[R01] Allergic eosinophilic esophagitis drives dysregulated innate immunity in esophageal fibroblasts

Ente: National Institute of Allergy and Infectious Diseases

Scadenza: 2031-06-30

Importo max: 1.496.677 EUR

Paese: US

Descrizione

Project Abstract Eosinophilic esophagitis (EoE) is a chronic food antigen driven type 2 inflammatory disease that requires repeated endoscopy with tissue biopsy for diagnosis and management. Chronic EoE leads to tissue fibrosis with resultant esophageal rigidity, strictures, food impactions, and failure to thrive. Before EoE, no other allergic disease lent itself to understanding remodeling longitudinally at the human tissue level. Delayed diagnosis, inconsistent clinical follow-up, non-adherence, non-response, or discontinuation of therapy, and eosinophil recurrence despite therapy are all common clinical scenarios; each increases the risk of strictures. Tissue remodeling begins in childhood, but we have no prediction or severity stratification models. Fibrosis is challenging, and sometimes impossible, to treat. Our inability to uniformly alter fibrosis is due to a critical knowledge gap in understanding pathogenic EoE fibroblast phenotypes and functions. Deepening our understanding of the mechanisms driving the development, retention, and activation of pathogenic inflammation associated fibroblasts (IAFs) and delineating their tissue spatial interactions with other cells is imperative. We have demonstrated that EoE IAFs retain transcriptional and proteomic memory of exposure to in vivo inflammation. Our new data based on single cell sequence and functional analysis of primary esophageal fibroblasts show EoE IAFs display a pro-inflammatory and interferon-stimulated gene response signature. A subset of IAFs express cell-surface CD14 and respond to CD14-TLR4 ligation with induced IAF and interferon gene expression. Spatial studies show that EoE IAFs reside near immune cells. We propose the novel central hypothesis that allergic inflammation drives chronic innate immune activation of fibroblasts and that the retention of IAF-rich spatial neighborhoods aligns with EoE severity and recidivism. We aim to define the spatial cell neighborhoods containing IAFs longitudinally and by severity with cutting edge multiplex spatial imaging (CODEX) and samples sourced during routine care and clinical trials. We will determine the immune mechanisms that perpetuate IAFs and their innate immune activation with a focus on how CD14-TLR4 ligation can immuno-program fibroblasts toward pathogenesis. CODEX integrated with single cell RNA sequence of biopsy fibroblasts will create an unparalleled view of tissue fibroblast phenotypes and dysfunctions over time and by biogeography in a chronic allergic disease. Primary esophageal fibroblasts isolated longitudinally from the same patient during active and remission EoE will be used to dissect the mechanisms underlying the retention of IAF transcriptomes. All studies will be contextualized to patient severity and clinical trajectory as defined by objective clinical measures. With our well phenotyped cohort of patients and a team of experts in translational EoE (Aceves, Dellon, Wechsler), innate immunity (Ulevitch), and compu Istituzione: UNIVERSITY OF CALIFORNIA, SAN DIEGO PI: Seema S Aceves Progetto: 1R01AI202280-01

Settori: National Institute of Allergy and Infectious Diseases

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