Unveiling the pathogenic mechanisms of Clostridium perfringens toxins and virulence factors

Abstract

Clostridium perfringens causes multiple diseases in humans and animals. Its pathogenic effect is supported by a broad and heterogeneous arsenal of toxins and other virulence factors associated with a specific host tropism. Molecular approaches have indicated that most C. perfringens toxins produce membrane pores, leading to osmotic cell disruption and apoptosis. However, identifying mechanisms involved in cell tropism and selective toxicity effects should be studied more. The differential presence and polymorphisms of toxin-encoding genes and genes encoding other virulence factors suggest that molecular mechanisms might exist associated with host preference, receptor binding, and impact on the host; however, this information has not been reviewed in detail. Therefore, this review aims to clarify the current state of knowledge on the structural features and mechanisms of action of the major toxins and virulence factors of C. perfringens and discuss the impact of genetic diversity of toxinotypes in tropism for several hosts.

Keywords: Clostridium perfringens; toxin type; enteritis; genetic diversity; host; toxinotypes.

Figure 1.

Schematic representation showing domain structure of Clostridium pefringens main toxins (A). CPA toxin (B). CPB toxin (C). ETX toxin (D). ITX toxin (E). CPE toxin and (F). NetB toxin are shown. Numbers indicate amino acids that mark domain boundaries.

Figure 2.

Action mechanisms of the primary C. perfringens toxins used for toxin typing. Molecular mechanism of action of the major toxins of C. perfringens. (A). CPA toxin: CPA toxin interacts with GM1a, hydrolysing phosphatidylcholine (PC) and sphingomyelin (SM), resulting in the formation of diacylglycerol (DAG) and ceramide (CER) with Tropomyosin kinase A receptor (TrKA) activation and triggers the activation of an intracellular signalling cascade with Interleukin - 8 (IL-8) release. The activation of phosphatidyl inositol 3 (IP3) promotes intracytoplasmic calcium (Ca⁺) entry (B). CPB toxin: CPB binds to platelet endothelial cell adhesion molecule-1 (PECAM-1) with subsequent release of adenosine triphosphate (ATP) and formation of pores that allow ion exchange to and from the cell (C). ETX toxin: ETX toxin interacts with protein “myelin and lymphocytes” (MAL), forming an active pore that induces ion transport and exchange across the cell membrane (D). ITX toxin: The binding of Ib to the lipolysis-stimulated lipoprotein receptor (LSR) receptor mediates its entry into the host cell, promoting the formation of channels for the entry of Ia by endocytosis with subsequent depolymerization of actin filaments, generating morphological changes and alteration of cell permeability (E). CPE toxin: the CPE toxin binds to claudin receptors, contributing to the formation of a pore on the cell surface with ion exchange and osmotic imbalance. (F). NetB toxin recognizes cholesterol-free regions in cell membranes by forming heptameric hydrophilic pores that allow the entry of ions such as Na⁺, Cl^- y, and Ca 2⁺.

Figure 3.

Schematic representation of principal hosts for each C. perfringens toxinotypes – each box representing a different toxinotype.