Intracellular escape strategies of Staphylococcus aureus in persistent cutaneous infections

Abstract

Pathogenic invasion of Staphylococcus aureus is a major concern in patients with chronic skin diseases like atopic dermatitis (AD), epidermolysis bullosa (EB), or chronic diabetic foot and venous leg ulcers, and can result in persistent and life-threatening chronic non-healing wounds. Staphylococcus aureus is generally recognized as extracellular pathogens. However, S. aureus can also invade, hide and persist in skin cells to contribute to wound chronicity. The intracellular life cycle of S. aureus is currently incompletely understood, although published studies indicate that its intracellular escape strategies play an important role in persistent cutaneous infections. This review provides current scientific knowledge about the intracellular life cycle of S. aureus in skin cells, which can be classified into professional and non-professional antigen-presenting cells, and its strategies to escape adaptive defense mechanisms. First, we discuss phenotypic switch of S. aureus, which affects intracellular routing and degradation. This review also evaluates potential intracellular escape mechanism of S. aureus to avoid intracellular degradation and antigen presentation, preventing an immune response. Furthermore, we discuss potential drug targets that can interfere with the intracellular life cycle of S. aureus. Taken together, this review aimed to increase scientific understanding about the intracellular life cycle of S. aureus into skin cells and its strategies to evade the host immune response, information that is crucial to reduce pathogenic invasion and life-threatening persistence of S. aureus in chronic cutaneous infections.

Keywords: Staphylococcus aureus; antigen-presenting cells; intracellular bacteria; skin; wounds.

FIGURE 1

(A) Difference between wild-type cytotoxic agr-positive and small colony variants (SCV)-like dormant agr-deficient Staphylococcus aureus colonies. (B) Intracellular routing of S. aureus wild-type cytotoxic agr-positive and SCV-like dormant agr-deficient S. aureus colonies

FIGURE 2

Activation of different T-cell populations through different pathways of antigen presentation. After host cell internalization, Staphylococcus aureus generally route through the phagosomal degradation pathway that, under normal circumstances, terminates into a highly degradative organelle with a low pH, the phagolysosome. 1) To circumvent lysosomal degradation, S. aureus can adapt to a low pH tolerant small colony variants (SCV)-like phenotype. 2) Staphylococcus aureus can also hide in autophagosomes where it prevents fusion with lysosomes preventing degradation and presentation on major histocompatibility complex (MHC) class II molecules. 3) Staphylococcus aureus that end up in the cytosol are ubiquitinated but not targeted for proteasomal degradation and subsequent MHC class I presentation escaping a cytotoxic T-cell response. 4) Staphylococcus aureus can also manipulate the expression of co-stimulatory molecules preventing an effective T-cell response

FIGURE 3

Potential antigen-presenting cells (APCs) that are present in the skin. When the skin barrier is disrupted, Staphylococcus aureus can colonize the open wound and become pathogenic. Professional APCs, such as macrophages, Langerhans cells, dendritic cells and B cells, can internalize and process S. aureus peptide fragments in lysosomes. Generated peptide fragments can be loaded onto major histocompatibility complex (MHC) class II molecules. Non-professional APCs, such as keratinocytes, fibroblasts and endothelial cells, also have the capacity to internalize and process peptide fragments of S. aureus. These cells activate their autophagy machinery as their lysosomal degradation capacity is limited. APC rely on Perforin-2–mediated kill of intracellular pathogens