Host Response to Staphylococcus epidermidis Colonization and Infections

Abstract

The majority of research in the Staphylococcus field has been dedicated to the understanding of Staphylococcus aureus infections. In contrast, there is limited information on infections by coagulase-negative Staphylococci (CoNS) and how the host responds to them. S. epidermidis, a member of the coagulase-negative Staphylococci, is an important commensal organism of the human skin and mucous membranes; and there is emerging evidence of its benefit for human health in fighting off harmful microorganisms. However, S. epidermidis can cause opportunistic infections, which include particularly biofilm-associated infections on indwelling medical devices. These often can disseminate into the bloodstream; and in fact, S. epidermidis is the most frequent cause of nosocomial sepsis. The increasing use of medical implants and the dramatic shift in the patient demographic population in recent years have contributed significantly to the rise of S. epidermidis infections. Furthermore, treatment has been complicated by the emergence of antibiotic-resistant strains. Today, S. epidermidis is a major nosocomial pathogen posing significant medical and economic burdens. In this review, we present the current understanding of mechanisms of host defense against the prototypical CoNS species S. epidermidis as a commensal of the skin and mucous membranes, and during biofilm-associated infection and sepsis.

Keywords: Staphylococcus epidermidis; biofilm-associated infection; biofilms; coagulase-negative staphylococci; host defense; innate immunity; sepsis.

Figure 1

Model of the host response to S. epidermidis colonization (A) S. epidermidis colonizes the skin epidermis, a highly organized structure composed mainly of keratinocytes. In response to S. epidermidis colonization, pattern recognition receptors (PRRs) such as TLR2 on keratinocytes bind to poorly characterized factor(s) secreted by S. epidermidis to stimulate a signaling cascade that results, for example, in the production of the antimicrobial peptides β-defensin 2 (hBD2) and hBD3. These antimicrobial peptides provide protection from cutaneous S. aureus and Group A Streptococcus infections. (B) S. epidermidis colonization induces a specific CD4⁺ FOXP3⁺ T_reg response, which is essential for immune tolerance toward S. epidermidis as a commensal. Immune tolerance is believed to be established only during the neonatal period, as colonization in adult mice failed to establish tolerance. (C) In a different model, based on results obtained in adult mice, skin colonization by S. epidermidis triggers a specific IL-17A⁺ CD8⁺ T-cell response. Primed in the skin draining lymph node by CD103⁺ dendritic cells, these T cells enhance the innate antimicrobial defense and prevent invasion by the fungus, C. albicans.

Figure 2

Model of the host response to S. epidermidis infections. Breaching through the skin can result in S. epidermidis dissemination into the bloodstream to cause bacteremia and acute cases of sepsis. Host immunity against septic infections heavily depends on neutrophils, complement, as well as activation of PRRs including G-protein coupled receptors (GPCRs) such as TLR2 (green) and FPR2 (blue). Biofilm-associated infections on medical implants originate from contaminations during device insertion or, in rare cases, from the bloodstream. Patients with medical implants are susceptible to S. epidermidis sepsis, as biofilm bacteria can often disseminate into the bloodstream. The immune response to biofilm-associated infections is generally thought to be not effective, as biofilms inhibit phagocytic killing by PMNs and macrophages. In addition, they skew the immune system toward enhanced production of anti-inflammatory cytokines such as IL-13 while limiting the secretion of pro-inflammatory cytokines, including IL1-beta, IL-12, and IFN-gamma.