 0.25 for mumps complications, and 3.78 for others. The incidence of aseptic meningitis (per 100,000 doses) was 7.90 (95% CI: 5.61–10.18) between 1998 and 2000 but declined by half, to 3.91 (2.46–5.36), between 2001 and 2003. The most recent incidence (per 100,000 doses) of aseptic meningitis, for the period 2016 to 2018, was 2.78 (1.94–3.62). ConclusionThe incidence of post-vaccination aseptic meningitis has declined significantly since 2001, and the incidence has remained stable at fewer than 3 cases per 100,000 doses since 2010. Multiple factors might have contributed to the decline in aseptic meningitis incidence, including (i) lowered misclassification of aseptic meningitis resulting from echovirus infection; (ii) changes in the vaccine manufacturing process in 2000; and (iii) publication in 2008 of the recommendation for vaccination of children at 1 year of age.

Human FcRn expression and Type I Interferon signaling control Echovirus 11 pathogenesis in mice.

Neonatal echovirus infections are characterized by severe hepatitis and neurological complications that can be fatal. Here, we show that expression of the human homologue of the neonatal Fc receptor (hFcRn), the primary receptor for echoviruses, and ablation of type I interferon (IFN) signaling are key host determinants involved in echovirus pathogenesis. We show that expression of hFcRn alone is insufficient to confer susceptibility to echovirus infections in mice. However, expression of hFcRn in mice deficient in type I interferon (IFN) signaling, hFcRn-IFNAR-/-, recapitulate the echovirus pathogenesis observed in humans. Luminex-based multianalyte profiling from E11 infected hFcRn-IFNAR-/- mice revealed a robust systemic immune response to infection, including the induction of type I IFNs. Furthermore, similar to the severe hepatitis observed in humans, E11 infection in hFcRn-IFNAR-/- mice caused profound liver damage. Our findings define the host factors involved in echovirus pathogenesis and establish in vivo models that recapitulate echovirus disease in humans.

Hsp70 Is a Potential Therapeutic Target for Echovirus 9 Infection.

Echovirus is an important cause of viral pneumonia and encephalitis in infants, neonates, and young children worldwide. However, the exact mechanism of its pathogenesis is still not well understood. Here, we established an echovirus type 9 infection mice model, and performed two-dimensional gel electrophoresis (2DE) and tandem mass spectrometry (MS/MS)-based comparative proteomics analysis to investigate the differentially expressed host proteins in mice brain. A total of 21 differentially expressed proteins were identified by MS/MS. The annotation of the differentially expressed proteins by function using the UniProt and GO databases identified one viral protein (5%), seven cytoskeletal proteins (33%), six macromolecular biosynthesis and metabolism proteins (28%), two stress response and chaperone binding proteins (9%), and five other cellular proteins (25%). The subcellular locations of these proteins were mainly found in the cytoskeleton, cytoplasm, nucleus, mitochondria, and Golgi apparatus. The protein expression profiles and the results of quantitative RT-PCR in the detection of gene transcripts were found to complement each other. The differential protein interaction network was predicted using the STRING database. Of the identified proteins, heat shock protein 70 (Hsp70), showing consistent results in the proteomics and transcriptomic analyses, was analyzed through Western blotting to verify the reliability of differential protein expression data in this study. Further, evaluation of the function of Hsp70 using siRNA and quercetin, an inhibitor of Hsp70, showed that Hsp70 was necessary for the infection of echovirus type 9. This study revealed that echovirus infection could cause the differential expression of a series of host proteins, which is helpful to reveal the pathogenesis of viral infection and identify therapeutic drug targets. Additionally, our results suggest that Hsp70 could be a useful therapeutic host protein target for echovirus infection.

