Virome and Immune Responses associated with IA and Type 1 Diabetes - 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.
