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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↗
PubMed1997

[Enterovirus infections in new disguise].

Enteroviruses (Coxsackie A and B, echovirus, poliovirus) belong to a group of small RNA-viruses, picomavirus, which are widespread in nature. Enteroviruses cause a number of wellknown diseases and symptoms in humans, from subclinical infections and the common cold to poliomyelitis with paralysis. The development of polio vaccines is the greatest accomplishment within the field of enterovirus research and the background work was awarded the Nobel prize in 1954. New knowledge implies that enteroviruses play a more important part in the morbidity panorama than was previously thought. Chronic (persistent) enteroviruses were formerly unknown. Serologic and molecular biology techniques have now demonstrated that enteroviral genomes, in certain situations, persist after the primary infection (which is often silent). Persistent enteroviral infection or recurrent infections and/or virus-stimulated autoimmunity might contribute to the development of diseases with hitherto unexplained pathogenesis, such as post polio syndrome, dilated cardiomyopathy, juvenile (type 1) diabetes and possibly some cases of chronic fatigue syndrome.

Cardiomyopathy, Dilated↗
PubMed1996

Outbreak of vertigo in Wyoming: possible role of an enterovirus infection.

An epidemiologic investigation was conducted to characterize and evaluate the possibility of a viral aetiology of an outbreak of acute vertigo in Hot Springs Country, Wyoming, during autumn 1992. Case-finding identified Hot Springs County residents who sought medical attention for new onset vertigo during 1 August, 1992-31 January 1993. Thirty-five case-patients and 61 matched controls were interviewed and serum specimens were obtained during January 1993. Case-patients were more likely than controls to report symptoms (e.g. fatigue, sore throat, fever, diarrhoea) of antecedent acute illness. Case-patients did not have a significantly greater prevalence or mean titre of IgG antibodies to respiratory syncytial virus, parainfluenza viruses, Epstein-Barr virus, and cytomegalovirus than controls. Serologic evidence of recent enterovirus infection (IgM antibodies) was found for 74% of case-patients compared with 54% of controls (P < 0.05), suggesting a possible association between vertigo and enterovirus infection. Future studies are needed to define the role of enteroviruses in innerear diseases.

Adolescent↗
PubMed2003

Frequency, viral loads, and serotype identification of enterovirus infections in Scottish blood donors.

BACKGROUND: Enteroviruses are non-enveloped, frequently pathogenic RNA viruses infecting humans. Infection is potentially transmissible through blood or blood component transfusion from donor in the viremic phase before seroconversion for antibody. To investigate the threat to blood safety from enteroviruses, a large-scale survey of frequency and levels of viremia in blood donors was conducted. STUDY DESIGNS AND METHODS: Blood donations from Scotland over a period of 22 calendar months were screened for enterovirus RNA sequences by PCR. Positive samples were quantified, and serotypes were identified by nucleotide sequencing of VP1. RESULTS: From a total of 3658 pools of 95 donations tested, 73 samples that were enterovirus-positive were identified (corrected annual frequency 0.024% or 1 in 4000). The highest rates of viremia were in late summer months (e.g., 0.055%, 1 in 1800 in July) and lowest from January to May (0.009 and 0.012%). Viral loads ranged from 500 (the lower cutoff of the assay) to greater than 100,000 amplifiable enterovirus template copies per mL. Coxsackievirus A16, echoviruses 11 and 30, and enterovirus 71 were most often identified. CONCLUSIONS: The detection of enterovirus-positive blood units indicates the potential for enteroviral transmission by blood components. Although the infrastructure established for PCR-based screening for HCV RNA would allow parallel screening for enteroviruses, any decision concerning donor testing would require further information on the outcome of transfusion-acquired enterovirus infections.

Blood↗
PubMed1995

Enterovirus infections in children.

International cooperation and widespread use of trivalent oral poliovaccine has almost eliminated paralytic poliomyelitis from developed countries and is now dramatically decreasing the disease in developing countries. The remarkable results are based on the strategies recommended by the World Health Organization, which include national mass campaigns for administering oral polio vaccine to all children younger than 5 years of age, enhanced surveillance to find patients with acute flaccid paralysis, creating a network of laboratories for viral diagnosis, and targeted immunization to populations in endemic areas. Another remarkable advance in clinical and research fields of enterovirus infections is the development of molecular genetic technologies such as polymerase chain reaction and in situ hybridization assays. A cloned enterovirus complementary DNA prepared from the highly conserved 5' region of the enterovirus genome can be used for rapid and sensitive group-specific diagnosis of enterovirus infections. This complementary DNA is currently being used to study the molecular mechanisms in the pathogenesis of enteroviral heart disease; lesions in acute and chronic myocarditis and even in end-stage dilated cardiomyopathy may be associated with replication of enteroviruses.

