title: Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells.
abstract: OBJECTIVE
  It is thought that enterovirus infections cause beta-cell damage and contribute to the development of Type 1 diabetes by replicating in the pancreatic islets. We sought evidence for this through autopsy studies and by investigating known enterovirus receptors in cultured human islets.
  
  
  METHODS
  Autopsy pancreases from 12 newborn infants who died of fulminant coxsackievirus infections and from 65 Type 1 diabetic patients were studied for presence of enteroviral ribonucleic acid by in situ hybridisation. Forty non-diabetic control pancreases were included in the study. The expression and role of receptor candidates in cultured human islets were investigated with receptor-specific antibodies using immunocytochemistry and functional assays.
  
  
  RESULTS
  Enterovirus-positive islet cells were found in some of both autopsy specimen collections, but not in control pancreases. No infected cells were seen in exocrine tissue. The cell surface molecules, poliovirus receptor and integrin alphavbeta3, which act as enterovirus receptors in established cell lines, were expressed in beta cells. Antibodies to poliovirus receptor, human coxsackievirus and adenovirus receptor and integrin alphavbeta3 protected islets and beta cells from adverse effects of poliovirus, coxsackie B viruses, and several of the arginine-glycine-aspartic acid motifs containing enteroviruses and human parechovirus 1 respectively. No evidence was found for expression of the decay-accelerating factor which acts as a receptor for several islet-cell-replicating echoviruses in established cell lines.
  
  
  CONCLUSIONS
  The results show a definite islet-cell tropism of enteroviruses in the human pancreas. Some enteroviruses seem to use previously identified cell surface molecules as receptors in beta cells, whereas the identity of receptors used by other enteroviruses remains unknown.
authors.affiliation: Enterovirus Laboratory, National Public Health Institute, Helsinki, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Ylipaasto
authors.forename: K
authors.initials: K
authors.lastname: Klingel
authors.forename: A M
authors.initials: AM
authors.lastname: Lindberg
authors.forename: T
authors.initials: T
authors.lastname: Otonkoski
authors.forename: R
authors.initials: R
authors.lastname: Kandolf
authors.forename: T
authors.initials: T
authors.lastname: Hovi
authors.forename: M
authors.initials: M
authors.lastname: Roivainen
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001344:Autopsy; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003384:Coxsackievirus Infections / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000821:virology; D004459:Echovirus 9 / Q000235:genetics / Q000254:growth & development; D004770:Enterovirus / Q000235:genetics / Q000254:growth & development*; D029822:Enterovirus B, Human / Q000235:genetics / Q000254:growth & development; D004769:Enterovirus Infections / Q000473:pathology*; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation / Q000473:pathology / Q000821:virology; D007328:Insulin / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D000078790:Insulin Secretion; D039302:Integrin alphaVbeta3 / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D008565:Membrane Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D010179:Pancreas / Q000737:chemistry / Q000473:pathology / Q000821:virology; D030061:Parechovirus / Q000235:genetics / Q000254:growth & development; D017955:Poliovirus / Q000235:genetics / Q000254:growth & development; D012367:RNA, Viral / Q000235:genetics; D011991:Receptors, Virus / Q000032:analysis / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007328:Insulin; D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D012367:RNA, Viral; D011991:Receptors, Virus; C066100:poliovirus receptor