Enteroviruses and type 1 diabetes

Tracy, Steven; Drescher, Kristen M.; Chapman, Nora M.

doi:10.1002/dmrr.1255

Cited by 36 publications

(40 citation statements)

References 13 publications

(26 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nonetheless, the role of enteroviruses as the etiologic agents of chronic diseases in the context of persistent viral infection has been described with increasing frequency. Several studies have associated persistent enterovirus infection with chronic diseases, such as amyotrophic lateral sclerosis, postpolio syn-drome, chronic fatigue syndrome, type 1 diabetes, and chronic cardiomyopathy (i.e., chronic myocarditis and dilated cardiomyopathy) (16)(17)(18)(19)(20)(42)(43)(44)(45)(46)(47). These chronic cardiac infections involved group B coxsackieviruses.…”

Section: Discussionmentioning

confidence: 99%

Functional Consequences of RNA 5′-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation

Lévêque

Garcia

Bouin

et al. 2017

J Virol

View full text Add to dashboard Cite

Group B coxsackieviruses are responsible for chronic cardiac infections. However, the molecular mechanisms by which the virus can persist in the human heart long after the signs of acute myocarditis have abated are still not completely understood. Recently, coxsackievirus B3 strains with 5=-terminal deletions in genomic RNAs were isolated from a patient suffering from idiopathic dilated cardiomyopathy, suggesting that such mutant viruses may be the forms responsible for persistent infection. These deletions lacked portions of 5= stem-loop I, which is an RNA secondary structure required for viral RNA replication. In this study, we assessed the consequences of the genomic deletions observed in vivo for coxsackievirus B3 biology. Using cell extracts from HeLa cells, as well as transfection of luciferase replicons in two types of cardiomyocytes, we demonstrated that coxsackievirus RNAs harboring 5= deletions ranging from 7 to 49 nucleotides in length can be translated nearly as efficiently as those of wild-type virus. However, these 5= deletions greatly reduced the synthesis of viral RNA in vitro, which was detected only for the 7-and 21-nucleotide deletions. Since 5= stem-loop I RNA forms a ribonucleoprotein complex with cellular and viral proteins involved in viral RNA replication, we investigated the binding of the host cell protein PCBP2, as well as viral protein 3CD pro , to deleted positive-strand RNAs corresponding to the 5= end. We found that binding of these proteins was conserved but that ribonucleoprotein complex formation required higher PCBP2 and 3CD pro concentrations, depending on the size of the deletion. Overall, this study confirmed the characteristics of persistent CVB3 infection observed in heart tissues and provided a possible explanation for the low level of RNA replication observed for the 5=-deleted viral genomes-a less stable ribonucleoprotein complex formed with proteins involved in viral RNA replication.IMPORTANCE Dilated cardiomyopathy is the most common indication for heart transplantation worldwide, and coxsackie B viruses are detected in about one-third of idiopathic dilated cardiomyopathies. Terminal deletions at the 5= end of the viral genome involving an RNA secondary structure required for RNA replication have been recently reported as a possible mechanism of virus persistence in the human heart. These mutations are likely to disrupt the correct folding of an RNA secondary structure required for viral RNA replication. In this report, we demonstrate that transfected RNAs harboring 5=-terminal sequence deletions are able to direct the synthesis of viral proteins, but not genomic RNAs, in human and murine cardiomyocytes. Moreover, we show that the binding of cellular and viral replication factors to viral RNA is conserved despite genomic deletions but that the impaired RNA synthesis as-

show abstract

Section: Discussionmentioning

confidence: 99%

Functional Consequences of RNA 5′-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation

Lévêque

Garcia

Bouin

et al. 2017

J Virol

View full text Add to dashboard Cite

show abstract

“…The hypothesis that a direct HEV infection of the pancreatic islets contributes to the disease has been supported by demonstration of immunoreactivity of an antibody against a HEV capsid protein, VP1, in islets from diabetic subjects [6-10], but only rarely has HEV genome been demonstrated convincingly in the pancreas by in situ hybridization (ISH) [11] or virus isolation [3]. The use of reverse transcriptase (RT)-PCR, theoretically the most sensitive method for virus detection [12], has yielded negative results in pancreatic tissue [6, 13, 14]. In many studies, the only available material was formalin-fixed and paraffin-embedded (FFPE) pancreatic tissue in which the quality of RNA may be impaired to the extent that presence of viral RNA is not detectable with RT-PCR [15], but with recent focused initiatives to collect pancreatic tissues from diabetic subjects, such as the Network for Pancreatic Organ Donors with Diabetes (nPOD; www.jdrfnpod.org) [16], nPOD-Europe (www.jdrfnpod.org/europe.php), and EXODIAB in collaboration with the Nordic Network for Islet Transplantation (www.exodiab.se), the availability of pancreatic tissue suitable for RT-PCR analysis is increasing rapidly.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of RT-PCR and immunohistochemistry as tools for detection of enterovirus in the human pancreas and islets of Langerhans

