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PubMed1999

Multicenter quality assessment of PCR methods for detection of enteroviruses.

We conducted a multicenter evaluation of commercial and in-house PCR methods for the detection of enteroviruses. Three coded panels of test and control RNA samples, artificial clinical specimens, and representative enterovirus serotypes were used to assess amplification methods, RNA extraction methods, and reactivities with different enterovirus serotypes. Despite several differences between PCR methods, there was good agreement, although some variation in sensitivity was observed. Most PCR methods were able to detect enterovirus RNA derived from 0.01 50% tissue culture infective dose (TCID50) and were able to detect at least 1 TCID50 of enterovirus in cerebrospinal fluid, stool, or throat swab specimens. Most were also able to detect a wide range of enterovirus serotypes, although serotypic identification was not possible. Some laboratories experienced false-positive results due to PCR contamination, which appeared to result mainly from cross-contamination of specimens during RNA extraction. Provided that this problem is overcome, these PCR methods will prove to be a sensitive and rapid alternative to cell culture for the diagnosis of enterovirus infection.

Base Sequence↗
PubMed2003

Identification of enteroviruses by using monoclonal antibodies against a putative common epitope.

A common epitope region of enteroviruses was identified by sequence-independent single-primer amplification (SISPA), followed by immunoscreening of 11 cDNA libraries from two Korean enterovirus isolates (echoviruses 7 and 30) and a coxsackievirus B3 (ATCC-VR 30). The putative common epitope region was localized in the N terminus of VP1 when the displayed recombinant proteins from the phages were chased by the convalescent-phase sera. The genomic region encoding the common epitope region was amplified and then expressed by using the vector pGEX-5X-1. The antigenicity of the expressed recombinant protein was identified by Western blotting with guinea pig antisera for six different serotypes of enteroviruses. After successive immunization of mice with the recombinant common epitope protein, splenocytes were extracted and hybridized with P3X63-Ag8-653 cells. A total of 24 hybridomas that produced monoclonal antibodies (MAbs) against the putative common epitope of enteroviruses were selected. Four of these were immunoglobulin G1 isotypes with a kappa light chain. These MAbs recognized 15 Korean endemic serotypes and prototypes of enteroviruses in an indirect immunofluorescence assay. These results suggest that the expressed protein might be a useful antigen for producing group common antibodies and that the use of the MAbs against the putative common epitope of enteroviruses might be a valuable diagnostic tool for rapidly identifying a broad range of enteroviruses.

Amino Acid Sequence↗
PubMed2006

Frequency and dynamics of recombination within different species of human enteroviruses.

Enteroviruses are members of the family Picornaviridae that cause widespread infections in human and other mammalian populations. Enteroviruses are genetically and antigenically highly variable, and recombination within and between serotypes contributes to their genetic diversity. To investigate the dynamics of the recombination process, sequence phylogenies between three regions of the genome (VP4, VP1, and 3Dpol) were compared among species A and B enterovirus variants detected in a human population-based survey in Scotland between 2000 and 2001, along with contemporary virus isolates collected in the same geographical region. This analysis used novel bioinformatic methods to quantify phylogenetic compatibility and correlations with serotype assignments of evolutionary trees constructed for different regions of the enterovirus genome. Species B enteroviruses showed much more frequent, time-correlated recombination events than those found for species A, despite the equivalence in population sampling, concordant with a linkage analysis of previously characterized enterovirus sequences obtained over longer collection periods. An analysis of recombination among complete genome sequences by computation of a phylogenetic compatibility matrix (PCM) demonstrated sharply defined boundaries between the VP2/VP3/VP1 block and sequences to either side in phylogenetic compatibility. The PCM also revealed equivalent or frequently greater degrees of incompatibility between different parts within the nonstructural region (2A-3D), indicating the occurrence of extensive recombination events in the past evolution of this part of the genome. Together, these findings provide new insights into the dynamics of species A and B enterovirus recombination and evolution and into the contribution of structured sampling to documenting reservoirs, emergence, and spread of novel recombinant forms in human populations.

Capsid Proteins↗
PubMed2004

Presentation, diagnosis, and management of enterovirus infections in neonates.

