title: Persistent infection of thymic epithelial cells with coxsackievirus B4 results in decreased expression of type 2 insulin-like growth factor.
abstract: It has been hypothesized that a disturbance of central self-tolerance to islet β cells may play a role in the enteroviral pathogenesis of type 1 diabetes. Whether enteroviruses can induce an impaired expression of β-cell self-antigens in thymic epithelial cells has been investigated in a murine thymic epithelial (MTE) cell line. This cell line was permissive to the diabetogenic group B4 coxsackievirus (CV-B4) strain CV-B4 E2 and spontaneously expressed type 2 insulin-like growth factor (Igf2), the dominant self-antigen of the insulin family. In this model, a persistent replication of CV-B4 E2 was obtained, as attested to by the prolonged detection of intracellular positive- and negative-strand viral RNA by reverse transcription-PCR (RT-PCR) and capsid protein VP1 by immunofluorescent staining and by the release of infectious particles in culture supernatants. The chronic stage of the infection was characterized by a low proportion of VP1-positive cells (1 to 2%), whereas many cells harbored enteroviral RNA, as displayed by RT-PCR without extraction applied directly to a few cells. Igf2 mRNA and IGF-2 protein were dramatically decreased in CV-B4 E2-infected MTE cell cultures compared with mock-infected cultures, whereas housekeeping and interleukin-6 (Il6) gene expression was maintained and Igf1 mRNA was decreased, but to a lower extent. Inoculation of CV-B3, CV-B4 JVB, or echovirus 1 resulted in a low level of IGF-2 in culture supernatants as well, whereas herpes simplex virus 1 stimulated the production of the protein. Thus, a persistent infection of a thymic epithelial cell line with enteroviruses like CV-B4 E2 can result in a disturbed production of IGF-2, a protein involved in central self-tolerance toward islet β cells.
authors.affiliation: Université Lille 2, Faculté de Médecine, CHRU, Laboratoire de Virologie/EA3610, Loos-lez-Lille, France.
authors.forename: Hela
authors.initials: H
authors.lastname: Jaïdane
authors.forename: Delphine
authors.initials: D
authors.lastname: Caloone
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Lobert
authors.forename: Famara
authors.initials: F
authors.lastname: Sane
authors.forename: Olivier
authors.initials: O
authors.lastname: Dardenne
authors.forename: Philippe
authors.initials: P
authors.lastname: Naquet
authors.forename: Jawhar
authors.initials: J
authors.lastname: Gharbi
authors.forename: Mahjoub
authors.initials: M
authors.lastname: Aouni
authors.forename: Vincent
authors.initials: V
authors.lastname: Geenen
authors.forename: Didier
authors.initials: D
authors.lastname: Hober
mesh_terms: D000818:Animals; D002460:Cell Line; D029822:Enterovirus B, Human / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000821:virology; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D017634:Self Tolerance; D013950:Thymus Gland / Q000378:metabolism / Q000821:virology*; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
chemical_list: C513121:IGF2 protein, mouse; D015850:Interleukin-6; D012333:RNA, Messenger; D012367:RNA, Viral; D014764:Viral Proteins; D007335:Insulin-Like Growth Factor II