Illuminating pediatric immunology through genetics

PROJECT 3 - PROJECT SUMMARY This project is designed to illuminate pediatric immunology through genetic analyses in children suffering from known or suspected inborn errors of immunity (IEIs). Remarkable advances in next-generation sequencing (NGS) of genomic DNA have facilitated the identification of causative genes for over 450 distinct IEI, and accompanying studies of the functional consequences of the underlying genetic variants have led to unprecedented insights into immune function in health and disease including novel precision therapies. We will build from (a) cohorts of three defined IEIs caused by mutations in the genes encoding phosphoinositide 3-kinase delta (PI3Kd), STAT1, or ELF4 and (b) our extensive experience and infrastructure in the Pediatric Genomics Discovery Program (PGDP) at Yale to discover novel gene defects in racially and ethnically diverse patients with suspected but unsolved IEIs. This will enable us to test our central hypothesis that rare, deleterious variants in genetic determinants of the core pathways of (i) PI3K/mTOR or (ii) interferon responses derail healthy immune homeostasis and development during childhood by perturbing critical signals that govern immune cell states. These two pathways emerged as prominent biological signals in both the core pathways identified in preliminary data from Project 1-2 and in IEI cohorts. Thus, for each pathway, we will combine unprecedented depth of profiling of peripheral blood immune cells from defined IEI patients versus healthy controls with new gene discovery to functionally assess genetic determinants of PI3K/mTOR- and interferon-related pathway impacts on immune health. In Aim 1, we will focus on PI3K/mTOR and assess immune landscapes of a cohort of patients with ‘Activated PI3Kd Syndrome’ longitudinally, novel genes impacting this pathway from our preliminary data, and candidate genes identified in newly enrolled, diverse IEI patient cohorts. In Aim 2, we will focus on interferon pathways and assess for our defined IEI cohorts STAT1 gain-of-function patients and ‘Deficiency in ELF4, X- linked’ patients longitudinally, together with new candidate genes. Our multiomics approaches will match those of Projects 1 and 2 for optimal data integration supported by the Cores’ expertise in single-cell sequencing and computational approaches, functional studies at the single-cell level with CyTOF, and longitudinal immune signature landscapes with spectral flow cytometry. Together, Project 3 will advance the Peds Program Overall aims by uncovering genetic determinants of cellular programs in childhood that are temporally ultra-stable or characteristically dynamic, thereby defining the functional effects of these programs on immune health. Project Number: 1P01AI179570-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Carrie Lucas | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $533,819 | Activity Code: P01 | Study Section: Special Emphasis Panel[ZAI1 JTS-I (S2)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1P01AI17957001A1