Severn, M. | bioRxiv Science

bioRxiv2026

Infection and sensitization reveal stimulus-specific immune remodeling in aged skin

Aging is associated with progressive declines in skin barrier integrity and immune protection, contributing to increased susceptibility to bacterial and viral skin infections in older adults. However, how aged skin senses and responds to infection or barrier disruption remains poorly defined. Here, we characterized the age-associated cutaneous immune response to epicutaneous Staphylococcus (S.) aureus infection and ovalbumin-induced sensitization in mouse models. Bulk RNA-seq of infected tissue showed that transcriptional variation was primarily driven by infection, not age, suggesting that aged skin retains a broadly inducible response to microbial challenge. In contrast, microneedle patch (MNP) sampling of skin interstitial fluid, which provides cellular resolution, revealed age-dependent differences in local immune dynamics after S. aureus infection, including altered magnitude and kinetics of cellular recruitment, such as an attenuated cutaneous T cell response in older mice. MNP profiling further showed that ovalbumin sensitization elicited a localized immune program distinct from the S. aureus response, which was incompletely reflected in systemic measurements. Together, these data demonstrate that aging does not uniformly impair cutaneous immunity but instead is a context-dependent remodeling of local tissue immune dynamics.

microbiology↗

bioRxiv2026

Species and strain diversity in Staphylococcus drive divergent host responses in human skin

The skin microbiome regulates key skin processes, yet the functional diversity of a dominant genus, Staphylococcus, remains poorly resolved at the strain level for multiple species across its pathogenic and commensal continuum. It is likely that Staphylococcus effects on skin are diverse at these finest taxonomic resolutions, but current skin models lack the physiological relevance and scalability needed to profile this diversity. Using an organotypic 3D human skin model (reconstructed human epidermis, RHE), we profiled skin responses to 187 Staphylococcus strains across seven dominant species. Canonically pathogenic species (e.g., S. aureus) induced broad inflammatory responses, whereas prototypical commensal species (e.g., S. hominis) elicited more nuanced effects on innate immune and skin barrier responses. Strikingly, S. epidermidis displayed pronounced strain-level heterogeneity, with subsets inducing either commensal or pathogen-like responses despite lacking canonical virulence factors, suggesting pleiotropic effects. Comparative genomics, dual-transcriptomics, untargeted metabolomics, and growth phenotyping revealed species- and strain-specific traits underlying these differential effects on RHE, including the presence of select cell surface proteins and differential arginine metabolism. Together, our study provides the first high-throughput, species- and strain-resolved analysis of skin-Staphylococcus interactions, offering mechanistic insights and a platform for microbiome-based strategies to modulate skin inflammation and diseases. One-line summaryHigh-throughput profiling of Staphylococcus in a human skin model shows that species- and strain-level diversity underlies a continuum of host barrier and immune responses.

microbiology↗