The nonpoliovirus enteroviruses commonly infect newborns, with consequences ranging from asymptomatic infection and benign illness, to severe, life-threatening disease. Frequently occurring symptoms include fever, irritability, lethargy, anorexia, and rash. Although most illnesses are mild, severe disease develops in a subset of newborns infected in the first 2 weeks of life. Severe disease may consist of sepsis, meningoencephalitis, myocarditis, pneumonia, hepatitis, and/or coagulopathy. Substantial mortality rates have been reported, and long-term sequelae may occur among survivors. Risk factors and clinical features associated with severe disease include absence of neutralizing antibody to the infecting serotype, maternal illness prior to or at delivery, prematurity, illness onset within the first few days of life, multiorgan disease, severe hepatitis, positive serum viral culture, and specific infecting serotype (e.g. group B coxsackieviruses and echovirus 11). Whereas the mainstay of diagnosis has traditionally been viral isolation in tissue culture, the polymerase chain reaction has been demonstrated to be more sensitive than culture, highly specific, and rapid. Immunoglobulin has been used as a therapeutic agent for neonates with enterovirus disease; however, clinical efficacy has not been proven. Specific antiviral therapy for enteroviruses is in development. Pleconaril is an investigational agent that inhibits viral attachment to host cell receptors and uncoating of viral nucleic acid. It has broad and potent anti-enterovirus activity, excellent oral bioavailability, and is well tolerated. Some clinical trials have demonstrated benefit in children and adults with enterovirus meningitis, and in adults with upper respiratory tract infections caused by picornaviruses (rhinoviruses or enteroviruses). Data summarizing compassionate use for severe enterovirus diseases (including neonatal sepsis) also suggest possible benefit. Limited pharmacokinetic data are available in infants and neonates. A multicenter, placebo-controlled, randomized trial of pleconaril in neonates with severe hepatitis, coagulopathy, and/or myocarditis is currently being conducted.

Adult↗
PubMed2006

Optimisation of RT-PCR for detection of enteroviruses.

Enteroviruses are members of Enterovirus genus of Picornaviridae family. On the basis of their pathogenesis and host range, most human enteroviruses are classified into one of three groups (Coxsackie's viruses, echoviruses and polioviruses). Some unclassified human enteroviruses may cause bronchitis (type 68), acute hemorrhagic conjunctivitis (type 70), meningitis and paralysis (types 70 and 71) and hepatitis (type 72 or hepatitis A virus). Enteroviruses can be propagate in primary cultures of human monkey kidney cells and in some cell lines such as HeLa, Vero and WI-38. Virions are small (22-30 nm diameters) containing ss RNA, monopartite and have icosahedra symmetry. The fast, high sensitive and specific detection of enteroviruses today is achieved by using of PCR (Polymerase chain reaction) method. But, PCR is so much more than just mixing reagents in a tube and running a thermal cycler. In each laboratory with PCR facilities, it is necessary to find optimal PCR conditions (performing of PCR optimization experiments). In this paper we presented results of PCR optimization for enteroviruses by using of poliovirus type 1(Sabin). Optimal obtained PCR parameters were: 2,5 mM MgCl2, dNTPs dilution 10(-1) and annealing temperature 50 degrees C, after 30 amplification cycles in Perkin Elmer 2400 thermal cycler.

Enterovirus↗
PubMed2003

Molecular typing and epidemiology of enteroviruses identified from an outbreak of aseptic meningitis in Belgium during the summer of 2000.

Non-polio enteroviruses are the most common cause of aseptic meningitis worldwide. From May to September 2000, a major outbreak of aseptic meningitis occurred in Belgium. Cerebrospinal fluid samples (CSF) of 122 patients were found to contain enterovirus RNA using diagnostic RT-PCR that targeted a 231-bp gene fragment in the 5' noncoding region. In addition, a molecular typing method was developed based on RT-nested PCR and sequencing directly from CSF(a) 358-bp fragment in the aminoterminal part of the VP1 capsid protein. To identify the enterovirus type, nucleotide sequences of the VP1 amplicons were compared to all the enterovirus VP1 sequences available in GenBank. Echovirus 30 (31.2%), echovirus 13 (23.8%), and echovirus 6 (20.5%) were identified most frequently during the epidemic. Coxsackievirus B5 was present in 15.6% of the samples, and could be subdivided in two distinct epidemic clusters, coxsackievirus B5a (10.7%) and B5b (4.9%). Other enteroviruses encountered were echovirus 16 (5.7%), echovirus 18 (1.6%), coxsackievirus B4 (0.8%) and echovirus 7 (0.8%). The high prevalence of echovirus 13, considered previously a rare serotype, indicates it is an emerging epidemic type. To verify the typing results and to explore further the intratypical genetic variation, phylogenetic analysis was carried out. Geographical clustering of most of the strains within each type and subtype could be observed. The RT-nested PCR strategy, carried out directly on clinical samples, is a simple and rapid method for adequate molecular typing of the Group B enteroviruses causing aseptic meningitis.

