Biology subjects

Perez-White, B.

Publications and source records attributed to Perez-White, B..

3 recordsLinked to original sources

bioRxiv2026

SKIN AS A POTENTIAL ENTRY POINT FOR SARS-COV-2

The primary route of SARS-CoV-2 entry is via respiratory epithelium. However, many COVID-19 patients developed dermatological lesions, and SARS-CoV-2 RNA has been detected in the patients skin. Inflammatory skin diseases, psoriasis and atopic dermatitis (AD), significantly increased the risk of COVID-19. To evaluate the potential role of skin in SARS-CoV-2 host interactions, we utilized 3D human skin organoids (HSO) generated from human epidermal keratinocytes, as well as neonatal skin explants. HSO were treated with cytokines involved in acute and chronic skin inflammation and cytokine storm in severe COVID-19 disease, TNF-, IL-6, IL-1{beta}, and IFN-{gamma}, individually and in combination. HSO were also treated with Th1 (TNF- + IL-17) and Th2 (IL-4 + IL-13) cocktails inducing pro-psoriasis and pro-AD HSO changes, respectively. All individual cytokines, and especially their combinations, elevated the expression of ACE2 and TMPRSS2 at mRNA/protein levels. The Th2 induced only TMPRSS2, the Th1 predominantly induced ACE2. Topically applied Spike-pseudotyped lentiviral Tomato reporter, which binds ACE2 similarly to SARS-CoV-2, successfully infected control and cytokine-treated HSO as well as neonatal skin explants. Cytokine treatment, especially TNF- + IL-6 + IL-1{beta} + IFN-{gamma} and the Th1, significantly increased viral entry. Transcriptomic analysis further revealed partial overlap between gene expression signatures induced by Spike-mediated entry in inflamed HSO and those observed in lung tissue from COVID-19 patients, supporting the biological relevance of skin models. Together, these findings demonstrate that inflammation enhances the permissiveness of human skin to SARS-CoV-2 entry, suggesting that the skin may represent a previously underappreciated interface in viral host interactions.

immunology↗

bioRxiv2025

Failed Metabolic Adaptation to Stress Underlies Pathogenesis in a Heterozygous Genetic Disorder

Disorders linked to heterozygous variants occupy a continuum in terms of the timing and severity of phenotypic emergence. An important question regarding this variability entails the effect stress has on the residual protein function. Using Darier disease (DD), caused by heterozygous variants of the SERCA2 calcium pump, as a model, we uncovered a potential connection between extrinsic stress and pathogenesis. The skin lesions characteristic of DD entail loss of intercellular adhesion and rarely appear pre-adolescence, suggesting that factors beyond heterozygosity contribute to disease pathogenesis. Testing whether age-related stressors contribute to DD, we show that DD patient-derived keratinocytes subjected to stress yield twice the reactive oxygen species of controls, accompanied by greater disruption of intercellular adhesion. Metabolic analysis of DD cells revealed perturbation of the pentose phosphate pathway (PPP), a stress response system responsible for regenerating antioxidants like glutathione. At baseline, DD cells had less free glutathione but an increase in protective glutathione-based modifications of SERCA2, a reversible form of protein oxidation. With stress, DD cells form an aberrant, heavily glutathionylated perinuclear halo consisting of keratin and the intercellular adhesion component, desmoplakin. We propose a model whereby SERCA2 heterozygosity causes mild oxidative stress that under homeostatic conditions can be buffered by glutathionylation. When stressed, the depleted glutathione store is shunted towards the desmoplakin-intermediate filament system at the expense of SERCA2, rendering it vulnerable to damage. A lesional flare, then, would represent a case of more complete SERCA2 inhibition and a novel example of how heterozygous disorders interact with stress to disrupt intercellular adhesion.

cell biology↗

bioRxiv2024

Activation of IL1A/IRAK1 axis and downstream proinflammatory signaling in healthy adult and neonatal African American skin

Differences in prevalence of inflammatory skin diseases including atopic dermatitis and psoriasis in African American (AA) versus White Non-Hispanic (WNH) population are well recognized. However, the underlying mechanisms are largely unknown. We previously observed significant differences in healthy AA skin transcriptome with differentially expressed genes (DEG) enriched for inflammation and cornification processes. Here we analyzed proteome in skin biopsies from healthy AA and WNH volunteers using Olink(R) Explore Inflammation 384 biomarker panel. Among proteins with higher expression in AA skin were IRAK1, IL1A, IL4, IL22RA1. IL1A binding to IL1R1 receptor is known to result in recruitment of adapter molecules such as IRAK1, and activation of downstream NF-{kappa}B and MAPK signaling. We confirmed NF-{kappa}B and ERK1/2 activation in AA skin by Western blot analysis of their phosphorylation at specific activating sites. Importantly, we observed similar differences between AA and WNH neonatal foreskin and between AA and WNH 3D skin organoids. Further analysis of DEG promoters by Gene Transcription Regulation Database (GTRD) pointed to NF-{kappa}B and AP1 as key transcription factors involved in AA DEG regulation. Overall, proinflammatory signaling in healthy AA skin starting early in childhood may contribute to the increased risk of certain inflammatory skin diseases within the AA population.

immunology↗