Absence of HIF-1α and Coxsackie Virus Infection: Two Sides of the Same Coin in the Development of Type 1 Diabetes (T1D)     — ASN Events
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  3. Absence of HIF-1α and Coxsackie Virus Infection: Two Sides of the Same Coin in the Development of Type 1 Diabetes (T1D)    

Absence of HIF-1α and Coxsackie Virus Infection: Two Sides of the Same Coin in the Development of Type 1 Diabetes (T1D)     (#163)

Amit Lalwani 1 , Joanna Warren 2 , Cecile King 2 , Jenny Gunton 1
  1. Diabetes, Obesity & Endocrinology, Westmead Millennium Institute, Westmead, NSW, Australia
  2. Mucosal Autoimmunity, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

Introduction: Coxsackie virus B4 (CVB4) is pancreatrophic and has long been implicated in the development of T1D. We previously reported that HIF-1α (Hypoxia-Inducible Factor-1α) is important for β-cell function and for survival after islet transplantation. However, the role of HIF-1α in the onset and development of viral-induced T1D remains unknown.

Objective: We sought to determine whether CVB4 infection in male NOD mice with β-cell-specific deletion of HIF-1α (β-HIF-1α) predisposes to increased insulitis and T1D. Male mice were used because they are normally diabetes resistant.

Methods: 8-10 week old floxed-control and β-HIF-1α male NODs were inoculated with the E2 strain, a murine diabetogenic strain of CVB4 at a dose of 105 pfu/mL. Blood ± pancreas was collected at 4 (initiation), 7 (peak) and 21 (clearance) days post infection (dpi). Body weights and random-fed blood glucose levels (BGLs) were assessed at each time point. Viral load was determined by direct quantification of infectious virions in pancreas by plaque assay. Pancreatitis was assessed by measuring pancreatic weights and serum amylase. ImageJ was used to measure the total insulin positive area (in mm2) by morphometry and the total number of inflammatory cells with ITCN (Image-based Tool for Counting Nuclei).

Results: At 4dpi there were no apparent differences between the groups. By 7dpi, however, β-HIF-1α had increased BGLs (4.5±0.2 versus 3.7±0.2 mmol/L, p=0.02), a trend to decreased body weight, had decreased pancreas weight (0.09±0.01 versus 0.17±0.02 grams, p=0.04) and a trend to increased amylase. β-HIF-1α mice had increased pancreatic CVB4 viral load (0.96±0.0001106 versus 0.34±0.00005669 pfu/µL, p=0.0001) and insulitis (2014 versus 1145 inflammatory cells/mm2 of insulin positive area, p=0.02). At 21 dpi CVB4 virus was cleared in both groups of mice. β-HIF-1α mice exhibited exacerbated viral aftermath with extensive exocrine pancreas destruction, marked inflammatory infiltrate and higher BGLs in the final week of the study (6.5±0.4 versus 4.6±0.3 mmol/L, p=0.006).

Conclusion: Absence of β-cell HIF-1α and CVB4 infection interacted to establish an aberrant adaptive response. Decreasing β-cell HIF-1α may predispose to T1D after insults such as Coxsackie virus. This has important implications for the role of β-cells in the development of T1D.