Detection and characterisation of enteroviruses and the gut virome in islet autoimmunity and type 1 diabetes using novel molecular methods

Type 1 diabetes (T1D) is a chronic autoimmune condition affecting over 8.4 million individuals globally. Usually preceded by islet autoimmunity (IA), T1D results from a complex interplay between host genetics and environmental factors, with virus infections, especially enteroviruses (EV) identified as a prominent candidate factor. Advances in molecular techniques including next generation sequencing (NGS) have enabled sensitive and high-throughput virus detection, improving on cell culture and serology techniques. There are over 110 human/primate EVs identified, classified within four species (A-D). Elucidation of which subtypes precipitate IA/T1D would inform the design of primary prevention studies. The project aimed to 1) develop a novel method of EV amplification using NGS; 2) optimise capture-based sequencing of viruses in stools of children at-risk of T1D; 3) characterise viruses in stools of participants in the Viruses in the Genetically at Risk (VIGR) and Environmental Determinants of Islet Autoimmunity (ENDIA) Australian longitudinal cohorts; and 4) update our previous systematic review examining the association between EVs and IA/T1D. Near full-length EV was detected in 67% of 113 VIGR stools and 96% of 23 EV prototypes examined. Coxsackievirus (CV)B3, ECHO18/30, and infection with multiple EV subtypes were associated with IA in VIGR stools. Polymorphisms frequently mapped to VP2/VP1 capsid regions in cases and to 2C/VP2/VP3/3A in controls. Children in the VIGR study had 129 differentially abundant gut viruses, with EV-As CVA2/5/6/8/14 and EV-Bs CVB3 and ECHO6/18/30 more abundant in cases. Infants of mothers with T1D enrolled in ENDIA were more likely to have a virus infection, with bocavirus/rotavirus more abundant and CVA6/RV-C/torque teno viruses less abundant. Systematic review of 3,266 publications revealed 60 eligible studies (40 T1D, 9 IA, 11 both) comprising 12,077 individuals. Meta-analysis demonstrated significant associations between EV and IA (odds ratio 2.1; 95% confidence interval 1.3 to 3.3; P=0.002), T1D (8.0; 4.9 to 13.0; P<0.00001); within one month of T1D (16.2; 8.6 to 30.5; P <0.00001). Substantial heterogeneity was observed between studies. These results strengthen the rationale for EV-targeted vaccines for primary prevention of IA/T1D. Future studies will examine virus infection during pregnancy and early life in populations with and without genetic risk for T1D.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2024

Author dc:creator

• Isaacs, Sonia

• enterovirus
• virome
• type 1 diabetes
• islet autoimmunity
• next generation sequencing
• VIGR
• ENDIA
• virus detection
• Illumina
• VirCapSeq-VERT
• SNP
• Meta-Analysis
• anzsrc-for: 3207 Medical microbiology
• anzsrc-for: 310706 Virology
• anzsrc-for: 320208 Endocrinology
• anzsrc-for: 3213 Paediatrics

Statement dc:rights

• open access
• CC BY 4.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/25526

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/101822