Type 1 diabetes 听is a lifelong autoimmune condition characterised by the immune-mediated damage and dysfunction of insulin-producing cells in the pancreas. Type 1 diabetes 听is among the most common chronic diseases of childhood and affects approximately 1 in 300 children in Australia. The global incidence of type 1 diabetes continues to increase (in a cyclic pattern) by an average of 3% per annum, which cannot be accounted for by genetic risk factors alone. 听
It is now widely established that type 1 diabetes 听is multifactorial and occurs from a complex interplay between environmental exposures and genetic predisposition. Of the diverse spectrum of environmental factors associated with type 1 diabetes, the greatest body of molecular and epidemiological data support the contribution of viral infections, particularly enterovirus infections, as environmental triggers of islet autoimmunity (also known as stages 1-2 diabetes, which precede the clinical onset of type 1 diabetes). Some of the most compelling evidence to date is the detection and isolation of cultivable enteroviruses in live pancreatic biopsies of individuals recently diagnosed with type 1 diabetes. Furthermore, enterovirus isolates from 听cadaveric donors with type 1 diabetes cause destruction of insulin-producing cells in vitro using purified human pancreatic islet cells and trigger type 1 diabetes in in vivo mice models. 听
We鈥檝e shown that enterovirus infection often precedes islet autoimmunity and the increased risk of type 1 diabetes , however direct evidence for a causal association between enterovirus infection and islet autoimmunity/type 1 diabetes 听is still missing.
Our goals
The Viruses and Diabetes Research Group is primarily involved in the , which is a nationwide prospective cohort study examining factors that may contribute to islet autoimmunity/type 1 diabetes pathogenesis. Our group comprises the 鈥渧iral theme鈥 of the study, where we investigate the viral exposures during pregnancy and early-life to examine the link between such viruses and islet autoimmunity/type 1 diabetes.
We aim to characterise the virome (population of all viruses in the body) of Australian children who are genetically at-risk of type 1 diabetes, with the application of cutting-edge Next-Generation Sequencing and high-throughput serological tests. Through an unbiased and comprehensive approach to profiling the human virome, we aim to determine which viruses (including 听non-enteroviruses) contribute to type 1 diabetes, and the mechanisms by which damage to the insulin producing beta cells in the pancreas is induced. Ultimately, we hope that this research will contribute to the development of vaccinations designed to prevent virus-mediated type 1 diabetes.
Research Strengths
Collective expertise in large cohort studies, molecular biology, virology, type 1 diabetes, translational research, epidemiology, bioinformatics, biostatistics, systematic reviews/meta-analyses and clinical guidelines.
Cutting-edge Next Generation Sequencing 听technologies.
Unbiased approach to characterising the complete population of viruses contributing to type 1 diabetes development, in contrast to previous targeted approaches with substantial investigation bias.
Unique collection of longitudinal pregnancy and childhood samples (1,500 mother-infant pairs in the nationwide ENDIA prospective cohort study) as well other at-risk cohorts.
Established collaboration with other large national and international cohort studies investigating risk of 听type 1 diabetes and other autoimmune conditions (access to external validation cohorts and data).
Our results
Our group has identified novel mechanisms underlying enterovirus-mediated pathogenesis of type 1 diabetes (microRNA dysregulation; Kim 2016 Diabetes and highlighted in Nature Rev Endo 2016) and a previously unknown association between higher enterovirus A abundance in the gut and the development of childhood islet autoimmunity (pre-diabetes). The systematic review and meta-analysis of the group continues to be widely cited (>600 citations) as evidence supporting the role of enteroviruses in the development of islet autoimmunity and type 1 diabetes (Yeung 2011 BMJ). Altogether, our work, published in a wide range of high-impact peer-reviewed journals and presented in leading scientific meetings nationally and internationally, has contributed to the global enterovirus vaccine effort for the prevention of type 1 diabetes.
To support our research, we have obtained competitive research funding from diverse national and international sources including (not limited to) the NHMRC, Diabetes Australia, Australian Diabetes Society, Juvenile Diabetes Research Foundation (JDRF) and the Helmsley Charitable Trust.
We continue to support and mentor students (ILP and Honours), HDR candidates and research staff to completion of their research degrees (>30 completions to date) or professional goals, respectively, providing a stimulating and conducive learning environment.
Selected Publications
Isaacs SR, Foskett DB, Maxwell AJ, Ward EJ, Faulkner CL, Luo JYX, Rawlinson WD, Craig ME, Kim KW. Viruses and Type 1 Diabetes: From Enteroviruses to the Virome. Microorganisms 2021;9:1519
Faulkner CL, Luo YX, Isaacs S, Rawlinson WD, Craig ME, Kim KW. The virome in early life and childhood and development of islet autoimmunity and type 1 diabetes: A systematic review and meta-analysis of observational studies. Reviews in medical virology 2020:e2209
Kim KW, Allen DW鈥awlinson WD, Craig ME (2020) Higher frequency of vertebrate-infecting viruses in the gut of infants born to mothers with type 1 diabetes. Pediatric diabetes, 21:271-279
Kim KW, Allen DW, Briese T, Couper JJ, Barry SC, Colman PG, Cotterill AM, Davis EA, Giles LC, Harrison LC, Harris M, Haynes A, Horton JL, Isaacs SR, Jain K, Lipkin WI, Morahan G, Morbey C, Pang ICN, Papenfuss AT, Penno MAS, Sinnott RO, Soldatos G, Thomson RL, Vuillermin PJ, Wentworth JM, Wilkins MR, Rawlinson WD, Craig ME. Distinct Gut Virome Profile of Pregnant Women With Type 1 Diabetes in the ENDIA Study. Open forum infectious diseases 2019;6:ofz025
Craig ME, Kim KW, Isaacs SR, Penno MA, Hamilton-Williams EE, Couper JJ, Rawlinson WD. Early-life factors contributing to type 1 diabetes. Diabetologia 2019;62:1823-1834
Kim KW, Horton JL, Pang CNI, Jain K, Leung P, Isaacs SR, Bull RA, Luciani F, Wilkins MR, Catteau J, Lipkin WI, Rawlinson WD, Briese T, Craig ME. Higher abundance of enterovirus A species in the gut of children with islet autoimmunity. Scientific Reports 2019;9:1749
Allen DW, Kim KW, Rawlinson WD, Craig ME. Maternal virus infections in pregnancy and type 1 diabetes in their offspring: Systematic review and meta-analysis of observational studies. Rev Med Virol 2018;28:e1974
Isaacs SR, Kim KW, Cheng JX, Bull RA, Stelzer-Braid S, Luciani F, Rawlinson WD, Craig ME. Amplification and next generation sequencing of near full-length human enteroviruses for identification and characterisation from clinical samples. Scientific Reports 2018;8:11889
Kim KW, Ho A, Alshabee-Akil A, Hardikar AA, Kay TWH, Rawlinson WD, Craig ME. Coxsackievirus B5 Infection Induces Dysregulation of microRNAs Predicted to Target Known Type 1 Diabetes Risk Genes in Human Pancreatic Islets. Diabetes 2016;65:996-1003
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