Skog

Ingvast

Korsgren

2014

Journal of Clinical Virology

View full text Add to dashboard Cite

Background Enteroviruses have been implicated in the etiology of type 1 diabetes, supported by immunoreactivity of enteroviral protein in islets, but presence of enteroviral genome has rarely been reported. Failure to detect enterovirus with RT-PCR has been attributed to the possible presence of PCR inhibitors and that only few cells are infected. Objectives The aim of this study was to evaluate strategies for detection of enterovirus in human islets. Study design A scenario was modeled with defined infected islets among a large number of uninfected pancreatic cells and the sensitivity of immunohistochemistry and PCR for detection of enterovirus was evaluated. Results Enterovirus was detected with PCR when only one single human islet, infected in vitro with a low dose of virus, was mixed with an uninfected pancreatic biopsy. Enterovirus could not be detected by immunohistochemistry under the same conditions, demonstrating the superior sensitivity of PCR also in pancreatic tissue with only a small fraction of infected cells. In addition, we demonstrate that pancreatic cell culture supernatant does not cause degradation of enterovirus at 37°C, indicating that under normal culture conditions released virus is readily detectable. Utilizing PCR, the pancreases of two organ donors that died at onset of type 1 diabetes were found negative for enterovirus genome despite islet cells being positive using immunohistochemistry. Conclusions These data suggest that PCR should be the preferred screening method for enterovirus in the pancreas and suggest cautious interpretation of immunostaining for enterovirus that cannot be confirmed with PCR.

show abstract

“…28,29 In our study, this reinfection/re-exposure mechanism would explain the development of cases of alopecia areata in older patients (who had probably been infected by enterovirus in the past) following the outbreak of HFMD in preschool-age children. Thus, the increased circulation of enterovirus during the HFMD outbreak would contribute to the higher-than-usual incidence of alopecia areata in the following weeks.…”

Section: Discussionmentioning

confidence: 67%

Posible relación entre alopecia areata e infecciones por enterovirus

Barreiro

Pelegrín

Val

et al. 2014

Rev Pediatr Aten Primaria

View full text Add to dashboard Cite

Posible relación entre alopecia areata e infecciones por enterovirus Introducción: la alopecia areata es una enfermedad autoinmune de etiología desconocida que se asocia a otras enfermedades autoinmunes. La enfermedad mano-pie-boca es una infección viral frecuente en la edad pediátrica, causada por diferentes serotipos de enterovirus y que en ocasiones asocia onicomadesis. El presente estudio pretende comprobar un incremento de los casos de alopecia areata tras un brote de enfermedad mano-pie-boca en nuestro entorno. Material y métodos: identificación de los pacientes menores de 14 años diagnosticados de enfermedadmano-pie-boca y/o alopecia areata en un área de salud entre el 1 de enero de 2011 y el 31 de diciembre de 2012. Revisión de historias clínicas, recogiendo fecha de nacimiento y diagnóstico, edad al diagnóstico y características clínicas. Resultados: se encontraron 49 pacientes diagnosticados de enfermedad mano-pie-boca y siete diagnosticados de alopecia areata. Se confirmó un brote de enfermedad mano-pie-boca con 42 casos en un periodo de ocho semanas. Se observó un incremento posterior de los casos de alopecia areata (cuatro casos en las cuatro semanas siguientes, frente a tres casos a lo largo de los 11 meses previos y ninguno durante el año anterior). Conclusiones: tras un brote de enfermedad mano-pie-boca se observó un incremento del número de casos de alopecia areata. Este hecho, unido a la asociación de la alopecia areata con otras enfermedades autoinmunes y a la relación encontrada entre infecciones por enterovirus y procesos autoinmunes como la diabetes mellitus tipo 1, plantea una posible relación causal entre infecciones por enterovirus y alopecia areata, así como un posible componente de autoinmunidad en la onicomadesis asociada a la enfermedad mano-pie-boca.

show abstract

Enteroviruses and type 1 diabetes

Cited by 36 publications

References 13 publications

Functional Consequences of RNA 5′-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation

Functional Consequences of RNA 5′-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation

Evaluation of RT-PCR and immunohistochemistry as tools for detection of enterovirus in the human pancreas and islets of Langerhans

Posible relación entre alopecia areata e infecciones por enterovirus

Contact Info

Product

Resources

About