Ca²⁺-dependent repair of pneumolysin pores: A new paradigm for host cellular defense against bacterial pore-forming toxins.

Pneumolysin (PLY), a key virulence factor of Streptococcus pneumoniae, permeabilizes eukaryotic cells by forming large trans-membrane pores. PLY imposes a puzzling multitude of diverse, often mutually excluding actions on eukaryotic cells. Whereas cytotoxicity of PLY can be directly attributed to the pore-mediated effects, mechanisms that are responsible for the PLY-induced activation of host cells are poorly understood.

Dealing with damage: plasma membrane repair mechanisms.

Eukaryotic cells have developed repair mechanisms, which allow them to reseal their membrane in order to prevent the efflux of cytoplasmic constituents and the uncontrolled influx of calcium. After injury, the Ca(2+)-concentration gradient fulfils a dual function: it provides guidance cues for the repair machinery and directly activates the molecules, which have a repair function. Depending on the nature of injury, the morphology of the cell and the severity of injury, the membrane resealing can be effected by lysosomal exocytosis, microvesicle shedding or a combination of both.

Microvesicle shedding and lysosomal repair fulfill divergent cellular needs during the repair of streptolysin O-induced plasmalemmal damage.

Pathogenic bacteria secrete pore-forming toxins that permeabilize the plasma membrane of host cells. Nucleated cells possess protective mechanisms that repair toxin-damaged plasmalemma. Currently two putative repair scenarios are debated: either the isolation of the damaged membrane regions and their subsequent expulsion as microvesicles (shedding) or lysosome-dependent repair might allow the cell to rid itself of its toxic cargo and prevent lysis.

P2X7 receptors mediate resistance to toxin-induced cell lysis.

In the majority of cells, the integrity of the plasmalemma is recurrently compromised by mechanical or chemical stress. Serum complement or bacterial pore-forming toxins can perforate the plasma membrane provoking uncontrolled Ca(2+) influx, loss of cytoplasmic constituents and cell lysis. Plasmalemmal blebbing has previously been shown to protect cells against bacterial pore-forming toxins.

The targeting of plasmalemmal ceramide to mitochondria during apoptosis.

Ceramide is a key lipid mediator of cellular processes such as differentiation, proliferation, growth arrest and apoptosis. During apoptosis, ceramide is produced within the plasma membrane. Although recent data suggest that the generation of intracellular ceramide increases mitochondrial permeability, the source of mitochondrial ceramide remains unknown.