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Longitudinal Stool Sampling Study Points to Virome Shifts in Children With Islet Autoimmunity

NEW YORK – An international team led by investigators at the University of South Florida has identified apparent differences in the viruses carried by children with type 1 diabetes (T1D) or insulin deficiency-related autoimmunity against pancreatic islet beta cells.

Although there have been hints from prior in vitro and in vivo analyses suggesting pancreatic beta cell infections with enteroviruses or other viruses may prompt altered autoimmunity and damage to the insulin-pumping pancreatic cells, it has been difficult to decisively link such viruses to disease.

"Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses and the selection of variants with altered pathogenicity, and ability to spread in populations," first and corresponding author Kendra Vehik, a researcher with the University of South Florida's Health Informatics Institute, and her colleagues explained in a study appearing online today in Nature Medicine.

For a prospective observation study known as the "Environmental Determinants of Diabetes in the Young" (TEDDY), the researchers used metagenomic sequencing to assess eukaryotic DNA and RNA virus repertoires in stool samples collected over time from almost 500 children with islet autoimmunity or T1D, searching through shards of viral DNA shed into the feces to find clues to the pancreatic islet cell viruses that might prompt disease-related autoimmunity.

The team's results suggested ongoing enterovirus B infections or lower-than-usual exposure to a double-stranded DNA virus known as human mastadenovirus C may be more common in children with islet autoimmunity. The analyses also highlighted a variant called rs6517774 in the host CXADR gene that appeared to coincide with islet autoimmunity — consistent with the pronounced expression of cell surface receptors for coxsackie and adenovirus receptor (CXADR) genes that have been documented in pancreatic beta cells in the past.

"This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children," Vehik and co-authors wrote, noting that "we found fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity."

For the analysis, the researchers did metagenomic next-generation sequencing on monthly fecal samples collected from 383 children with islet autoimmunity and 112 pediatric T1D patients from half a dozen study sites in the US, Germany, Sweden and Finland, following the children from the age of three months old until diagnoses with T1D or islet autoimmunity.

All told, the team focused on almost 8,700 prospectively collected fecal samples from the children with islet autoimmunity and nearly 3,400 samples from children who developed T1D, comparing the RNA and DNA virus profiles with those found in nested-matched paired controls from the same locations. To complement that analysis, enteroviruses found in the fecal samples were grown with the help of virus-susceptible cell cultures before being sequenced and analyzed with a VirMAP virus taxonomy classification method.

The researchers tracked down viruses from 96 eukaryotic virus genera and dozens of bacteria-infecting bacteriophage viruses in the samples, which contained a total of 621 known viral taxa. Among them were viruses identified in children in the past, they reported, including human mastadenoviruses, parechoviruses, bocaviruses, mamastroviruses, noroviruses, and enteroviruses.

"Overall, the observed virome composition aligned with the existing knowledge about viral epidemiology in children," the authors reported.

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