Biology subjects

Schwartz, D. A.

Publications and source records attributed to Schwartz, D. A..

12 recordsLinked to original sources

bioRxiv2026

Early Pulmonary Fibrosis is Defined by Niche- and Cell-Specific Molecular Programs

RationalePreclinical familial pulmonary fibrosis (FPF) represents an early stage of fibrotic lung disease, yet the compartment- and cell-specific molecular programs preceding fibrosis remain poorly understood. ObjectiveTo define spatially organized molecular signatures associated with preclinical FPF and identify tissue-informed circulating biomarkers linked to early fibrotic remodeling. MethodsWe performed integrated multi-omic profiling of histologically preserved and remodeled lung regions from subjects with preclinical FPF, Idiopathic Pulmonary Fibrosis (IPF), and controls using spatial transcriptomics, single-nucleus RNA sequencing (snRNAseq), and blood proteomics. Differential expression and pathway enrichment analyses were performed across spatial compartments and epithelial cell states. ResultsHistologically preserved lung regions in preclinical FPF demonstrated transcriptional abnormalities including stress-response, ciliary, and extracellular matrix-associated programs despite minimal architectural distortion. Spatial analyses identified alterations in alveolar niche molecular programs accompanied by increasing profibrotic signaling across preserved and tissue remodeled lung compartments. Compared with advanced IPF, preclinical FPF retained epithelial repair and surfactant-associated signatures. Integration with snRNAseq demonstrated enrichment of alveolar and airway epithelial cell dysregulated states associated with transitional phenotypes previously implicated in IPF. Compartment- and epithelial-associated transcriptional signatures identified in lung tissue were partially represented in the peripheral blood. ConclusionPreclinical FPF is characterized by compartment- and cell-specific molecular programs that precede established fibrosis. We identified distinct alveolar, airway, and vascular molecular signatures and epithelial remodeling states represented in the peripheral blood. These findings provide an initial framework for molecular classification of early stages of pulmonary fibrosis and support future studies evaluating minimally invasive approaches for disease stratification and precision therapeutics. At a Glance Commentary Scientific Knowledge on the SubjectThe molecular events preceding a diagnosis of pulmonary fibrosis remain poorly understood. Most mechanistic studies in Idiopathic Pulmonary Fibrosis (IPF) have relied on end-stage explanted lungs, limiting insight into the compartment- and cell-specific molecular programs associated with early stages of pulmonary fibrosis. What this study adds to the fieldUsing integrated spatial transcriptomics, single-cell sequencing, and peripheral blood proteomic profiling, we demonstrate that preclinical familial pulmonary fibrosis (FPF) is characterized by compartment- and cell-specific molecular programs that precede clinically detectable fibrosis. Spatial analyses identified distinct alveolar, airway, and vascular molecular signatures, while single cell analysis confirmed the presence of epithelial dysregulated states. These signatures are partially represented in the peripheral blood. Our findings provide an initial framework for biologically informed classification of early stages of pulmonary fibrosis and future minimally invasive approaches for disease stratification.

genomics↗

bioRxiv2026

Proteomic analysis reveals regional sex differences in healthy and fibrotic human lung

Biological sex has systemic effects on gene expression, cell behavior, and disease etiology. Despite these widespread effects, sex as a biological variable is understudied, particularly in chronic lung diseases. In idiopathic pulmonary fibrosis (IPF), 70% of patients are male, and male patients have overall worse survival post-diagnosis. While behavioral differences between sexes might account for some of the epidemiological differences, the contribution of underlying biology is not known. In this study, we performed regional proteomic analysis via laser-captured microdissection-coupled mass spectrometry and analyzed the data for sex-biased protein expression. We discovered that even in control lung, sex differences existed in both airway and alveolar regions. Sex differences became more pronounced in diseased regions, with sex-biased expression of diverse proteins including those involved in extracellular vesicle secretion, cellular metabolism, and extracellular matrix remodeling. These data suggest that baseline sex differences in lung proteome may contribute to sex-specific susceptibility, progression, and clinical outcomes in IPF, underscoring the need for future mechanistic and clinical studies to account for sex as a biological variable.

