Abstract
Aims/hypothesisEnterovirus infections have been associated with the development of type 1 diabetes in multiple studies, but little is known about enterovirus-induced responses in children at risk for developing type 1 diabetes. Our aim was to use genome-wide transcriptomics data to characterise enterovirus-associated changes in whole-blood samples from children with genetic susceptibility to type 1 diabetes.MethodsLongitudinal whole-blood samples (356 samples in total) collected from 28 pairs of children at increased risk for developing type 1 diabetes were screened for the presence of enterovirus RNA. Seven of these samples were detected as enterovirus-positive, each of them collected from a different child, and transcriptomics data from these children were analysed to understand the individual-level responses associated with enterovirus infections. Transcript clusters with peaking or dropping expression at the time of enterovirus positivity were selected as the enterovirus-associated signals.ResultsStrong signs of activation of an interferon response were detected in four children at enterovirus positivity, while transcriptomic changes in the other three children indicated activation of adaptive immune responses. Additionally, a large proportion of the enterovirus-associated changes were specific to individuals. An enterovirus-induced signature was built using 339 genes peaking at enterovirus positivity in four of the children, and 77 of these genes were also upregulated in human peripheral blood mononuclear cells infected in vitro with different enteroviruses. These genes separated the four enterovirus-positive samples clearly from the remaining 352 blood samples analysed.Conclusions/interpretationWe have, for the first time, identified enterovirus-associated transcriptomic profiles in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Our results provide a starting point for understanding the individual responses to enterovirus infections in blood and their potential connection to the development of type 1 diabetes.Data availabilityThe datasets analysed during the current study are included in this published article and its supplementary information files (www.btk.fi/research/computational-biomedicine/1234-2) or are available from the Gene Expression Omnibus (GEO) repository (accession GSE30211).
Highlights
Enteroviruses are among the most common viruses causing infections in humans
We have identified enterovirus-associated transcriptomic profiles in whole-blood samples from seven children with genetic susceptibility to type 1 diabetes and characterised their individual responses to enterovirus infections
Interferon response is a central part of the innate antiviral immune response, and several enterovirus strains induce a profound interferon response in human blood cells [14, 28]
Summary
Enteroviruses are among the most common viruses causing infections in humans. They are single-stranded RNA viruses that replicate typically in the intestine, but can occasionally spread to blood and certain internal organs. Enterovirus infections are mostly asymptomatic or cause only mild symptoms, they can cause severe illnesses such as meningitis, myocarditis and hand-foot-and-mouth disease. Several studies have associated viral infections, especially human enterovirus infections, with the development of type 1 diabetes [1,2,3,4]. Enteroviruses have a clear tropism to pancreatic beta cells [5], and low-grade enterovirus infection has been detected in pancreatic islets of living individuals with
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