Biology subjects

Wearne, S.

Publications and source records attributed to Wearne, S..

5 recordsLinked to original sources

bioRxiv2026

Host recovery after skin barrier disruption is individual-specific and associated with microbial functions

The human skin is repeatedly exposed to mechanical and environmental stress, particularly in common skin diseases such as eczema, and yet the determinants of recovery remain poorly understood. Using longitudinal, multimodal profiling of skin physiology, structure (Raman spectroscopy), and microbial communities (shotgun metagenomics), we investigated in a human cohort (n=36 subjects, x2 sites, x6 timepoints) how host-microbe interactions could jointly shape recovery. Despite baseline variability in physiological parameters, we established that our protocol enables a defined disruption of the stratum corneum. While recovery trajectories for host attributes were notably consistent across age groups and body sites, individual-specific differences in recovery timelines were observed. To assess the role of the skin microbiome, several key time-dependent changes in microbial species were identified including enrichment of select Cutibacterium and Staphylococcus species and depletion of Corynebacterium and Malassezia species. Clustering of microbiome stability profiles across subjects and sites identified 6 distinct groups which associate with varying host-recovery patterns and microbial functions. Finally, joint hazards modelling of recovery timing revealed significant contributions from microbial taxa, functions and stability groups, highlighting the under-appreciated role of host-microbial interactions in response to skin stress and in the recovery process.

genomics↗

bioRxiv2026

Two orthogonal MAP3K-driven pathways of NLRP1 inflammasome activation revealed by poisonous beetles.

Environmental toxins that cause irritant dermatitis remain poorly understood as activators of innate immune pathways. Here, we identify rove beetle (Paederus) and blister beetle (Meloidae) toxins as previously unrecognized triggers of the human NLRP1 inflammasome in keratinocytes. Rove beetles, likely through the ribosome inhibitor pederin, activate NLRP1 via translational stalling and the ZAK-dependent ribotoxic stress response. In contrast, the phosphatase inhibitor cantharidin from blister beetles induces NLRP1 through TAK1-driven hyperphosphorylation of its linker region, independent of ZAK. In their hyperactivated states, ZAK and TAK1 share overlapping phosphosites on the NLRP1 disordered linker, including a common essential TZ motif. In addition, we show that TAK1 and ZAK are jointly responsible for NLRP1 linker phosphorylation and activation caused by dsRNA and CHIKV infection. These findings reveal medically relevant insect toxins as activators of NLRP1, and uncover parallel MAP3 kinase pathways as converging upstream activating signals for the human NLRP1 inflammasome. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=172 HEIGHT=200 SRC="FIGDIR/small/701189v1_ufig1.gif" ALT="Figure 1000"> View larger version (50K): org.highwire.dtl.DTLVardef@ee34b9org.highwire.dtl.DTLVardef@c79ec9org.highwire.dtl.DTLVardef@189c373org.highwire.dtl.DTLVardef@17ec853_HPS_FORMAT_FIGEXP M_FIG C_FIG KEY POINTSTwo dermatitis-causing beetle species induce NLRP1-driven pyroptosis of human keratinocytes Rove beetles, likely via pederin, activate NLRP1 via ribosome inhibition and ZAK[a]-driven RSR Cantharidin from blister beetles activates human via TAK1-, instead of ZAK[a]-driven hyperphosphorylation of the NLRP1 linker region Shared phosphosites by TAK1 and ZAK[a] on NLRP1 contribute to dsRNA-driven NLRP1 activation

immunology↗

bioRxiv2025

Large-scale skin metagenomics reveals extensive prevalence, coordination, and functional adaptation of skin microbiome dermotypes across body sites

