The goal of this project is to integrate analysis of viral and immune responses using white blood
cells, nasal swabs and plasma from 450 children previously collected from the prospective cohort
TEDDY study, to build upon previous TEDDY findings that strongly implicated prolonged
infections with Type B enteroviruses in the development of islet autoimmunity (IA). This will further
determine if prolonged enterovirus infections are linked to development of IA and type 1 diabetes
(T1D), and will provide mechanistic insights into how prolonged infections may trigger disease
outcomes. Specifically, this project will combine two nested case control studies within TEDDY
using stool virome analysis currently underway to find additional instances of children with
prolonged infections, work being carried out by coPIs in this application. In Aim 1 we will complete
the longitudinal disease risk profile of enterovirus infections for all TEDDY children developing IA
or T1D by the age of 6. This will combine analysis of stool, peripheral blood mononuclear cells
(PBMC) and nasal swabs using proven qRT-PCR, ampliseq approaches. The findings will be
used to select PBMC samples from children with confirmed prolonged infection with enterovirus
in Aim 2. These will be subjected to detailed multi-‘omic single cell analysis to define cellular
immune changes associated with prolonged infection and with the subsequent development of
autoimmunity. Aim 3 will analyze plasma samples from a subset of children to determine whether
quantitative or qualitative changes in humoral immunity to enteroviral infection may contribute to
disease outcomes. These aims together investigate, for the first time, the interaction between
virus exposure, resulting cellular and humoral immune changes and subsequent risk of
autoimmunity or T1D. The proposed work is significant as it will apply the power of the large,
international TEDDY cohort and its prospective collection of biosamples (stool, sera and viable
immune cells) to both control for potential confounders and as a source of accessory genetic and
genomic data to inform to determine how prolonged infection with enterovirus is linked to islet
autoimmunity. The proposed work is innovative because it will provide the first comprehensive
and integrated analysis of the virome, immune-cell intrinsic genomic responses and altered
antibody responses as causal drivers of islet autoimmunity and T1D. These findings will lead to a
better understanding of what triggers islet autoimmunity and T1D that will further inform
hypotheses of causal mechanisms and will open conceptual avenues for key diagnostic or
preventative interventions.