The Role of the Oral Immune System in Oropharyngeal Candidiasis-Facilitated Invasion and Dissemination of Staphylococcus aureus

Abstract

Candida albicans and Staphylococcus aureus account for most invasive fungal and bacterial bloodstream infections (BSIs), respectively. However, the initial point of invasion responsible for S. aureus BSIs is often unclear. Recently, C. albicans has been proposed to mediate S. aureus invasion of immunocompromised hosts during co-colonization of oral mucosal surfaces. The status of the oral immune system crucially contributes to this process in two distinct ways: firstly, by allowing invasive C. albicans growth during dysfunction of extra-epithelial immunity, and secondly following invasion by some remaining function of intra-epithelial immunity. Immunocompromised individuals at risk of developing invasive oral C. albicans infections could, therefore, also be at risk of contracting concordant S. aureus BSIs. Considering the crucial contribution of both oral immune function and dysfunction, the aim of this review is to provide an overview of relevant aspects of intra and extra-epithelial oral immunity and discuss predominant immune deficiencies expected to facilitate C. albicans induced S. aureus BSIs.

Keywords: Candida albicans; Staphylococcus aureus; bloodstream infection (BSI); immunocompromised; oral.

Figure 1

Graphical overview of the intricate interplay between the oral immune system and C. albicans/S. aureus infections. C. albicans first adheres to the oral epithelium, starts propagating and initiates hyphal growth. Extra-epithelial antimicrobial proteins, AMPs, complement factors and neutrophils limit pathogenic overgrowth and tissue invasion. Hyphal invasion, induced tissue damage and candidalysin induce a cascade of intra-epithelial immune reactions. Dendritic cells are able to take up and present pathogenic antigens to naïve T cells in the cervical lymph nodes which, together with IL-1, IL-6 and IL-23, stimulate Th17 differentiation. Simultaneously, oral EC produce IL-1α, IL-1β and IL-36 to activate other type 17 cells. Together, the activated type 17 cells start producing IL-17, IL-22 and IFN-γ. IL-17 and IL-22 sequentially trigger the corresponding receptors on oral ECs and stimulate the production/secretion of both AMPs (also by salivary glands) and chemokines plus aid in the repair of damaged barrier areas. Secreted chemokines attract more neutrophils and macrophages to the site of infection and stimulate their activation. Neutrophils and macrophages phagocytose and break down C. albicans yeast cells, hyphal fragments and S. aureus cells besides which they produce various cytokines and chemokines to further stimulate phagocyte attraction and activation. Phagocyte attraction and activation is also stimulated by candidal and staphylococcal activated NK cells. Neutrophils respond to activation by phagocytosing and killing the threat when possible, producing NETs, secreting granular components and utilizing ROS. Additionally, neutrophils have been found able to prime/activate T cells and APCs besides which they are able to produce extra cytokines and chemokines to stimulate Th17 differentiation and further neutrophil attraction/activation. This positive feedback loop continues until the microbial threat has been eliminated.

Figure 2

Graphical summary regarding (A) the attraction of macrophages and neutrophils toward C. albicans hyphae which sequentially are scavenged for parts/attached microbes that can be phagocytosed. (B) Once phagocytosed by macrophages, the phagosome containing S. aureus will be fused with a lysosome to form a phagolysosome that utilizes ROS, RNS, acidity, degrading enzymes and AMPs to eliminate the phagocytosed threat. In response to phagocytosing S. aureus, macrophages can produce METs and secrete pro-inflammatory cytokines/chemokines which help attract/activate T cells, NK cells, dendritic cells and neutrophils. (C) Once phagocytosed by neutrophils, granules start fusing with the phagosome during a process deemed degranulation and utilize various kinds of ROS, degrading enzymes and AMPs to eliminate the phagocytosed threat. In response to phagocytosis/activation, neutrophils can produce NETs and secrete granules plus pro-inflammatory cytokines/chemokines. (D) S. aureus has developed numerous ways to inhibit phagocytic killing by macrophages and neutrophils rendering it able to survive the harsh phagosomal/phagolysosomal environment, propagate, and kill the concerning phagocyte. Released staphylococcal cells can, thereafter, be phagocytosed to repeat the process. This misemployment of phagocytes could aid S. aureus dissemination to various other body sites and initiate lethal infection.