bioengineering↗

bioRxiv2026

IPF AT2 cells are stuck in transition and biophysically dysfunctional

Idiopathic Pulmonary Fibrosis (IPF) is an incurable disease with extensive molecular, cellular, and organ level dysfunction. A major gap in IPF research is the lack of understanding of how short-term cellular behavior causes long-term tissue remodeling. By optimizing lung slices from explanted human lungs, we discovered foci of migratory non-canonical alveolar type 2 (AT2) cells in regions of established lung fibrosis and found that these cells are trapped in states of cellular transition that are driven by persistent developmental repair programs. Consistent with these biophysical behaviors, pharmacological activation of {beta}-catenin reproduced persistent migration, whereas YAP activation restrained it. We conclude that imbalanced developmental programs drive AT2 cell motility and lesion heterogeneity, providing a mechanistic link between short-term cellular dynamics and slowly progressive fibrosis of IPF.

cell biology↗

bioRxiv2024

The MUC5B promoter variant results in proteomic changes in the non-fibrotic lung

The gain-of-function MUC5B promoter variant is the dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF). However, its impact on protein expression in both non-fibrotic control and IPF lung specimens have not been well characterized. Utilizing laser capture microdissection coupled to mass spectrometry (LCM-MS), we investigated the proteomic profiles of airway and alveolar epithelium in non-fibrotic controls (n = 12) and IPF specimens (n = 12), stratified by the presence of the MUC5B promoter variant. Through qualitative and quantitative analyses, as well as pathway analysis and immunohistological validation, we have identified a distinct MUC5B-associated protein profile. Notably, the non-fibrotic control alveoli exhibited substantial MUC5B-associated protein changes, with an increase of IL-3 signaling. Additionally, we found that the epithelial cells overlying IPF fibroblastic foci cluster closely to alveolar epithelia and express proteins associated with cellular stress pathways. In conclusion, our findings suggest that the MUC5B promoter variant leads to protein changes in alveolar and airway epithelium that appears to be associated with the initiation and progression of lung fibrosis.

pathology↗

bioRxiv2024

Siglec-F Deficiency Prevents Fibrosis After Bleomycin-Induced Acute Lung Injury

Injury to the lungs causes acute inflammation that can lead to pathological lung fibrosis. Airspace macrophages (AMs) are critical for repair of injured tissue, but they can contribute fibrosis through mechanisms that are incompletely understood. Siglecs are expressed by immune cells. In mice, Siglec-F is chiefly expressed AMs where it is considered inflammosuppressive. We hypothesized that its deletion would worsen lung injury and fibrosis in response to intratracheal bleomycin challenge. We evaluated Siglec-F expression and function in mice challenged with bleomycin on days 7, 14, and 21 post-challenge (2.5 U/kg). AMs were the predominant inflammatory cells at all timepoints, and they included resident (RAM) and recruited (RecAM) subsets. Siglec-F deficiency prevented fibrosis than in Siglecf-/- mouse lungs, as evident from biochemical and histologic readouts. We performed RNAseq on pooled RAMs and RecAMs from wild type and Siglec-F deficient mice. Lung fibrosis 21 d after bleomycin challenge was associated with differentially expressed genes (DEGs) related to cholesterol synthesis and metabolism. In AMs from healthy lung lavage fluid and idiopathic pulmonary fibrosis patient tissues, the human paralogs Siglec-7 and Siglec-9 were expressed. Findings here identify novel mechanisms that control protective and detrimental functions of AMs after lung injury.

physiology↗

bioRxiv2024

Toll-Like-Receptor 5 protects against pulmonary fibrosis by reducing lung dysbiosis

Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease with no curative treatment other than lung transplantation. IPF results from maladaptive responses to lung epithelial injury, but the underlying mechanisms remain unclear. Here, we show that deficiency in the innate immune receptor, toll-like receptor 5 (TLR5), is associated with IPF in humans and with increased susceptibility to epithelial injury and experimental fibrosis in mice, while activation of lung epithelial TLR5 through a synthetic flagellin analogue protects from experimental fibrosis. Mechanistically, epithelial TLR5 activation induces antimicrobial gene expression and ameliorates dysbiosis after lung injury. In contrast, TLR5 deficiency in mice and IPF patients is associated with lung dysbiosis. Elimination of the microbiome in mice through antibiotics abolishes the protective effect of TLR5 and reconstitution of the microbiome rescues the observed phenotype. In aggregate, TLR5 deficiency is associated with IPF and dysbiosis in humans and in the murine model of pulmonary fibrosis. Furthermore, TLR5 protects against pulmonary fibrosis in mice and this protection is mediated by effects on the microbiome. One-sentence summaryDeficiency in the innate immune receptor TLR5 is a risk factor for pulmonary fibrosis, because TLR5 prevents microbial dysbiosis after lung injury.

immunology↗

bioRxiv2024

Bacterium secretes chemical inhibitor that sensitizes competitor to bacteriophage infection

To overtake competitors, microbes produce and secrete secondary metabolites that kill neighboring cells and sequester nutrients. This natural product-mediated competition likely evolved in complex microbial communities that included viral pathogens. From this ecological context, we hypothesized that microbes secrete metabolites that "weaponize" natural pathogens (i.e., bacteriophages) to lyse their competitors. Indeed, we discovered a bacterial secondary metabolite that sensitizes other bacteria to phage infection. We found that this metabolite provides the producer (a Streptomyces sp.) with a fitness advantage over its competitor (Bacillus subtilis) by promoting phage infection. The phage-promoting metabolite, coelichelin, sensitized B. subtilis to a wide panel of lytic phages, and it did so by preventing the early stages of sporulation through iron sequestration. Beyond coelichelin, other natural products may provide phage-mediated competitive advantages to their producers--either by inhibiting sporulation or through yet-unknown mechanisms.

microbiology↗

bioRxiv2023

A Specialized Epithelial Cell Type Regulating Mucosal Immunity and Driving Human Crohn's Disease

Crohns disease (CD) is a complex chronic inflammatory disorder that may affect any part of gastrointestinal tract with extra-intestinal manifestations and associated immune dysregulation. To characterize heterogeneity in CD, we profiled single-cell transcriptomics of 170 samples from 65 CD patients and 18 non-inflammatory bowel disease (IBD) controls in both the terminal ileum (TI) and ascending colon (AC). Analysis of 202,359 cells identified a novel epithelial cell type in both TI and AC, featuring high expression of LCN2, NOS2, and DUOX2, and thus is named LND. LND cells, confirmed by high-resolution in-situ RNA imaging, were rarely found in non-IBD controls, but expanded significantly in active CD. Compared to other epithelial cells, genes defining LND cells were enriched in antimicrobial response and immunoregulation. Moreover, multiplexed protein imaging demonstrated that LND cell abundance was associated with immune infiltration. Cross-talk between LND and immune cells was explored by ligand-receptor interactions and further evidenced by their spatial colocalization. LND cells showed significant enrichment of expression specificity of IBD/CD susceptibility genes, revealing its role in immunopathogenesis of CD. Investigating lineage relationships of epithelial cells detected two LND cell subpopulations with different origins and developmental potential, early and late LND. The ratio of the late to early LND cells was related to anti-TNF response. These findings emphasize the pathogenic role of the specialized LND cell type in both Crohns ileitis and Crohns colitis and identify novel biomarkers associated with disease activity and treatment response.