Adolescent↗
PubMed1988

A solid-phase reverse immunosorbent test for the detection of enterovirus IgM.

IgM antibodies against enterovirus antigen were determined by solid-phase reverse immunosorbent test (SPRIST). The 145 sera studied were sampled from cases of enterovirus infections diagnosed by virus isolation and/or complement fixation. In 91 sera from enterovirus infections diagnosed by virus isolation 11/40, 16/28 and 9/23 were positive in SPRIST against ECHO 3 and/or Coxsackie B3 antigen during the first, during the second and third, and after 3 weeks of illness, respectively. The corresponding figures for 85 sera from enterovirus infections diagnosed by a greater than or equal to 4-fold rise in complement fixing (CF) antibody titre against antigen from ECHO 18 and/or Coxsackie B5 antigen were 10/39, 12/20 and 9/26. None out of 22 sera with rheumatoid factor reacted in SPRIST, but 1/92 and 1/154 sera from blood donors was positive in SPRIST with Coxsackie B3 and ECHO 3 antigen, respectively. IgM antibodies against ECHO 3 antigen as determined by SPRIST were found to be cross-reactive over a broad range of enterovirus types and positive results were recorded with sera from infections with Coxsackie A9, B3, B4, B5, ECHO 3, 9, 17, 18, 25 and 30. Heterotypic titres in SPRIST were of the same magnitude (up to 25,600) as recorded against the homotypic virus, 12,800 and 1,600, in two sera from one patient with an ECHO 3 infection. SPRIST was found to be a rapid convenient, cross-reactive and a cheap mu-capture assay for enteroviruses with more than 50% sensitivity during the second and third weeks after onset of illness.

Coxsackievirus Infections↗
PubMed1999

A novel serological technique: polymerase chain reaction enhanced immunoassay. Application to enterovirus IgM diagnosis.

The polymerase chain reaction (PCR) method is a sensitive, specific and rapid technique for virus detection. The principles of a PCR enhanced immunoassay (PIA) are described. The method combines solid phase serological techniques with the PCR, providing a versatile and sensitive method for antibody detection. By linking the antigenicity of virus particles with their content of nucleic acid, the method provides new possibilities for virus serology: for example, antibody specificity can be coupled to viral sequence in patients with chronic infections caused by highly variable viruses such as HIV and HCV. An application of the PIA technique is described for the detection of anti-enterovirus IgM. IgM is captured to anti-human IgM-coated microwell plates. The anti-enterovirus IgM is allowed to bind crude enterovirus antigen. Bound virus is heat denatured and the released RNA is used as a template for reverse transcription PCR (RT-PCR) amplification. Amplicons are detected by hybridisation to an affinity labelled probe in a microwell colorimetric assay. In a pilot study, 18 serum specimens from patients with enterovirus infections were examined. Using a mixture of ten crude enterovirus antigens, the frequency of IgM positivity was 6/18 (33%). Titres between 1/500 and 1/100,000 were recorded. Predominantly type-specific antibodies were detected. The results were compared with a procapsid enterovirus radioimmunoassay (RIA). After further optimisation, the PIA has the potential to be a clinically useful assay for the detection of antiviral antibodies.

Adult↗
PubMed1980

Enteroviruses in Vermont, 1969-1978: an important cause of illness throughout the year.

Enteroviruses continue to play an important role in both epidemic and sporadic febrile diseases. Of the clinical specimens submitted for diagnosis during a 10-year period (1969-1978) at the Medical Center of Vermont Hospital, Burlington, a wide variety of diseases were associated with the isolation of enteroviruses. Among these diseases were aseptic meningitis, hand-foot-and-mouth disease, diarrhea, pleurodynia, myocarditis, herpangia, and fevers. In 1972 a single enterovirus serotype, coxsackievirus B5, WAS SOLELY RESPONSIBLE FOR EPIDEMIC DISEASE. During the other nine years of the study, a variety of enteroviruses were isolated during epidemics. Although epidemics were always seen during the summer and early fall, enteroviruses which may cause sporadic disease were isolated in each of the 12 months. An awareness by both practicing physicians and health officers not only of the epidemic potential of enteroviruses in summer and fall but also throughout the year will aid in the diagnosis and therapy of these illnesses.