Central Nervous System Diseases↗
PubMed2000

Restricted TCR V beta gene expression and enterovirus infection in type I diabetes: a pilot study.

AIMS/HYPOTHESIS: High frequencies of T-cell receptor (TCR) V beta 7+ T cells were detected among the lymphocytes isolated from pancreatic islets of children at the onset of Type I (insulin-dependent) diabetes mellitus. We assessed whether a preferential expression of certain TCR V beta gene families could also be detected among the peripheral blood mononuclear cells from diabetic patients. METHODS: T-cell receptor repertoires were evaluated by using a semi-quantitative RT-PCR-based technique and confirmed by FACS analysis in peripheral blood mononuclear cells from diabetic patients before, at and after onset of the disease. These patients were also tested for exposure to enteroviruses by RT-PCR and by measuring titres of enterovirus-specific antibodies of the IgA, IgG, and IgM classes. RESULTS: T-cell receptor V beta 7 gene family values were higher in recently-diagnosed diabetic patients (10.5% +/- 3.7) than in age-matched non-diabetic control subjects (5.1% +/- 1.6) (p < 0.001). In a time-course analysis of people who developed diabetes during clinical monitoring (i.e., converters), T-cell receptor V beta 7 gene expression showed values consistently above 10% (p < 0.0005). Long-standing diabetic patients showed lower percentage of V beta 7 expression compared to values measured at disease onset. In the longitudinal study of the converters, multiple acute enterovirus infections were also detected. These infections appeared to be temporally related to increased percentage of V beta 7 gene transcripts. CONCLUSION/INTERPRETATION: The deviation in the T-cell receptor V beta repertoire among circulating T cells from diabetic patients seems to re-emphasize the importance of enterovirus infections in accelerating the progression of Type I diabetes.

Adolescent↗
PubMed2003

Diagnosis of enterovirus infection by genus-specific PCR and enzyme-linked immunosorbent assays.

PCR for the diagnosis of enterovirus infections is resource intensive but is increasingly used due to wide availability. Enzyme-linked immunosorbent assays (ELISAs) that detect heterotypical antibodies against enterovirus immunoglobulin M (IgM), IgA, and IgG were compared with reverse transcription-PCR by using primers specific to the 5' untranslated regions of 60 enterovirus species. The ELISAs were less sensitive than the PCR, and only the ELISA for IgM was highly specific. When retrospective diagnosis is important or when specimens are unsuitable for PCR, the ELISA has a limited role if PCR is not available.

Enterovirus↗
PubMed1995

Enterovirus-infected immune cells of spleen and lymph nodes in the murine model of chronic myocarditis: a role in pathogenesis?

Molecular hybridization studies have demonstrated that human enteroviruses, including group B coxsackieviruses (CVB), are detectable not only in endomyocardial biopsies of patients with acute enterovirus myocarditis but also in those with chronic disease. Such infections are observed in some patients with end-stage dilated cardiomyopathy, indicating the possibility of persistent heart muscle infection. Enterovirus persistence in the human heart is supported by the recent discovery in various murine models of enterovirus myocarditis that chronic inflamed heart muscle lesions are consistently associated with enterovirus persistence. Application of in-situ hybridization in a multiorgan study of CVB3-infected immunocompetent mice now reveals that, in addition to the myocardium, spleen and lymph nodes are persistently infected. During acute myocarditis, the majority of infected spleen cells was found to be located within the follicles of spleen and lymph nodes. At later stages of the disease, enteroviral infection was shown to be restricted to cells of the germinal centre in secondary follicles of spleen and lymph nodes. Thus, infected immunocompetent cells may play an important role in dissemination of the virus in the host and maintenance of a non-cardiac viral reservoir.

Animals↗
PubMed1990

Notes on the pathogenesis of enterovirus infections. Observations, experiments, and speculations.

Despite extensive investigations over the last decades, several aspects of the pathogenesis of enterovirus infections in humans and animals are only poorly understood, such as the molecular basis of virulence (in particular of neurovirulence), tissue tropisms (e.g. the precise site of initial virus replication in the human intestinal tract), and precipitating factors of paralytic disease ("disposition"). Studies on poliovirus myocarditis in man are reviewed. Unequivocal evidence on replication of poliovirus type 2 (strains MEF1 and Lansing) in newborn and suckling mice and on poliovirus myocarditis is presented. Our observations strengthen the thesis of similar pathogenic potentials of the enterovirus group.

Animals↗
PubMed1975

Influence of certain immunodepressants on experimental flavivirus and enterovirus infections in mice.

