Biology subjects

Corridoni, D.

Publications and source records attributed to Corridoni, D..

3 recordsLinked to original sources

bioRxiv2026

A ML-framework for the discovery of next-generation IBD targets using a harmonized single-cell atlas of patient tissue

Target discovery for IBD has traditionally relied on genetic associations, which lack the cellular resolution needed to identify novel, actionable, cell type-specific disease pathways. Here, we describe an integrated analytical and experimental framework that leverages harmonized single-cell data to systematically discover novel therapeutic strategies for IBD. We used AMICA DBTM, Immunais harmonized database of single-cell RNA datasets to construct a harmonized 1 million single-cell atlas of the human intestine. We applied a machine learning framework (Immune Patient Representation, IPR) to identify disease-associated transcriptional programs and cell type-specific gene targets. Candidate targets were prioritized using atlas-derived metrics, refined using custom criteria emphasizing translational actionability, and validated across independent clinical cohorts. Select candidates were evaluated in human primary-cell models reflecting the targets cell-type context. The IPR framework identified 85 disease-associated transcriptional programs and ranked 400 cell type-specific target genes across immune and stromal lineages. Disease-associated programs were interpreted using a structured AI-assisted reasoning framework for structured biological reasoning, linking them to IBD-relevant pathways and guiding the identification of novel, promising gene targets. Functional validation of two cell-type-specific candidates, PTGIR in myeloid cells and IL6ST in fibroblasts, confirmed the reduction of inflammatory and fibrotic pathways linked to IBD pathology. Multi-omic profiling and projection of in vitro phenotypes to patient datasets demonstrated the reversal of disease-associated programs via mechanisms distinct from those of existing biologics. Our single-cell anchored, machine-learning framework integrates in silico discovery with experimental validation, revealing new cell type-specific therapeutic opportunities and supporting a scalable approach for precision target discovery in IBD and other immune-mediated diseases.

bioinformatics↗

bioRxiv2019

Ataxin-3 links NOD2 and TLR2 mediated innate immune sensing and metabolism in myeloid cells

The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wall peptidoglycan is well established, however their role in redirecting metabolic pathways in myeloid cells to degrade pathogens and mount antigen presentation remains unclear. We show NOD2 and TLR2 mediate phosphorylation of the deubiquitinase ataxin-3 via RIPK2 and TBK1. In myeloid cells ataxin-3 associates with the mitochondrial cristae protein MIC60, and is required for oxidative phosphorylation. Depletion of ataxin-3 leads to impaired induction of mitochondrial reactive oxygen species (mROS) and defective bacterial killing. A mass spectrometry analysis of NOD2/TLR2 triggered ataxin-3 deubiquitination targets revealed immunometabolic regulators, including HIF-1 and LAMTOR1 that may contribute to these effects. Thus, we define how ataxin-3 plays an essential role in NOD2 and TLR2 sensing and effector functions in myeloid cells.\n\nSignificance StatementIn recent years it has become clear that cross-talk between metabolic and immune pathways is central to the regulation of host defence. This interplay appears of particular importance in myeloid cells including dendritic cells and macrophages, but it is unclear how two of their key bacterial sensors NOD2 and TLR2 influence metabolism. Here, we define how NOD2/TLR2 signal in myeloid cells to drive optimal mitochondrial functioning required for bacterial destruction. We uncover a new role for Ataxin-3, a deubiquitinase required for non-selective autophagy, in this pathway. We provide a non-biased analysis of Ataxin-3 targets generating evidence for a role in deubiquitination of metabolic mediators during myeloid cell differentiation that will provide an important basis for further study.

immunology↗

bioRxiv2019

NOD2 and TLR2 Signal via TBK1 and PI31 to Direct Cross-presentation and CD8 T Cell Responses

NOD2 and TLR2 recognize components of bacterial cell wall peptidoglycan and direct defense against enteric pathogens. CD8+ T cells are important for immunity to such pathogens but how NOD2 and TLR2 induce antigen specific CD8+ T cell responses is unknown. Here, we define how these pattern recognition receptors (PRRs) signal in primary dendritic cells (DCs) to influence MHC class I antigen presentation. We show NOD2 and TLR2 phosphorylate PI31 via TBK1 following activation in DCs. PI31 interacts with TBK1 and Sec16A at endoplasmic reticulum exit sites (ERES), which positively regulates MHC class I peptide loading and immunoproteasome stability. Following NOD2 and TLR2 stimulation, depletion of PI31 or inhibition of TBK1 activity in vivo impairs DC cross-presentation and CD8+ T cell activation. DCs from Crohns patients expressing NOD2 polymorphisms show dysregulated cross-presentation and CD8+ T cell responses. Our findings reveal unidentified mechanisms that underlie CD8+ T cell responses to bacteria in health and in Crohns.

immunology↗