Adolescent↗
PubMed2006

Molecular typing of enteroviruses associated with viral meningitis in Cyprus, 2000-2002.

Human enteroviruses are responsible for a wide spectrum of clinical diseases affecting many different organ systems. Although infection is usually asymptomatic, infections of the central nervous system manifested as meningitis or encephalitis can pose a serious public health problem, especially during outbreaks. In this study, samples from 218 patients diagnosed with enteroviral meningitis between January 2000 and December 2002 were analysed in order to assess the epidemiology of human enteroviruses as a cause of viral meningitis in Cyprus. A new typing strategy, based on partial sequencing of the 5' non-coding region (5'NCR), prediction of type, and selection of type-specific primers for sensitive VP1 PCR amplification, was developed. As clustering in the 5'NCR was concordant with clustering in the VP1 region, quick and reliable typing by VP1 sequencing was achieved without virus isolation in cell culture. The most frequent enterovirus serotypes identified were Human echovirus 30 (55.5%), Human echovirus 13 (15.1%), Human echovirus 6 (13.8%) and Human echovirus 9 (8.3%). Human coxsackieviruses B2, B1 and B5, Human echovirus 4, Human enterovirus 71 and Human coxsackievirus A6 represented rather rare serotypes. This is the first molecular epidemiological study of enterovirus meningitis in Cyprus. Serotype distribution corresponded basically with observations in other European countries, suggesting the spread of enteroviruses by tourism.

5' Untranslated Regions↗
PubMed1990

Secondary enterovirus infection in the murine model of myocarditis. Pathologic and immunologic aspects.

Enteroviruses are implicated as etiologic agents in the inflammatory diseases myocarditis and polymyositis. In this report, we show that a previous enterovirus exposure in mice can influence development of myocardial inflammation with a second enteroviral exposure. Inoculation of 25-day-old male C3H/HeJ mice with 10(3) or 10(5) plaque-forming units (PFU) of infectious or ultra violet (UV)-inactivated coxsackievirus B2 (CVB2), followed by inoculation 28 days later with 10(5) PFU of a myocarditic variant of coxsackievirus B3 (CVB3-m) results in more intense myocardial inflammation and injury than is seen in age-matched mice inoculated with CVB3-m alone. More severe disease occurs with the lower primary dose of CVB2. Neutralizing antibody to CVB2 is detected early after primary inoculation and neutralizing antibody to CVB3 is first detected 5 days after secondary inoculation. In vitro proliferation of splenocytes from mice inoculated with one or both viruses occurs in response to both CVB2 and CVB3 antigens. We recently demonstrated that murine T cells are capable of recognizing an enterovirus group antigen. Thus cell-mediated immune responses to a conserved antigenic epitope(s) among the enteroviruses may be involved in the exacerbation of myocardial inflammatory disease during a second enterovirus infection. The secondary infection model described here may more accurately mirror virus-induced myocarditis in the human population because the majority of adults have been exposed to several enteroviruses before induction of disease.

Animals↗
PubMed2000

Expression of capsid [correction of caspid] protein VP1 for use as antigen for the diagnosis of enterovirus 71 infection.

To produce enterovirus 71 antigen for diagnostic purposes, the gene encoding the entire capsid protein VP1 was amplified by reverse transcription-polymerase chain reaction (RT-PCR), cloned and expressed in Escherichia coli as a poly-histidine fusion protein. Western blotting experiments with sera from patients with enterovirus 71 infection indicated that immunoglobulin G (IgG) and IgM antibodies bound to a single polypeptide VP1. According to these results, IgM anti-VP1 appeared in sera of patients with a symptomatic enterovirus 71 acute infection, whereas IgG anti-VP1 was present in sera of past infection. This finding suggests that detecting IgG and IgM immune responses against linear epitopes of recombinant VP1 is an effective means of determining the different phases of enterovirus 71 infection. In addition, sera containing coxsackie virus 16 (CA16) antibodies did not cross-react with the recombinant VP1 of enterovirus 71, despite the homology between VP1 proteins of both viruses. Comparison with reference PCR and neutralization assays showed these antibody tests to be appropriate for the serodiagnosis of enterovirus 71 infection.