Relationship between Echovirus Epidemics and Incidence of Aseptic Meningitis following Mumps Vaccination Based on Previous Japanese Reports: Possibility of Misclassification of Echovirus Infection in Previous Reports

In Japan, the vaccination for mumps has been on a voluntary basis since 1993 because of safety concerns arising from the high incidence of aseptic meningitis associated with Japanese mumps vaccine strains. However, recent reports on the voluntary mumps vaccination have described the decreased incidence of postvaccination aseptic meningitis for unknown reasons. To explore the underlying reason for this decrease, we analyzed the influence of echoviruses, the most common causative viruses for community-acquired aseptic meningitis, on the previously reported incidence of aseptic meningitis following mumps vaccination. We used available data on the yearly number of cases of echovirus detection from the Infectious Agents Surveillance Reports issued by the National Institute of Infectious Diseases as well as previously reported nationwide data on the incidence of postvaccination aseptic meningitis. The incidence of postvaccination aseptic meningitis tended to be higher during the period of an echovirus epidemic and lower during the period without such as epidemic. The present ecological trend analysis suggests the influence of echovirus epidemics on the previous reported incidence of aseptic meningitis following mumps vaccination. It is necessary to carry out a differential diagnosis of echovirus infection to identify the true causative viruses in aseptic meningitis following mumps vaccination.

Concerning the discovery of mechanism for enterovirus B infection published in Cell.

Concerning the discovery of mechanism for enterovirus B infection published in Cell.

The neonatal Fc receptor is a pan-echovirus receptor

Echoviruses are amongst the most common causative agents of aseptic meningitis worldwide and are particularly devastating in the neonatal population, where they are associated with severe hepatitis, neurological disease, including meningitis and encephalitis, and even death. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of FcRn or its binding partner beta 2 microglobulin (β2M) renders cells resistant to infection by a panel of echoviruses at the stage of virus attachment, and that a blocking antibody to β2M inhibits echovirus infection in cell lines and in primary human intestinal epithelial cells. We also show that expression of human, but not mouse, FcRn renders nonpermissive human and mouse cells sensitive to echovirus infection and that the extracellular domain of human FcRn directly binds echovirus particles and neutralizes infection. Lastly, we show that neonatal mice expressing human FcRn are more susceptible to echovirus infection by the enteral route. Our findings thus identify FcRn as a pan-echovirus receptor, which may explain the enhanced susceptibility of neonates to echovirus infections.

Prevalence of Enterovirus Meningitis in Children: Report from a Tertiary Center.

Meningitis is the most frequent infection of the central nervous system and viruses aret he most common agents. Enteroviruses are among the most important causative agents. The goal of this study was to determine Coxsackievirus and echovirus infections in children referred to Bahrami Hospital with the diagnosis of meningitis. Forty children with the diagnosis of meningitis, who were referred betweeen January 2017 and February 2018, were evaluated. Forty cases were evaluated. Twenty two (55%) were males and 18 (45%) females (M/F=2.1). The most common age group was 0-4 years and the most cases were admitted in autumn and summer. Entroviruses are the causative agent of meningitis in 26 (65%) cases, including coxsackieviruse type B5 in 18(69%) and coxsackieviruse type B4 in 2(10%). Six meningitis cases were caused by echoviruses(30%). In both coxsackieviruus and echovirus groups, the most frequent age group was less than four year. Among the 26 cases with enterovirus infection, three were admitted in spring (11.5%), eight in summer (30.7%), 10 in autumn (38.4%) and fice (19.2%) in winter. The most common symptoms in cases with entroviruses infection were fever in 26 (100%) patients and nausea/vomiting in 18 (69.2%). Entroviruses are among the most common viral infections leading to meningitis in Iranian children. Rapid diagnosis will result in early and proper treatment.