While skin microbiome studies have increasingly highlighted its importance in health and disease, our understanding of inter-individual heterogeneity in structure and function remains limited, impacting the ability to develop microbiome-based stratification and therapeutics. Powered by comprehensive skin microbiome characterization in a multi-ethnic population-based cohort (>3,550 shotgun metagenomes across 18 sampling sites), we established significant undescribed inter-individual heterogeneity and the extensive prevalence of distinct microbial configurations (17 species-resolution dermotypes) in seven out of nine body sites. Combining functional in silico and in vitro studies revealed insights into how these dermotypes assemble as a function of niche-dependent microbial interactions (e.g. hypoxia-dependent inhibition of S. hominis by S. epidermidis/M. luteus) and metabolic resource utilization (e.g. differential galactose and histidine metabolism). Integration of demographic, skin physiological, and behavioral data further identified >30 significant associations with host attributes. Cross-site analysis revealed remarkable coordination across disparate skin regions (predictive AUC-ROC>0.8) and bilateral consistency (Pearson {pi}>0.95), emphasizing the role of specific microbial and host factors in shaping dermotypes. Finally, we provide multiple lines of evidence that dermotype states impact the risk for skin discomfort (e.g. irritation, itch) and diseases (e.g. eczema), that when combined with our highly accurate dermotype classifiers (AUC-ROC>0.98), provide a new paradigm for understanding skin microbiome function and stratifying patients in the context of skin and other diseases.

genomics↗

bioRxiv2024

Skin metatranscriptomics reveals landscape of variation in microbial activity and gene expression across the human body

The skin microbiome plays an important role in immune homeostasis and skin health, and yet our understanding of in vivo microbial gene activity is hindered by the lack of a robust, non-invasive protocol for metatranscriptomics across skin sites. Circumventing the challenges of low microbial biomass, host contamination, and RNA stability, we developed a clinically tractable skin metatranscriptomics workflow that provides high technical reproducibility of profiles (Pearson r>0.95), uniform coverage across gene bodies, and strong enrichment of microbial mRNAs (2.5-40x). Applying this protocol to a cohort of healthy adults (n=27) across five different skin sites (n=102, paired metatranscriptomes and metagenomes), identified a striking divergence between transcriptomic and genomic abundances, with Staphylococcus species and the skin fungi Malassezia having an outsized contribution to the metatranscriptomic landscape at most sites despite their modest representation in metagenomes. Species-level analysis showed skin site-specific enrichment of gene expression (e.g. increased levels of secreted fungal phospholipase C on cheeks relative to scalp), and revealed how key pathways were transcriptionally active in vivo (e.g. propionate and 4-aminobutyrate metabolism, potentially impacting skin barrier function). Gene-level analysis identified diverse antimicrobial genes transcribed by skin commensals in situ, including several uncharacterized bacteriocins, some of which are expressed at levels comparable to known antimicrobial genes. Correlation of microbial gene expression with organismal abundances uncovered >20 genes that putatively mediate interactions between microbes (e.g. a secreted Malassezia restricta protein with strongly negative in vivo association with Cutibacterium acnes; Spearman {rho}>0.7). This work showcases the potential for leveraging skin metatranscriptomics to identify microbes whose activities play an outsized role in the community, and for uncovering pivotal microbial pathways and biomarkers linked to skin health and disease.

genomics↗

bioRxiv2024

Life stage impact on the human skin ecosystem: lipids and the microbial community

While research into gut-microbe interactions is common and advanced, with multiple defined impacts on human health, studies exploring the significance of skin-microbe interactions remain underrepresented. Skin is the largest human organ, has a vast surface area, and is inhabited by a plethora of microorganisms which metabolise sebaceous lipids. Sebaceous free fatty acids are metabolized into bioactive lipid mediators with immune-modulatory properties by skin-resident microbes, including Malassezia. Intriguingly, many of the same lipid mediators are also found on human skin, implying these compounds may have microbial or mixed microbial/human origin. To support this hypothesis, we isolated lipids and microbial DNA from the skin of prepubescent, adult, pre- and post-menopausal volunteers and performed correlational analyses using skin lipidomics and metagenomics to compare lipid mediator profiles and microbiome compositions on skin with either low or high sebaceous gland activity. We found that specific microbial taxonomies were positively and negatively correlated with skin lipid mediator species with high statistical significance. 2D in vitro co-cultures with Malassezia and keratinocytes also directly linked the production of specific lipid mediators, detected on healthy human skin, to secretion of immuno-stimulatory cytokines. Together, these findings further support the hypothesis that microbial-derived skin lipid mediators influence healthy skin homeostasis and skin disease development and progression, thereby spotlighting the relevance of the skin microbiomes footprint on human health.

microbiology↗