α-Hemolysin enhancesStaphylococcus aureusinternalization and survival within mast cells by modulating the expression of β1 integrin

Abstract

Mast cells (MCs) are important sentinels of the host defence against invading pathogens. We previously reported that Staphylococcus aureus evaded the extracellular antimicrobial activities of MCs by promoting its internalization within these cells via β1 integrins. Here, we investigated the molecular mechanisms governing this process. We found that S. aureus responded to the antimicrobial mediators released by MCs by up-regulating the expression of α-hemolysin (Hla), fibronectin-binding protein A and several regulatory systems. We also found that S. aureus induced the up-regulation of β1 integrin expression on MCs and that this effect was mediated by Hla-ADAM10 (a disintegrin and metalloproteinase 10) interaction. Thus, deletion of Hla or inhibition of Hla-ADAM10 interaction significantly impaired S. aureus internalization within MCs. Furthermore, purified Hla but not the inactive HlaH35L induced up-regulation of β1 integrin expression in MCs in a dose-dependent manner. Our data support a model in which S. aureus counter-reacts the extracellular microbicidal mechanisms of MCs by increasing expression of fibronectin-binding proteins and by inducing Hla-ADAM10-mediated up-regulation of β1 integrin in MCs. The up-regulation of bacterial fibronectin-binding proteins, concomitantly with the increased expression of its receptor β1 integrin on the MCs, resulted in enhanced S. aureus internalization through the binding of fibronectin-binding proteins to integrin β1 via fibronectin.

Mast cells as protectors of health

“…45 MCs can also directly participate in bacterial killing through phagocytosis 46 or release of extracellular traps (Fig 3, A) composed of DNA, histones, and MC-specific granule proteins, such as tryptase and cathelin-related antimicrobial peptide (CRAMP)/LL-37, where pathogens are captured and killed. 39,44,[47][48][49] However, some pathogens have evolved sophisticated strategies to counteract the antimicrobial activities of MCs. 44,48,50,51 In this regard it has been reported that Escherichia coli can evade MC phagocytic killing by entering into a compartment within the MC that bypasses phagolysosomal fusion and facilitates bacterial survival.…”

Regulation of the pleiotropic effects of tissue-resident mast cells

“…Furthermore, some bacterial strains can enter MCs and thereby protect themselves from immune attack, although at least some of the bacteria, such as Staphylococcus aureus, will be destroyed intracellularly. 179,180 The pathogenic fungus Candida albicans is found on mucosa and thus at a site prominently populated by MCs. The contribution of MCs to defense against Candida albicans is controversial because some authors suggest that MCs primarily fight the fungi through extracellular means, 181 whereas others describe phagocytotic killing of the fungus.…”

Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

“…A recent study found that S. aureus that survive within phagocytes serve as a reservoir of infection during systemic disease, resulting in increased bacterial outgrowth and reduced host survival [183]. Hla- induced changes in intracellular signaling causes increased β1-integrin surface expression and subsequent phagocytosis, allowing bacteria to escape the extracellular-bactericidal functions of mast cells [184, 185]. In addition, the LukAB receptor CD11b is a component of CR3, a receptor that detects C3bi opsonization or pathogen-associated molecular patters (PAMPs) to induce phagocytosis and signaling [186].…”