bioinformatics↗

bioRxiv2023

Coevolution with a seed bank

Dormancy is as an adaptation to living in fluctuating environments. It can also influence species interactions, for example, by providing organisms with a refuge from predators and parasites. Here we test the hypothesis that dormancy generates a seed bank of protected individuals that can modify antagonistic coevolutionary dynamics. We experimentally evolved a spore-forming bacterial host along with a phage parasite that can infect active but not dormant cells. Seed banks buffered population dynamics against phage infection and retained phenotypic diversity that was otherwise lost to directional selection. By storing genetic diversity, seed banks also altered the distribution of host alleles, which contributed to dampened coevolutionary dynamics. Our findings demonstrate that dormancy generates a seed bank that can modify the eco-evolutionary outcomes of host-parasite systems.

evolutionary biology↗

bioRxiv2021

Phage-encoded sigma factors alter bacterial dormancy

By entering a reversible state of reduced metabolic activity, dormant microorganisms are able to tolerate suboptimal conditions that would otherwise reduce their fitness. Dormancy may also benefit bacteria by serving as a refuge from parasitic infections. Here we focus on dormancy in the Firmicutes, where endospore development is transcriptionally regulated by the expression of sigma factors. A disruption of this process could influence the survivorship and reproduction of phages that infect spore-forming hosts with implications for coevolutionary dynamics. Here, we characterized the distribution and diversity of sigma factors in nearly 3,500 phage genomes. Homologs of sporulation-specific sigma factors were identified in phages that infect spore-forming hosts. Unlike sigma factors required for phage reproduction, the sporulation-like sigma factors were non-essential for lytic infection. However, when expressed in the spore-forming Bacillus subtilis, sigma factors from phages activated the bacterial sporulation gene network and reduced spore yield. Our findings suggest that the acquisition of host-like transcriptional regulators may allow phages to manipulate a complex and ancient trait in one of the most abundant cell types on Earth.

microbiology↗

bioRxiv2020

Identification of Influential Variants in Significant Aggregate Rare Variant Tests

IntroductionStudies that examine the role of rare variants in both simple and complex disease are increasingly common. Though the usual approach of testing rare variants in aggregate sets is more powerful than testing individual variants, it is of interest to identify the variants that are plausible drivers of the association. We present a novel method for prioritization of rare variants after a significant aggregate test by quantifying the influence of the variant on the aggregate test of association. MethodsIn addition to providing a measure used to rank variants, we use outlier detection methods to present the computationally efficient Rare Variant Influential Filtering Tool (RIFT) to identify a subset of variants that influence the disease association. We evaluated several outlier detection methods that vary based on the underlying variance measure: interquartile range (Tukey fences), median absolute deviation and standard deviation. We performed 1000 simulations for 50 regions of size 3kb and compared the true and false positive rates. We compared RIFT using the Inner Tukey to two existing methods: adaptive combination of p-values (ADA) and a Bayesian hierarchical model (BeviMed). Finally, we applied this method to data from our targeted resequencing study in idiopathic pulmonary fibrosis (IPF). ResultsAll outlier detection methods observed higher sensitivity to detect uncommon variants (0.001 < MAF > 0.03) compared to very rare variants (MAF < 0.001). For uncommon variants, RIFT had a lower median false positive rate compared to the ADA. ADA and RIFT had significantly higher true positive rates than that observed for BeviMed. When applied to two regions found previously associated with IPF including 100 rare variants, we identified six polymorphisms with the greatest evidence for influencing the association with IPF. DiscussionIn summary, RIFT has a high true positive rate while maintaining a low false positive rate for identifying polymorphisms influencing rare variant association tests. This work provides an approach to obtain greater resolution of the rare variant signals within significant aggregate sets; this information can provide an objective measure to prioritize variants for follow-up experimental studies and insight into the biological pathways involved.

genetics↗

bioRxiv2018

Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. To broaden COPD genetic risk loci discovery and identify cell type and phenotype associations we performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P value < 5x10-8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and alveolar type II cells. We found 9 shared genomic regions between COPD and asthma and 5 between COPD and pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD.

genetics↗