The effects of cyclophosphamide and 1,3-(piperidinomethyl)-5-phenyl-5-ethylbarbituric acid on certain flavi- and enterovirus infections in mice were studied. Differential enhancement of mortality rates after extraneural and, less markedly, intracerebral virus inoculation was noted. While depression of humoral and/or cell-mediated immunity is considered to be responsible for the effects observed in flavivirus infections, impaired function of the reticuloendothelial system seems to contribute mainly to the potentiation of Mengo virus infection by the immunodepressants used.

Animals↗
PubMed2002

Enterovirus infection can induce immune responses that cross-react with beta-cell autoantigen tyrosine phosphatase IA-2/IAR.

Insulin-dependent (type 1) diabetes is characterized by progressive destruction of insulin-producing beta cells probably by autoreactive T lymphocytes. Viral infections, especially those caused by coxsackieviruses, are postulated to play a role in the pathogenesis of the disease in humans. One mechanism by which viral infections could initiate or accelerate diabetogenic processes is "molecular mimicry," induction of antiviral immune responses cross-reacting with epitopes in the beta-cell autoantigens. Tyrosine phosphatases (IA-2, IAR) represent a major target autoantigen in type 1 diabetes. Both humoral and cellular immune responses are directed to the carboxy-terminal (C-terminal) part of the protein. This region has a 5-amino acid sequence identity, followed by five amino acid similarity with the conservative motif in the VP1-protein of enteroviruses (PALTAVETGA/HT), which is a highly immunogenic B- and T-cell epitope in enterovirus infection-induced immune responses. This observation prompted us to investigate potential humoral cross-reactions between immune responses induced by tyrosine phosphatases and enteroviruses. The reactivities of various peptide- and virus-induced rabbit antisera clearly demonstrated that cross-reactions do exist, and in both directions. Using epitope mapping, we were able to show that several diabetes-linked epitopes in IA-2 were also recognized by CBV-4-induced antisera. Immunization of female NOD-mice with formalin-inactivated purified strain of coxsackievirus B4 (CBV-4-E2) induced an immune response that recognized the IA-2/IAR diabetogenic peptide. The results obtained with human paired sera, collected during enterovirus infection, indicated that enterovirus infection in humans may also occasionally induce a humoral response that cross-reacts with IA-2/IAR.

Amino Acid Sequence↗
PubMed1995

Neonatal enterovirus infection: virology, serology, and effects of intravenous immune globulin.

A prospective study of the virology of and serological responses to enterovirus infection in 16 neonates (< or = 2 weeks of life) and their mothers was performed. At study entry, 11 neonates did not have detectable serum neutralizing antibody to their own viral isolates, despite the presence of neutralizing antibody in 9 of 11 mothers of these infants. Viremia and viruria were demonstrated in 8 and 7 neonates, respectively, with maximal detected titers of 6.3 x 10(3) 50% tissue culture infective dose per mL (TCID50) and 6.8 x 10(1) TCID50/mL, respectively. Viremia was associated with onset of illness in the first 5 days of life, low initial serum neutralization titer, and the presence of echovirus serotypes. Randomized administration of intravenous immune globulin (IVIG; 750 mg/kg) to nine neonates overall modestly increased serum neutralization titers but did not reduce the daily incidence of viremia and viruria compared with that of controls. However, receipt of IVIG containing a neutralization titer of > or = 1:800 to the patients' own viral isolates was associated with significantly higher serum neutralization titers and more rapid cessation of viremia and viruria. Future trials of IVIG for neonatal enterovirus disease should assess the efficacy and safety of higher or repeated doses of this agent and/or of IVIG selected for their high titers to frequently circulating and/or particularly virulent enterovirus serotypes.

Antibodies, Viral↗
PubMed1980

The response of institutionalized Down's syndrome subjects to enterovirus infections.

In a study comparing the responses of institutionalized Down's syndrome (DS) and non-Down's (ND) inmates to enterovirus infections, the frequency of wild enteric viruses and the excretion patterns of oral polio vaccine (OPV) viruses were similar in both groups. Antibody titres developed to poliovirus types 2 and 3 following vaccination were similar in DS and ND vaccinees, but the response to type I virus was significantly less in DS vaccinees. As judged by the development of poliovirus antibody in non-vaccinees, the spread of virus from OPV-immunized to unimmunized subjects in the institution was not noticeably different in DS and ND subjects. An unexpected finding was that the excretion patterns of all three serotypes of poliovirus were strikingly similar for each individual, although the patterns varied considerably from individual to individual. The similarity of excretion occurred despite wide differences within an individual in the titres of neutralizing serum antibodies to the three serotypes. It is suggested that the rate at which a given individual eliminates enteroviruses may be largely determined by factors, the activities of which are not reflected in serum antibody titres.

Adolescent↗