Biology subjects

Hagood, J. S.

Publications and source records attributed to Hagood, J. S..

6 recordsLinked to original sources

bioRxiv2025

A Multimodal Spatial and Epigenomic Atlas of Human Adult Lung Topography

Developing high-resolution reference maps of disease-susceptible spatial niches is a critical step to mitigating the profound effects of lung disease. Here, we present an integrated multimodal single-nucleus human lung atlas (snHLA) profiling 746,047 nuclei from 49 mapped lung blocks spanning clinically relevant distal airways, alveoli, and interstitium across 11 healthy adults. Integrating snRNA-seq and SNARE-seq2, which co-assays chromatin accessibility and gene expression from the same nucleus, we resolved 70 molecularly distinct populations and captured 332,846 accessible chromatin regions, nominating new transcriptional regulators of human lung cell diversity. Spatial transcriptomics using MERFISH mapped 25 cell populations across 7 structural neighborhoods and multiplexed immunofluorescence localized cell subtypes and distal airway-defining protein markers, expanding and validating distinct lung structure-specific cell populations. This open access snHLA and companion Cell Type and Marker Gene Dictionary with anatomically aligned nomenclature delivers a foundational resource at an unprecedented resolution to interrogate the origins of lung pathophysiology.

cell biology↗

bioRxiv2024

Temporal High-Resolution Atlas of Human Blood Leukocyte Composition in Response to Respiratory Virus Inoculation

BackgroundRespiratory viral infections produce highly variable clinical outcomes, even after controlled exposure. Human viral challenge studies are well suited to study this variation because they capture immune profiles before inoculation and across defined post-challenge intervals. However, how circulating immune-cell populations change over time, and which responses are shared or virus-specific across respiratory viruses, remains incompletely defined. MethodsWe leveraged HR-VILAGE-3K3M, a curated human respiratory viral challenge transcriptomic resource, to analyze longitudinal whole-blood profiles from H1N1, H3N2, RSV, and HRV challenge studies. Using statistical deconvolution and xCell-based digital sorting, we estimated changes in major leukocyte populations and 28 immune-cell subtypes in symptomatic infected (Sx/Inf) and asymptomatic uninfected (Asx/Uninf) participants. Across viruses, symptomatic infection was marked by a broad shared pattern of innate immune activation together with reduced circulating lymphocyte enrichment. Activated dendritic cells, monocytes, and neutrophils increased following challenge, whereas strong pDC activation was observed primarily in influenza studies. Most T-cell and B-cell populations decreased after challenge. Plasma-cell enrichment increased progressively over time. Despite this shared architecture, response timing differed by virus: H3N2 showed the earliest changes, followed by H1N1, whereas RSV responses were delayed and HRV showed more distinct immune-cell trajectories. Migration-associated transcriptional programs were detected across both innate and adaptive immune-cell populations, supporting coordinated immune-cell trafficking during infection. Baseline immune composition also differed between outcome groups, suggesting that pre-existing immune-state differences may influence infection outcomes. ConclusionsThese findings define a cellular atlas of human respiratory viral challenge responses and show that respiratory viruses induce a broadly conserved immune-response program with distinct virus-specific kinetics. This framework may help clarify immune features associated with natural resistance, symptomatic infection, and vaccine-relevant antiviral immunity.

genomics↗

bioRxiv2024

A curated collection of transcriptome datasets to study the transcriptional response in blood and nasal samples following viral respiratory inoculation and vaccination

Our understanding of the human immune systems response to viral respiratory tract infections (VRTIs) and vaccines, including the molecular mechanisms and correlates of protection, remains incomplete. Extensive transcriptomic data from inoculation and vaccination studies have been deposited in publicly available databases. However, these studies are often separate and difficult to locate. We provide a curated compendium of public gene expression data repositories for researchers to reanalyze transcriptomes from human whole blood, peripheral blood mononuclear cells (PBMCs), and nasal swab samples. This enables the study of transcriptional responses to viral inoculation or vaccination. This collection includes 18 datasets from inoculation studies and 37 datasets from vaccination studies, sourced from the NCBI Gene Expression Omnibus (GEO), ImmPort Shared Data, and ArrayExpress.

genomics↗

bioRxiv2024

Prolonged airway explant culture enables study of health, disease, and viral pathogenesis

In vitro models play a major role in studying airway physiology and disease. However, the native lungs complex tissue architecture and non-epithelial cell lineages are not preserved in these models. Ex vivo tissue models could overcome in vitro limitations, but methods for long-term maintenance of ex vivo tissue has not been established. We describe methods to culture human large airway explants, small airway explants, and precision-cut lung slices for at least 14 days. Human airway explants recapitulate genotype-specific electrophysiology, characteristic epithelial, endothelial, stromal and immune cell populations, and model viral infection after 14 days in culture. These methods also maintain mouse, rabbit, and pig tracheal explants. Notably, intact airway tissue can be cryopreserved, thawed, and used to generate explants with recovery of function 14 days post-thaw. These studies highlight the broad applications of airway tissue explants and their use as translational intermediates between in vitro and in vivo studies.

bioengineering↗

bioRxiv2023

A Multi-omic Analysis of the Human Lung Reveals Distinct Cell Specific Aging and Senescence Molecular Programs

Age is a major risk factor for lung disease. To understand the mechanisms underlying this association, we characterized the changing cellular, genomic, transcriptional, and epigenetic landscape of lung aging using bulk and single-cell RNAseq (scRNAseq) data. Our analysis revealed age-associated gene networks that reflected hallmarks of aging, including mitochondrial dysfunction, inflammation, and cellular senescence. Cell type deconvolution revealed age-associated changes in the cellular composition of the lung: decreased alveolar epithelial cells and increased fibroblasts and endothelial cells. In the alveolar microenvironment, aging is characterized by decreased AT2B cells and reduced surfactant production, a finding that was validated by scRNAseq and IHC. We showed that a previously reported senescence signature, SenMayo, captures cells expressing canonical senescence markers. SenMayo signature also identified cell-type specific senescence-associated co-expression modules that have distinct molecular functions, including ECM regulation, cell signaling, and damage response pathways. Analysis of somatic mutations showed that burden was highest in lymphocytes and endothelial cells and was associated with high expression of senescence signature. Finally, aging and senescence gene expression modules were associated with differentially methylated regions, with inflammatory markers such as IL1B, IL6R, and TNF being significantly regulated with age. Our findings provide new insights into the mechanisms underlying lung aging and may have implications for the development of interventions to prevent or treat age-related lung diseases.

genomics↗

bioRxiv2022

A model of persistent post SARS-CoV-2 induced lung disease for target identification and testing of therapeutic strategies

COVID-19 survivors develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal samples. Mouse-adapted SARS-CoV-2 MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute disease through clinical recovery. At 15-120 days post-virus clearance, histologic evaluation identified subpleural lesions containing collagen, proliferative fibroblasts, and chronic inflammation with tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal upregulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

microbiology↗