Biology subjects

Deiter, F.

Publications and source records attributed to Deiter, F..

3 recordsLinked to original sources

bioRxiv2026

Comparative molecular analysis of histopathologic subtypes reveals shared epithelial remodeling yet distinct fibroblast programs in scleroderma lung disease

Rationale: Interstitial lung disease (ILD) drives mortality in systemic sclerosis (SSc), with a subset developing progressive pulmonary fibrosis (PPF) resembling idiopathic pulmonary fibrosis (IPF). Despite recognition of two distinct histopathologic patterns, the cellular basis of nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP) remains poorly understood. Objectives: To define shared and distinct cellular and molecular features of SSc-NSIP and SSc-UIP compared to IPF. Methods: Single-nucleus RNA sequencing and spatial transcriptomics were performed on explanted lungs from patients with SSc-NSIP (n=6), SSc-UIP (n=6), or IPF (n=6), and control donors (n=12) with immunohistochemistry and western blot validation. Main Results: Across 120,254 nuclei from 35 cell types, there was striking similarity across fibrotic subgroups in epithelial, endothelial, and immune compartments, including alveolar type 1 cell loss, pathologic alveolar type 2 (AT2) gene expression, and expansion of COL15A1 endothelial cells and profibrotic macrophages. Diseased AT2s showed activation of the p53/DNA damage pathway. Aberrant basaloid (AB) cells were present in both SSc-ILD subtypes and transcriptionally similar to IPF ABs. They consistently neighbored profibrotic CTHRC1 fibroblasts, even in SSc-NSIP, despite lacking fibroblast foci. Fibroblast heterogeneity differentiated the histopathologic subtypes. Inflammatory fibroblasts were enriched in SSc-NSIP and CTHRC1 fibroblasts in UIP. AB-to-pathologic fibroblast crosstalk was defined by profibrotic signaling, with amplified TGF-{beta} signaling in UIP. Conclusions: Convergent epithelial remodeling is a hallmark of PPF in SSc-ILD and IPF. Fibroblast heterogeneity characterized by altered TGF-beta signaling distinguishes SSc-NSIP from SSc-UIP and IPF. Accelerated aging, DNA damage, and p53-dependent senescence pathways may represent shared drivers of PPF.

genomics↗

bioRxiv2022

Human Galectin-9 Potently Enhances SARS-CoV-2 Replication and Inflammation in Airway Epithelial Cells

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a {beta}-galactoside-binding lectin involved in immune regulation and viral immunopathogenesis, were reported to be elevated in the setting of severe COVID-19 disease. However, the impact of Gal-9 on SARS-CoV-2 infection and immunopathology remained to be elucidated. Here, we demonstrate that Gal-9 treatment potently enhances SARS-CoV-2 replication in human airway epithelial cells (AECs), including primary AECs in air-liquid interface (ALI) culture. Gal-9-glycan interactions promote SARS-CoV-2 attachment and entry into AECs in an ACE2-dependent manner, enhancing the binding affinity of the viral spike protein to ACE2. Transcriptomic analysis revealed that Gal-9 and SARS-CoV-2 infection synergistically induce the expression of key pro-inflammatory programs in AECs including the IL-6, IL-8, IL-17, EIF2, and TNF signaling pathways. Our findings suggest that manipulation of Gal-9 should be explored as a therapeutic strategy for SARS-CoV-2 infection. ImportanceCOVID-19 continues to have a major global health and economic impact. Identifying host molecular determinants that modulate SARS-CoV-2 infectivity and pathology is a key step in discovering novel therapeutic approaches for COVID-19. Several recent studies have revealed that plasma concentrations of the human {beta}-galactoside-binding protein galectin-9 (Gal-9) are highly elevated in COVID-19 patients. In this study, we investigated the impact of Gal-9 on SARS-CoV-2 pathogenesis ex vivo in airway epithelial cells (AECs), the critical initial targets of SARS-CoV-2 infection. Our findings reveal that Gal-9 potently enhances SARS-CoV-2 replication in AECs, interacting with glycans to enhance the binding between viral particles and entry receptors on the target cell surface. Moreover, we determined that Gal-9 accelerates and exacerbates several virus-induced pro-inflammatory programs in AECs that are established signature characteristics of COVID-19 disease and SARS-CoV-2-induced acute respiratory distress syndrome (ARDS). Our findings suggest that Gal-9 is a promising pharmacological target for COVID-19 therapies.

microbiology↗

bioRxiv2019

The crystal structure of a cardiac calsequestrin filament reveals an atomic mechanism of calsequestrin-associated catecholaminergic polymorphic ventricular tachycardia

Mutations in the calcium-binding protein calsequestrin cause a highly lethal familial arrhythmia, catecholaminergic polymorphic ventricular tachycardia (CPVT). In vivo, calsequestrin multimerizes into filaments, but a compelling atomic-resolution structure of a calsequestrin filament is lacking. We report a crystal structure of a cardiac calsequestrin filament with supporting mutation analysis provided by an in vitro fomentation assay. We also report and characterize a novel disease-associated calsequestrin mutation, S173I, which localizes to the filament-forming interface. In addition, we show that a previously reported dominant disease mutation, K180R, maps to the same multimerization surface. Both mutations disrupt filamentation, suggesting that dominant disease arises from defects in multimer formation. A ytterbium-derivatized structure pinpoints multiple credible calcium sites at filament-forming interfaces, explaining the atomic basis of calsequestrin filamentation in the presence of calcium. This work advances our understanding of calsequestrin biochemistry and provides a unifying structure-function molecular mechanism by which dominant-acting calsequestrin mutations provoke lethal arrhythmias.

biochemistry↗