Abstract Type 1 diabetes (T1D) is a multifactorial disease caused by a complex interplay of genetic and environmental factors. The genes that mediate disease susceptibility have largely been discovered. The importance of environmental factors is widely acknowledged but their identification has been challenging. Virus infections have long been among the prime candidates, but progress has been hindered by the narrow “candidate microbe” approach and limited availability of large prospective studies. The present study fills this major knowledge gap by combining the tremendous power of modern immunoproteomics technologies to detect antibodies against a wide range of different microbes with world largest prospective birth cohort study evaluating the role of environmental factors in the pathogenesis of T1D (the TEDDY study). The goal is to obtain a comprehensive and holistic picture on microbial infections which are associated with increased or decreased risk of islet autoimmunity (IA) and T1D. This goal directly addresses the founding aims of the TEDDY study. We have assembled a highly integrative multi-disciplinary team with synergizing expertise in T1D, immunoproteomics, high throughput arrays, virus diseases, metagenomics, virome analyses and advanced statistics. We use three supplementary high-throughput arrays with full proteins as antigens to enable the detection of antibody responses against both structural and linear antigen epitopes to increase the screening sensitivity. First, the highest protein capacity Nucleic Acid Programmable Protein Array (NAPPA) technology is used to carry out a wide screening of antibodies against 2000 different whole microbial proteins representing 171 viruses, bacteria, and parasites selected specifically for their relevance to T1D at a critical time-point of T1D pathogenesis, the serum sample where IA was first detected (600 TEDDY IA+ children and 600 matched control children); Second, the quantitative Multiplexed In-Solution Protein Array (MISPA) technology is used to identify infections and their timing in childhood by analyzing antibodies to 400 best microbial protein candidates selected based on Aim 1 results from all prospective serum samples from infancy through IA (the same 600 cases plus 1200 HLA matched controls at ~7 time points ≈ 12,600 samples). Third, widely used commercial Meso Scale Discovery (MSD) and other technologies are employed to confirm the microbe-IA associations observed on the MISPA platform (the same cohort as used on MISPA plus additional samples after the initiation of IA to study accelerants of progression to clinical T1D). Overall, the results from this well-powered study will shape the landscape in this field as this study represents the largest and widest screening of infections in children who develop IA/T1D. This information is not only crucial for the understanding of T1D pathogenesis and for opening new possibilities to prevent and treat the disease by vaccines or other antimicr...