Abstract
The anaerobic bacterium Clostridium perfringens expresses multiple toxins that promote disease development in both humans and animals. One such toxin is perfringolysin O (PFO, classically referred to as θ toxin), a pore-forming cholesterol-dependent cytolysin (CDC). PFO is secreted as a water-soluble monomer that recognizes and binds membranes via cholesterol. Membrane-bound monomers undergo structural changes that culminate in the formation of an oligomerized prepore complex on the membrane surface. The prepore then undergoes conversion into the bilayer-spanning pore measuring approximately 250–300 Å in diameter. PFO is expressed in nearly all identified C. perfringens strains and harbors interesting traits that suggest a potential undefined role for PFO in disease development. Research has demonstrated a role for PFO in gas gangrene progression and bovine necrohemorrhagic enteritis, but there is limited data available to determine if PFO also functions in additional disease presentations caused by C. perfringens. This review summarizes the known structural and functional characteristics of PFO, while highlighting recent insights into the potential contributions of PFO to disease pathogenesis.
Highlights
Clostridium perfringens is an anaerobic, spore-forming Gram-positive bacterium often found as a normal inhabitant of animal and human intestines [1,2,3]
perfringolysin O (PFO) contains a typical signal peptide that facilitates its secretion by the general secretory pathway (GSP), which results in an extracellular water-soluble monomer [10,24]
Wade et al [72] recently showed that the rotation of β5 away from the core β-sheet in D3 allows the formation of a strong intermolecular electrostatic interaction, which drives the transition from the prepore to the pore by providing the free energy necessary to disrupt the interface between D3 and domain 1 (D1),2
Summary
Clostridium perfringens is an anaerobic, spore-forming Gram-positive bacterium often found as a normal inhabitant of animal and human intestines [1,2,3]. The PFO pore-forming mechanism has been well studied, leading to several insights into the PFO structure and function. The role of PFO in disease development is not often evaluated in pathogenesis models, despite the fact that PFO harbors characteristics that suggest a more important role in animal and human diseases than previously thought. We present an overview of the known characteristics of PFO and hypothesize about PFO contributions to the pathology of animal and human diseases. Similar toxins have been identified in Streptococcus, Bacillus, Listeria and many other genera These CDCs share a high degree of primary structural homology. PFO is viewed as the archetype CDC, and data presented in this review for PFO can be partially extrapolated to other CDCs and provide the basis for a general CDC pore-forming mechanism [10]
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