Antibodies, Viral↗
PubMed1998

Onset of type 1 diabetes mellitus in infancy after enterovirus infections.

Enterovirus infections may initiate and accelerate the beta-cell damaging process leading to Type 1 (insulin-dependent) diabetes mellitus (Type 1 DM). Recent prospective studies have suggested that this can happen long before overt disease and even in utero. We describe an infant, followed regularly from birth, who progressed to clinical Type 1 DM at the age of 14 months. He had a strong enterovirus exposure exceptionally early in life; the first enterovirus infection occurred before the age of 3 months and the second between the age of 9 and 12 months. The first infection probably occurred at birth, when the child had symptoms of a respiratory infection. This infection was followed by the appearance of beta-cell autoimmunity, and clinical Type 1 DM was diagnosed shortly after the second infection. The child had a low level of maternal enterovirus antibodies and short duration of breast-feeding, both associated with increased risk for enterovirus infections during the fetal period and infancy. This case fits with the current hypothesis that enterovirus infections can induce the process resulting in Type 1 DM, especially when occurring early in life. Furthermore, this demonstrates the feasibility of the present study design, which is applicable also in large-scale birth-cohort studies.

Antibodies, Viral↗
PubMed2004

Persistence of rhinovirus and enterovirus RNA after acute respiratory illness in children.

The persistence of rhinovirus and enterovirus RNAs was studied in the nasal secretions of children with acute expiratory wheezing (median age: 1.7 years). On admission, 84 samples from 161 (52%) children admitted to hospital were positive by reverse transcriptase-polymerase chain reaction (RT-PCR), which detects rhino- and enteroviruses simultaneously. Of the samples, 26 (16%) were positive for rhinovirus, 29 (18%) enterovirus and 29 (18%) nontypable rhino-enterovirus. After 2 weeks, 16 of these 84 (19%) samples were still positive. Rhinovirus RNA remained positive in 13 of 26 (50%) cases, whereas enterovirus RNA remained positive only in 1 of 29 (3%) cases (P=0.0001). Respiratory symptoms at 2 weeks or systemic glucocorticoid treatment during hospital stay were not related to the persistence of viral RNA. After 5 weeks, only one sample remained PCR-positive. Thirteen of the 79 (16%) asymptomatic control children were PCR-positive for respiratory picornavirus. Five of the 13 (38%) PCR-positive children developed respiratory symptoms in the following week. The study shows that after the onset of symptomatic respiratory infection enterovirus RNA may take 2-3 weeks and rhinovirus RNA 5-6 weeks to disappear from nasal mucus.

Adolescent↗
PubMed2001

Circulation of enteroviruses and persistence of meningitis cases in the winter of 1999-2000.

The seasonal incidence of enterovirus meningitis was analyzed in a prospective study of patients admitted for suspected meningitis from October 1, 1998 to April 30, 2000. In-house reverse transcription-polymerase chain reaction (RT-PCR) in cerebrospinal fluid (CSF) was used irrespective of cytological results. Fifty-two (45.2%) of the 115 patients had positive RT-PCR in CSF, including 44/86 children (51.2%) and 8/29 adults (27.6%). Six of the 52 (11.5%) had no pleocytosis. The numbers of CSF specimens with a predominance of lymphocytes or a predominance of neutrophils were closely similar. In 33 of the positive patients, an enterovirus, mainly echoviruses type 6 (48%) and 30 (24%), was recovered in one or more specimens. Sixteen cases of enteroviral meningitis were observed between November 1999 and March 2000 as against 2 cases between November 1998 and March 1999, showing that the disease persisted through the winter months of 1999-2000. During the same period, 96 enterovirus isolates were recovered from clinical specimens from other patients. The number of isolates was higher in the winter of 1999-2000 (P < 0.01) than in the winter of 1998-1999, indicating that the risk of enterovirus infection increased significantly in winter 1999-2000. Sixteen patients had aseptic meningitis, made a rapid recovery and had an enterovirus in throat swabs and stools (9/16) or in one of the two (7/16). RT-PCR was not requested. Nine patients were admitted during the cold months. The clinical management of both adult and child patients could be improved by year-round use of enterovirus generic RT-PCR.

Adolescent↗
PubMed2006

Molecular detection and characterization of human enteroviruses directly from clinical samples using RT-PCR and DNA sequencing.

