Role of pore-forming toxins in bacterial infectious diseases

Abstract

Pore-forming toxins (PFTs) are the most common bacterial cytotoxic proteins and are required for virulence in a large number of important pathogens, including Streptococcus pneumoniae, group A and B streptococci, Staphylococcus aureus, Escherichia coli, and Mycobacterium tuberculosis. PFTs generally disrupt host cell membranes, but they can have additional effects independent of pore formation. Substantial effort has been devoted to understanding the molecular mechanisms underlying the functions of certain model PFTs. Likewise, specific host pathways mediating survival and immune responses in the face of toxin-mediated cellular damage have been delineated. However, less is known about the overall functions of PFTs during infection in vivo. This review focuses on common themes in the area of PFT biology, with an emphasis on studies addressing the roles of PFTs in in vivo and ex vivo models of colonization or infection. Common functions of PFTs include disruption of epithelial barrier function and evasion of host immune responses, which contribute to bacterial growth and spreading. The widespread nature of PFTs make this group of toxins an attractive target for the development of new virulence-targeted therapies that may have broad activity against human pathogens.

Fig 1

Generalized mechanism of pore formation by PFTs. Soluble PFTs bind membrane receptors, which leads to oligomerization and insertion of an aqueous pore into the plasma membrane (5). Note that during the oligomerization step, some PFTs remain associated with their receptor, whereas others have already disassociated at this point.

Fig 2

Protein structures of various PFT classes. (A and B) Structures of a single molecule (A) and an assembled pore (B) of the E. coli α-PFT HlyE (295, 296) (Protein Data Bank [PDB] accession number 1QOY). (C) Structure of aerolysin, a β-PFT produced by A. hydrophila (485) (PDB accession number 1PRE). (D) PFO monomer (83) (PDB accession number 1PFO). (E) Hypothetical arrangement of CDC monomers into an assembled pore. This image was created by mapping PFO monomers onto a PLY cryo-electron microscopy (cryo-EM) image (180) (PDB accession number 2BK1). Structures were visualized using PyMOL (D) or MMDB (486) (A to C and E).

Fig 3

Overview of global in vivo effects of PFTs. Note that not all pathways are relevant to all toxins and hosts.

Fig 4

Overview of host pathways that are activated by PFTs. Note that not all pathways are relevant to all toxins and hosts.