Histotoxic Clostridial Infections

Abstract

The pathogenesis of clostridial myonecrosis or gas gangrene involves an interruption to the blood supply to the infected tissues, often via a traumatic wound, anaerobic growth of the infecting clostridial cells, the production of extracellular toxins, and toxin-mediated cell and tissue damage. This review focuses on host-pathogen interactions in Clostridium perfringens-mediated and Clostridium septicum-mediated myonecrosis. The major toxins involved are C. perfringens α-toxin, which has phospholipase C and sphingomyelinase activity, and C. septicum α-toxin, a β-pore-forming toxin that belongs to the aerolysin family. Although these toxins are cytotoxic, their effects on host cells are quite complex, with a range of intracellular cell signaling pathways induced by their action on host cell membranes.

FIGURE 1

Structure of α-toxin. The structure of α-toxin was obtained from the Protein Data Bank (code 1QM6) and was created using MacPyMOL. A ribbon representation is shown, colored from blue (N-terminal) to red (C-terminal). Two zinc metal ions in the active site are shown as red spheres.

FIGURE 2

Binding model of α-toxin and membrane phospholipids. The structure of α-toxin was obtained from the Protein Data Bank (code 1QM6) and was created using MacPyMOL. Phospholipids are shown as light gray spheres for head groups and light gray lines for tail groups. The head group of a phospholipid, from the outer membrane into the active site of α-toxin, is displayed. Amino acids that may play a role in membrane interaction are shown.

FIGURE 3

Relationship between phospholipid metabolism and the biological activities of α-toxin. (A) Signaling events involved in α-toxin-induced hemolysis of sheep or rabbit erythrocytes. (B) Signaling events involved in α-toxin-activated generation of O₂^– in neutrophils and in α-toxin-mediated release of IL-8 from A549 cells. Abbreviations: SM, sphingomyelin; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; DG, diacylglycerol; PC, phosphatidylcholine; SMase, sphingomyelinase; PLD, phospholipase D; PA, phosphatidic acid; PKCθ, protein kinase Cθ; PI3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol 3,4,5-trisphosphate; CDase, ceramidase; CER, ceramide; SPH, sphingosine; S1P, sphingosine 1-phosphate; DGK, DG kinase; PDK1, phosphatidylinositide dependent kinase 1; DRM, detergent-resistant membrane; TrkA, neurotrophic tyrosine kinase receptor type1; MAPKK, mitogen-activated protein kinase kinase; Erk1/2, extracellular signal-regulated kinase 1/2.

FIGURE 4

Model of α-toxin-induced membrane dynamics and clustering of the GM1a and TrkA complex. α-Toxin binds to GM1a and, through the phospholipase C activity of the toxin itself, causes diacylglycerol (DG) production at the outer membrane. The flip-flop movement of DG affects membrane dynamics, facilitating clustering of GM1a and TrkA activation by phosphorylation. Activation of TrkA results in the activation of PLCγ-1, leading to the increased production of DG. Finally, DG formation results in the enhanced activation of TrkA, triggering activation of signal transduction pathways, which induce neutrophil activation. Abbreviations: PIP₂, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; DG, diacylglycerol; PC, phosphatidylcholine; TrkA, neurotrophic tyrosine kinase receptor type 1.

FIGURE 5

Inhibition of granulopoiesis and erythropoiesis in a C. perfringens-infected host. Infection with C. perfringens diminishes mature hematopoietic cells in the bone marrow, leading to impairment of replenishment of differentiated neutrophils and erythrocytes in the peripheral circulation and resulting in host innate immune deficiency. The major virulence factor of C. perfringens, α-toxin, plays an important role in this phenomenon by interfering with cell differentiation of myeloblasts and erythroblasts.

FIGURE 6

Structure of perfringolysin O. The structure of perfringolysin O was obtained from the Protein Data Bank (code 1PFO) and was created using MacPyMOL. A ribbon representation is shown, colored from blue (N-terminal) to red (C-terminal).

FIGURE 7

Crystal structure of aerolysin and molecular model of C. septicum α-toxin. Domains are indicated. Note that domain 1 (D1) of aerolysin is not present in α-toxin. AT, C. septicum α-toxin. Reprinted with permission from reference . Copyright (2006) American Chemical Society.