Human Three-Dimensional Models for Studying Skin Pathogens.

Skin is the most exposed surface of the human body, separating the microbe-rich external environment, from the sterile inner part. When skin is breached or its homeostasis is perturbed, bacterial, fungal and viral pathogens can cause local infections or use the skin as an entry site to spread to other organs. In the last decades, it has become clear that skin provides niches for permanent microbial colonization, and it actively interacts with microorganisms. This crosstalk promotes skin homeostasis and immune maturation, preventing expansion of harmful organisms. Skin commensals, however, are often found to be skin most prevalent and dangerous pathogens. Despite the medical interest, mechanisms of colonization and invasion for most skin pathogens are poorly understood. This limitation is due to the lack of reliable skin models. Indeed, animal models do not adequately mimic neither the anatomy nor the immune response of human skin. Human 3D skin models overcome these limitations and can provide new insights into the molecular mechanisms of microbial pathogenesis. Herein, we address the strengths and weaknesses of different types of human skin models and we review the main findings obtained using these models to study skin pathogens.

Staphylococcus aureus-Specific Tissue-Resident Memory CD4+ T Cells Are Abundant in Healthy Human Skin.

The skin is an immunocompetent tissue that harbors several kinds of immune cells and a plethora of commensal microbes constituting the skin microbiome. Staphylococcus aureus is a prominent skin pathogen that colonizes a large proportion of the human population. We currently have an incomplete understanding of the correlates of protection against S. aureus infection, however genetic and experimental evidence has shown that CD4+ T cells play a key role in orchestrating a protective anti-S. aureus immune response. A high S. aureus-specific memory CD4+ T cell response has been reported in the blood of healthy subjects. Since T cells are more abundant in the skin than in blood, we hypothesized that S. aureus-specific CD4+ T cells could be present in the skin of healthy individuals. Indeed, we observed proliferation of tissue-resident memory CD4+ T cells and production of IL-17A, IL-22, IFN-γ and TNF-ß by cells isolated from abdominal skin explants in response to heat-killed S. aureus. Remarkably, these cytokines were produced also during an ex vivo epicutaneous S. aureus infection of human skin explants. These findings highlight the importance of tissue-resident memory CD4+ T cells present at barrier sites such as the skin, a primary entry site for S. aureus. Further phenotypical and functional characterization of these cells will ultimately aid in the development of novel vaccine strategies against this elusive pathogen.