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Abstract
Bacterial infectious diseases are a leading cause of death. Pore-forming toxins (PFTs) are important virulence factors of Gram-positive pathogens, which disrupt the plasma membrane of host cells and can lead to cell death. Yet, host defense and cell membrane repair mechanisms have been identified: i.e., PFTs can be eliminated from membranes as microvesicles, thus limiting the extent of cell damage. Released into an inflammatory environment, these host-derived PFTs-carrying microvesicles encounter innate immune cells as first-line defenders. This study investigated the impact of microvesicle- or liposome-sequestered PFTs on human macrophage polarization in vitro. We show that microvesicle-sequestered PFTs are phagocytosed by macrophages and induce their polarization into a novel CD14+MHCIIlowCD86low phenotype. Macrophages polarized in this way exhibit an enhanced response to Gram-positive bacterial ligands and a blunted response to Gram-negative ligands. Liposomes, which were recently shown to sequester PFTs and so protect mice from lethal bacterial infections, show the same effect on macrophage polarization in analogy to host-derived microvesicles. This novel type of polarized macrophage exhibits an enhanced response to Gram-positive bacterial ligands. The specific recognition of their cargo might be of advantage in the efficiency of targeted bacterial clearance.
Highlights
During infection, membrane damaging toxins are released by numerous bacterial pathogens and contribute significantly to their virulence [1]
In contrast to the pro-inflammatory signature, these macrophages showed a downregulation of MHCII and co-stimulatory receptor CD86, which is attributed to M2-polarization (Figure S1 in Supplementary Material)
We show that inactive Pore-forming toxins (PFTs), sequestered by liposomes or shed on microvesicles during membrane repair processes, polarize macrophages to enhance responses to Gram-positive pathogen-associated molecular patterns (PAMPs)
Summary
Membrane damaging toxins are released by numerous bacterial pathogens and contribute significantly to their virulence [1]. An important family of membrane perforating toxins are the cholesterol-dependent cytolysins (CDCs) consisting of more than 20 members, which are secreted by Gram-positive bacteria. Recent work from our laboratory showed that—in response to the rise in cytoplasmic Ca2+—the annexins, members of a phospholipid-binding protein family translocate to the plasmalemma, quarantine the toxin pore within a membrane fold, which is shed into the extra cellular space [6]. By this route, PLY-pores are actively removed from epithelial cell membranes [7]. FACS analysis and cryoelectronmicroscopy of PLY-microvesicles confirm an association of PLY-pores and annexin family members and demonstrated that 90% of the vesicles were smaller than 500 nm with a median size of 160 nm [7]
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