Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients.
Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic beta cells. Several studies have suggested an association between Coxsackie enterovirus seroconversion and onset of disease. However, a direct link between beta cell viral infection and islet inflammation has not been established. We analyzed pancreatic tissue from six type 1 diabetic and 26 control organ donors. Immunohistochemical, electron microscopy, whole-genome ex vivo nucleotide sequencing, cell culture, and immunological studies demonstrated Coxsackie B4 enterovirus in specimens from three of the six diabetic patients. Infection was specific of beta cells, which showed nondestructive islet inflammation mediated mainly by natural killer cells. Islets from enterovirus-positive samples displayed reduced insulin secretion in response to glucose and other secretagogues. In addition, virus extracted from positive islets was able to infect beta cells from human islets of nondiabetic donors, causing viral inclusions and signs of pyknosis. None of the control organ donors showed signs of viral infection. These studies provide direct evidence that enterovirus can infect beta cells in patients with type 1 diabetes and that infection is associated with inflammation and functional impairment.
Dotta
Francesco
F
Department of Internal Medicine, Endocrine and Metabolic Sciences, and Biochemistry, University of Siena, 53100 Siena, Italy.
Censini
Stefano
S
van Halteren
Astrid G S
AG
Marselli
Lorella
L
Masini
Matilde
M
Dionisi
Sabrina
S
Mosca
Franco
F
Boggi
Ugo
U
Muda
Andrea Onetti
AO
Del Prato
Stefano
S
Elliott
John F
JF
Covacci
Antonello
A
Rappuoli
Rino
R
Roep
Bart O
BO
Marchetti
Piero
P
D000293:Adolescent; D000328:Adult; D015551:Autoimmunity / Q000276:immunology; D002675:Child, Preschool; D003384:Coxsackievirus Infections / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000821:virology*; D004770:Enterovirus / Q000302:isolation & purification / Q000502:physiology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000473:pathology* / Q000648:ultrastructure / Q000821:virology*; D016753:Interleukin-10 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D016753:Interleukin-10; D005947:Glucose