Skin immunity in protection against Staphylococcus aureus infections

Abstract

Gram-positive bacterium Staphylococcus aureus is a common member of the human microbiome colonizing up to 30% of the population. Mostly residing in the nares and on the skin S. aureus is a leading cause of surgical site infections and skin infections. Treatment of infections is hampered by the continuous emergence of antimicrobial resistance, most prominently methicillin-resistant S. aureus and vancomycin-resistant S. aureus. Understanding the molecular mechanisms underlying different S. aureus infections will support the development of new treatment strategies including vaccines.

The skin is the most extensive outer surface of the human body and constitutes a harsh, nutrient-poor, acidic and dry landscape. Especially the epidermis is exposed to the external environment through colonization with a heterogeneous community of microbes—the skin microbiota. Skin is not only a habitat for beneficial microorganisms but also a common entry point for pathogens; bacteria, fungi, viruses and parasites can enter the body when the cutaneous barrier is breached, for example by minor abrasions, an injury, or a surgical incision. Overall, skin and soft tissue infections (SSTIs) represent a heterogeneous group of clinical conditions affecting the skin and underlying tissues. SSTIs represent the most common S. aureus infections. Despite the high burden of skin infections in the population, the molecular mechanisms mediating the entry of most pathogens through the skin and the immune defense mechanisms are still poorly understood. Defense against S. aureus infection requires the contribution of both innate and adaptive arms of the immune system. Understanding which bacterial molecules are important for the S. aureus recognition by dendritic cells (DCs) could represent an important factor in vaccine design, especially in the context of formation of T cell memory responses. In the first part of my thesis I described a new interaction between C-Type Lectin Receptors (CLRs) and S. aureus and how this impacted proinflammatory responses. Next, I investigated preexisting memory T cell responses towards S. aureus in the skin and blood of healthy individuals. In Chapter 2, I describe the impact of Wall Teichoic Acid (WTA) glycosylation on the recognition of S. aureus isolates from the ST395 lineage by monocyte-derived dendritic cells (moDCs). I discovered that the CLR Macrophage Galactose-Type C-Type Lectin receptor (MGL) detects these particular isolates through interaction with the GalNAc-attached glycan moiety attached to GroP-WTA. Chapter 3 describes the adaptive responses towards S. aureus in the skin of healthy subjects. S. aureus-specific skin-resident memory T cells (Tsrm) were identified in cell suspensions prepared from healthy human skin. Chapter 4 is dedicated to identification of S. aureus-specific CD4+ T cells in the blood of healthy subjects. Based on activation induced markers (AIM) S. aureus-specific CD4+ T cells were single-cell sorted for further analysed by mRNA-sequencing. Preliminary results show presence of cytotoxic (CTL) and regulatory (Treg) CD4+ T cells specific for S. aureus. In addition, comparison of expression profiles of skin-tropic cells expressing Cutaneous Lymphocyte Associated (CLA) antigen versus CLA-, non-skin homing cells, revealed high frequency of regulatory T cells in the CLA+ population.