Enteroviruses are common human pathogens associated with a wide spectrum of symptoms ranging from asymptomatic infection to acute flaccid paralysis and neonatal multi-organ failure. Molecular methods that provide rapid diagnosis and increased sensitivity have been developed for the diagnosis of enterovirus infection using oligonucleotide primers complementary to conserved sequences located in the 5' untranslated region (UTR), but data generated from these regions are not sufficiently discriminatory for typing due to the lack of correlation between their nucleic acid sequence and serotype specificity. Sequences derived from the gene encoding the capsid VP1 correlate with serotype, and therefore provide the opportunity for the development of molecular typing methods consistent with present serogical methods. In this study, oligonucleotide primers that amplify a region of the 5'UTR to detect enterovirus RNA, and the region encoding the enterovirus VP1 N-terminus to characterize virus strains were used in nested and semi-nested RT-PCRs, respectively. The ability of the VP1 RT-PCR to amplify diverse viruses within genotypes and genogroups was confirmed by the correct identification of both prototype strains, and strains circulating currently of the same genotypes. The molecular methods proved their utility through the detection of enteroviruses that failed to grow in cell culture, their subsequent characterization and the characterization of strains that failed to serotype in neutralization assays. Molecular methods increased significantly the sensitivity of detection (P < 0.001) and of characterization (P < 0.01) of enteroviruses when compared to classical methods.

Amino Acid Sequence↗
PubMed2002

Effect of coincident enterovirus infection and cows' milk exposure on immunisation to insulin in early infancy.

AIMS/HYPOTHESIS: Insulin autoantibodies appear often as the first autoantibody in children who develop islet-cell autoimmunity. Our recent studies indicate that primary immunisation to insulin is induced in early infancy by exposure to dietary bovine insulin present in cows' milk formulas. As gut-associated lymphoid tissue is also the primary replication site of enteroviruses, we tested whether enterovirus infections could modify the development of immune response to dietary insulin in early infancy. METHODS: We studied the development of IgG-antibodies to dietary bovine insulin by enzyme immunoassay in relation to enteroviral infections determined by T-cell proliferation response to the Coxsackie B4 virus and by serological tests for enterovirus antigens in 57 infants who carried the HLA DQB1(*)02/0302 diabetes risk genotype and participated in a Finnish population-based birth-cohort study (Diabetes Prediction and Prevention Project, DIPP, study). RESULTS: In the infants exposed to cows' milk formulas before the age of 3 months, those who had a T-cell proliferation response to enterovirus antigen at 3 months of age ( n = 12) had higher concentrations of IgG-antibodies to bovine insulin at the age of 6 and 9 months than those who did not have T-cell proliferation response to enterovirus antigen ( n = 25) (median OD were 0.742 vs 0.427, p = 0.04, and 0.477 vs 0.293, p = 0.02, respectively). CONCLUSION/INTERPRETATION: Our results suggest that two epidemiological risk factors of Type I (insulin-dependent) diabetes mellitus, enterovirus infections and exposure to cows' milk formulas, could modify the immunisation to insulin in early infancy.

Animals↗
PubMed2006

Induction of the chemokine interferon-gamma-inducible protein-10 in human pancreatic islets during enterovirus infection.

AIMS/HYPOTHESIS: Enterovirus infections have long been suspected to be environmental factors that may cause type 1 diabetes, but the pathways leading from infection to beta cell destruction are still unknown. We therefore examined whether enterovirus infection of human islets leads to upregulation of interferon-gamma-inducible protein (IP-10, now known as chemokine [C-X-C motif] ligand 10 [CXCL10]), a chemokine important for the induction of insulitis. METHODS: Isolated human islets were infected with three different strains of Coxsackie B4 virus. IP-10 expression and secretion from the infected human islets were then measured using RT-PCR and ELISA at several time points. RESULTS: IP-10 was clearly upregulated in and secreted from human islets during enterovirus infection. This was demonstrated with three different strains of Coxsackie B4 virus, two of which are lytic to islets and one which is non-lytic and can establish a persistent infection in human islets. CONCLUSIONS/INTERPRETATION: We propose that enterovirus-induced upregulation of IP-10 during infection of the islets in vivo is the first step towards destructive insulitis. Our findings support the idea that enterovirus infection triggers immune-mediated beta cell destruction, and for the first time suggest a possible mechanism behind enterovirus-induced diabetes.

Actins↗