Lack of islet neogenesis plays a key role in beta-cell depletion in mice infected with a diabetogenic variant of coxsackievirus B4.
Group B coxsackieviruses (CVBs) have a well-established association with type 1 diabetes but the mechanism of depletion of beta-cell mass following infection has not yet been defined. In this report we show that the major difference in pathogenesis between the E2 diabetogenic strain of CVB4 and the prototypic JVB strain in SJL mice is not in tropism for islet cells but in the degree of damage inflicted on the exocrine pancreas and the resulting capacity for regeneration of both acinar and islet tissue by the host. Both strains replicated to a high titre in acinar tissue up to day 3 post-infection (p.i.), while the islets of Langerhans were largely spared. However, the pancreas in the JVB-infected animals then regenerated and many small islets were seen throughout the tissue by day 10 p.i. In contrast, the acinar tissue in E2-infected mice became increasingly necrotic until all that remained by day 21 p.i. were large islets containing varying numbers of dead cells, caught up in strands of connective tissue. Surviving beta cells were found to synthesize little insulin, although islet amyloid polypeptide was detected and glucagon synthesis in alpha cells appeared normal or enhanced. Our results suggest that the key to CVB-E2-induced damage lies in the exocrine tissue and prevention of islet neogenesis rather than from direct effects on existing islets.
The British Columbia Research Institute for Children's and Women's Health, Department of Pathology and Laboratory Medicine, University of British Columbia, #318, BCRICWH, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.
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The British Columbia Research Institute for Children's and Women's Health, Department of Pathology and Laboratory Medicine, University of British Columbia, #318, BCRICWH, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.
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Giddings
The British Columbia Research Institute for Children's and Women's Health, Department of Pathology and Laboratory Medicine, University of British Columbia, #318, BCRICWH, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.
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Pocock
The British Columbia Research Institute for Children's and Women's Health, Department of Pathology and Laboratory Medicine, University of British Columbia, #318, BCRICWH, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.
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Chantler
D000818:Animals; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000473:pathology / Q000821:virology; D029822:Enterovirus B, Human / Q000145:classification / Q000472:pathogenicity*; D005947:Glucose / Q000378:metabolism; D051273:Glucose Transporter Type 2; D006706:Homeostasis; D007107:Immune System / Q000502:physiology; D008297:Male; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000032:analysis; D013045:Species Specificity; D014779:Virus Replication
D051273:Glucose Transporter Type 2; D009004:Monosaccharide Transport Proteins; D005947:Glucose