An Investigation of a Cluster of Echovirus 6 Infection with an Encephalitis Death in Samut Prakan Province, Thailand, 2015

On 16 Dec 2016, the Bureau of Epidemiology in the Ministry of Public Health, Thailand, was notified of a suspected echovirus 6 encephalitis death in Samut Prakan Province. An investigation was launched for active case detection and confirmation of causative agent. Out of 32 people identified, two (6.3%) were confirmed for echovirus 6, including the index case, and there were 30 suspected cases. The index case was a 5-year-old Thai boy and kindergarten student. On 8 Dec 2015, he developed encephalitis. Echovirus 6 was detected in his cerebrospinal fluid, nasal and rectal swab samples. Chest x-ray revealed pulmonary edema and elevated cardiac enzyme as signs of rhombencephalitis. There were also five (2.9%) out of 173 asymptomatic contacts tested positive for echovirus 6 infection. Potential risks for infection were sharing of utensils and toys, and playing together. Lack of intensive health screening in the school and inadequate hand washing facilities were also observed. We recommended households and the school to improve sanitation, and health education was provided in the communities and schools. Physician's knowledge and awareness of echovirus infection among children should be raised to provide proper treatment and early referral if needed.

Annular Eruptive Pseudoangiomatosis and Adenovirus Infection: A Novel Clinical Variant of Paraviral Exanthems and a Novel Virus Association

Eruptive pseudoangiomatosis is a distinct exanthem thought to be caused by viruses. The usual rash configu-ration is erythematous papules and macules. An association with echovirus infection has been reported. We present here one adult and one child with this exanthem, supported by clinical, histopathological, and immunohistochemical findings. Both patients presented with prodromal symptoms, widespread angioma-like macules in annular configuration, blanchable telangiectasia, followed by spontaneous remission in 6-8 weeks. Lesional histopathology of the adult patient revealed dilated dermal blood vessels and lymphohistiocytic infiltrates predominated by CD4+ lymphocytes with a 5:1 ratio of CD4:CD8 lymphocytes. No B cells or CD56+ natural killer cells were found. Serology of both patients revealed evidence of active infections by adenoviruses, and a range of other viruses were excluded. We believe that these 2 patients manifested annular eruptive pseudoangio-matosis, a novel variant of the rash with a probable adenovirus association that has not yet been reported.

Targeting a metabolic pathway to fight the flu

Our antiviral arsenal to fight influenza viruses is limited and we need novel anti-flu drugs. Recently, cellular drug targets came into focus and omics analysis were instrumental to suggest candidate factors. In this issue of The FEBS Journal, Kainov and colleagues used transcriptome data to investigate virus-induced changes in tryptophan metabolism that may serve as immunomodulatory approach against viruses.

Echovirus serotypes circulating in Malaysia from 2002 to 2013.

To identify the circulating serotypes of human echovirus in Malaysia from 2002 to 2013. A total of 31 retrospective samples from non-polio acute flacid paralysis, hand-food-and-mouth disease, viral meningitis and enterovirus cases were subjected to amplification of partial VP1 gene by RT-PCR. Sequencing and phylogenetic analysis of the partial sequences identified presence of human echovirus and human coxsackie viruses. It was found that echovirus 11 was the commonly circulating serotype followed by echovirus 6, echovirus 7, echovirus 3, echovirus 9, echovirus 30 and echovirus 1 in decreasing order. Additionally two types of human coxsackie virus isolates were detected which were coxsackie A24 and B3. From the findings, there is a possibility that echovirus 11 is the predominant serotype among Malaysian patients with echovirus infection. However, a larger sample size will yield a more confident result to support this evidence.

Differential effects of three echovirus strains on cell lysis and insulin secretion in beta cell derived lines.

In an earlier study, infection of human pancreatic islets with epidemic strains of echovirus (E4, E16, E30), with proven but differently ability to induce islet autoimmunity, resulted either in a severe damage (i.e., E16 and E30) or proceeded without visible changes in infected islets (i.e., E4). In this study, the ability of these strains to replicate in beta cells and the consequence of such an infection for beta cell lysis and beta cell function was studied in the pancreatic beta cell lines INS-1, MIN6, and NIT-1. The strains of E16 and E30 did replicate in INS1, MIN6, and NIT1 cells and resulted in a pronounced cytopathic effect within 3 days following infection. By contrast, E4 replicated in all examined insulinoma cells with no apparent cell destruction. The insulin release in response to high glucose stimulation was hampered in all infected cells (P < 0.05) when no evidence of cytolysis was present; however, the adverse effect of E16 and E30 on insulin secretion appeared to be higher than that of the E4 strain. The differential effects of echovirus infection on cell lysis, and beta cell function in the rodent insulinoma INS1, MIN6, and NIT 1 cells reflect those previously obtained in primary human islets and support the notion that the insulin-producing beta cells can harbor a non-cytopathic viral infection.

