Biology subjects

Jackson, N. D.

Publications and source records attributed to Jackson, N. D..

4 recordsLinked to original sources

bioRxiv2023

Atopic dermatitis complicated by recurrent eczema herpeticum is characterized by multiple, concurrent epidermal inflammatory endotypes

BACKGROUNDA subgroup of atopic dermatitis (AD) patients suffer from recurrent, disseminated herpes simplex virus (HSV) skin infections, termed eczema herpeticum (EH), which can be life-threatening and contribute to AD morbidity. The pathobiology underlying ADEH is unknown. OBJECTIVETo determine transcriptional mechanisms of skin and immune system pathobiology that underlie ADEH disease. METHODSWe performed whole transcriptome RNA-sequencing of non-lesional skin samples (epidermis, dermis) of AD patients with (ADEH+, n=15) and without (ADEH-, n=13) recurrent EH history, and healthy controls (HC, n=15). We also performed RNA-sequencing on plasmacytoid dendritic cells (pDCs) collected from these participants and infected in vitro with HSV-1. Differential expression, gene set enrichment, and endotyping analyses were performed. RESULTSADEH+ disease was characterized by dysregulation in skin gene expression, which was limited in dermis (differentially expressed genes [DEGs]=14) and widespread in epidermis (DEGs=129). ADEH+-upregulated epidermal DEGs were enriched in type 2 cytokine (T2) (IL4R, CCL22, CRLF2, IL7R), interferon (CXCL10, ICAM1, IFI44, and IRF7), and IL-36{gamma} (IL36G) inflammatory pathway genes. At a person-level, all ADEH+ participants exhibited T2 and interferon endotypes and 87% were IL36G-high. In contrast, these endotypes were more variably expressed among ADEH- participants. ADEH+ patient skin also exhibited dysregulation in epidermal differentiation complex (EDC) genes within the LCE, S100, and SPRR families, which are involved in skin barrier function, inflammation, and antimicrobial activities. pDC transcriptional responses to HSV-1 infection were not altered by ADEH status. CONCLUSIONSADEH+ pathobiology is characterized by a unique, multi-faceted epidermal inflammation that accompanies dysregulation in the expression of EDC genes. Key MessagesO_LIAD patients with a history of recurrent EH exhibit molecular skin pathobiology that is similar in form, but more severe in degree, than in AD patients without this complication. C_LIO_LINon-lesional skin of ADEH+ patients concurrently exhibits excessive type 2 cytokine, interferon, and IL-36{gamma}-driven epidermal inflammation. C_LIO_LIExpression of these inflammatory skin endotypes among ADEH+ patients is associated with dysregulation in expression of epidermal differentiation complex genes involved in barrier function, inflammation, and antimicrobial activity. C_LI Capsule SummaryAD patients with a history of recurrent disseminated HSV-1 skin infections form a unique molecular skin endotype group that concurrently exhibits type 2 cytokine, interferon, and IL-36{gamma}-driven skin inflammation, accompanied by dysregulation in expression of epidermal differentiation complex genes involved in barrier function, inflammation, and antimicrobial activity.

molecular biology↗

bioRxiv2022

An integrated cell atlas of the human lung in health and disease

Organ- and body-scale cell atlases have the potential to transform our understanding of human biology. To capture the variability present in the population, these atlases must include diverse demographics such as age and ethnicity from both healthy and diseased individuals. The growth in both size and number of single-cell datasets, combined with recent advances in computational techniques, for the first time makes it possible to generate such comprehensive large-scale atlases through integration of multiple datasets. Here, we present the integrated Human Lung Cell Atlas (HLCA) combining 46 datasets of the human respiratory system into a single atlas spanning over 2.2 million cells from 444 individuals across health and disease. The HLCA contains a consensus re-annotation of published and newly generated datasets, resolving under- or misannotation of 59% of cells in the original datasets. The HLCA enables recovery of rare cell types, provides consensus marker genes for each cell type, and uncovers gene modules associated with demographic covariates and anatomical location within the respiratory system. To facilitate the use of the HLCA as a reference for single-cell lung research and allow rapid analysis of new data, we provide an interactive web portal to project datasets onto the HLCA. Finally, we demonstrate the value of the HLCA reference for interpreting disease-associated changes. Thus, the HLCA outlines a roadmap for the development and use of organ-scale cell atlases within the Human Cell Atlas.

cell biology↗

bioRxiv2020

Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium

Coronavirus disease 2019 (COVID-19) outcomes vary from asymptomatic infection to death. This disparity may reflect different airway levels of the SARS-CoV-2 receptor, ACE2, and the spike protein activator, TMPRSS2. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci (eQTL) for both ACE2 and TMPRSS2, that vary in frequency across world populations. Importantly, we find TMPRSS2 is part of a mucus secretory network, highly upregulated by T2 inflammation through the action of interleukin-13, and that interferon response to respiratory viruses highly upregulates ACE2 expression. Finally, we define airway responses to coronavirus infections in children, finding that these infections upregulate IL6 while also stimulating a more pronounced cytotoxic immune response relative to other respiratory viruses. Our results reveal mechanisms likely influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

genomics↗

bioRxiv2019

Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium

Cigarette smoke first interacts with the lung through the cellularly diverse airway epithelium and goes on to drive development of most chronic lung diseases. Here, through single cell RNA-sequencing analysis of the tracheal epithelium from smokers and nonsmokers, we generated a comprehensive atlas of epithelial cell types and states, connected these into lineages, and defined cell-specific responses to smoking. Our analysis inferred multi-state lineages that develop into surface mucus secretory and ciliated cells and contrasted these to the unique lineage and specialization of submucosal gland (SMG) cells. Our analysis also suggests a lineage relationship between tuft, pulmonary neuroendocrine, and the newly discovered CFTR-rich ionocyte cells. Our smoking analysis found that all cell types, including protected stem and SMG populations, are affected by smoking, through both pan-epithelial smoking response networks and hundreds of cell type-specific response genes, redefining the penetrance and cellular specificity of smoking effects on the human airway epithelium.

cell biology↗