Intracellular Staphylococcus aureus: live-in and let die

Abstract

Staphylococcus aureus uses a plethora of virulence factors to accommodate a diversity of niches in its human host. Aside from the classical manifestations of S. aureus-induced diseases, the pathogen also invades and survives within mammalian host cells.The survival strategies of the pathogen are as diverse as strains or host cell types used. S. aureus is able to replicate in the phagosome or freely in the cytoplasm of its host cells. It escapes the phagosome of professional and non-professional phagocytes, subverts autophagy, induces cell death mechanisms such as apoptosis and pyronecrosis, and even can induce anti-apoptotic programs in phagocytes. The focus of this review is to present a guide to recent research outlining the variety of intracellular fates of S. aureus.

Keywords: Staphylococcus aureus; autophagy; bacterial persistence; host cell death; phagocytosis; phagosomal escape.

FIGURE 1

A map of intracellular fates of S. aureus. (1) α₅β₁ integrins are sequestered by FnBP-dependent fibronectin cross-linking at focal adhesions. (2) Centripetal movement and loss of FAK lead to development of fibrillar adhesions, at which phagocytic cups are formed and bacteria are eventually endocytosed. (3) Assembly of α-toxin pores on the plasma membrane of host cells leads is dependent on ADAM10. α-Toxin pores are permeable for cations. Ca²⁺ has been reported to induce macroautophagy. (4a) Bacteria are disinfected by phagolysosomes or (4b) survive and grow within endosomes or (4c) in the cytoplasm after phagosomal escape. (5a) Phagosomal escape can be mediated by α-toxin in cystic fibrosis cells and (5b) also by a combination of phenol-soluble modulins and phospholipases. (6) Cytoplasmic S. aureus peptidoglycan is recognized by NOD2, which activates NFκB and results in cytokine production. (7) The mode of cell death induced by S. aureus is not completely understood. While caspase-independent cell death exists, α-toxin is capable of inducing extrinsic apoptosis. Upon alpha-toxin induced potassium efflux caspase 2 has recently been shown to lead to mitochondrial outer membrane permeabilization. (8) PVL has been reported to permeabilize mitochondrial outer membrane thereby releasing cytochrome c and thus inducing the apoptosome in a Bax-independent pathway of intrinsic apoptosis. Caspase 9 subsequently activates executioner caspases. (9) Cathepsin release from permeabilized phagosomes activates the inflammasome. Activated caspase 1 leads to IL1β maturation and inflammatory pyronecrotic cell death. (10) Toxin-permeabilized endocytic vesicles are targeted by autophagy. During autophagy an isolation membrane engulfs leaky endosomes or cytoplasmically located bacteria. Within these autophagosomes bacterial replicate and eventually escape the organelle ultimately leading to host cell death. ADAM, a metalloprotease and disintegrin; ARP2/3, actin-related protein 2 and 3; Atl, autolysin; CytC, cytochrome c; Eap, extracellular adherence protein; FAK, focal adhesion kinase; FnBP, fibronectin-binding protein; HSP, heat shock protein; IL, interleukin; NF?B, nuclear factor κB; NWASP, neural Wiskott–Aldrich syndrome protein; PAX, paxillin; SR, scavenger receptor; VCL, vinculin; WTA, wall teichoic acid.

FIGURE 2

Model of phagosomal escape by S. aureus by synergistic action of δ-toxin and β-toxin. After cleavage of sphingomyelin to ceramide and phosphocholine, δ-toxin is capable of interacting more efficiently with the outer leaflet of the eukaryotic plasma membrane. δ-Toxin accumulates in the resulting hydrophobic ceramide membrane domains and eventually permeabilizes the target membrane.