The Editor takes a closer look at some of this month's articles

Clinical & Experimental AllergyVolume 45, Issue 10 p. 1477-1477 Editor's ChoiceFree Access The Editor takes a closer look at some of this month's articles First published: 15 September 2015 https://doi.org/10.1111/cea.12629AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Viral immunity: key differences between the gut and lung in asthma Rhinoviruses play an important part in asthma exacerbations, and viral antibody titres against these members of the enterovirus genus are higher in asthmatic children than healthy controls. Iwasaki et al. (pp. 1523–1530) have asked whether this was also the case for the gut tropic enteroviruses echovirus 30, which causes an acute febrile illness in children, and the Sabin 1 poliovirus. They found that IgG titres against echovirus, but not poliovirus, were lower in asthmatic children compared to matched healthy controls. Whether this was due to a protective effect of echovirus infection on the development of asthma or a diminished antibody immune response to echovirus in asthmatics is not clear. However, the study emphasizes the potential importance of differential, organ-specific, mucosal immune responses in the development of asthma. Jua Iwasaki Total (a) and species-specific (b) IgG1 antibody binding to echovirus 30 VP1 and human Sabin 1 poliovirus VP1 antigens in Emergency Department (ED) asthmatics and nonasthmatic children. [See Figure 1b in J. Iwasaki et al. (pp. 1523–1530)]. Predicting anaphylaxis with bee venom immunotherapy: a role for the basophil test? Measuring the sensitivity of basophil activation to in vitro allergen challenge, either by mediator release or changes in receptor expression, has been a test without an established clinical role for a long time. Korošec et al. (pp. 1579–1589) have investigated which factors including basophil sensitivity predict allergic reactions to ultra-rush immunotherapy for bee venom anaphylaxis. They studied a range of clinical and immunological measurements in 93 patients, 13 of whom had severe systemic reactions (5 had to have their IT stopped). Pre-treatment basophil sensitivity was the only independent predictor of both a severe systemic reaction and having to stop treatment. A useful test therefore for groups which undertake this approach to bee venom IT. Peter Korosec A bee. (Photo credit: James Petts, London, England; Wikimedia Commons). Prostaglandin E2: how can we harness its protective properties? It has been known for many years that prostaglandin E2 has bronchoprotective properties on both airway inflammatory cells and airway smooth muscle contraction, but so far this potent inhibitory pathway has not been exploited in drug development 1. In part, this is because the exact mechanisms involved remain unclear. Further clarity is brought to the subject by Torres et al. (pp. 1590–1600) who have investigated the effects of PGE2 in the asthma allergen challenge model using two strains of mice; BALB/c which is a mast cell-dependent model and C57BL/6 mice which is mast cell independent. They convincingly demonstrate that the inhibitory properties of PGE2 on inflammation and airway hyperresponsiveness are mast cell dependent and mediated through the mast cell E prostanoid 2 (EP2) receptor. There must be a therapeutic target somewhere in this pathway. Rosa Torres and Mariona Serra The molecular structure of Prostaglandin E2. (Photo credit: NEUROtiker; Wikimedia Commons). Reference 1Pavord ID, Tattersfield AE. Bronchoprotective role for endogenous prostaglandin E2. Lancet 1995; 345: 436– 8. Caption to cover illustration: Immune mechanisms of tolerance and sensitization to foods. [See figure 1 of M. C. Berin (pp. 1483–1496)]. This logo highlights the Editor's choice articles on the cover and the first page of each of the articles. Volume45, Issue10October 2015Pages 1477-1477 ReferencesRelatedInformation

Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome

Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome