Mechanisms of Action and Cell Death Associated with Clostridium perfringens Toxins

Abstract

Clostridium perfringens uses its large arsenal of protein toxins to produce histotoxic, neurologic and intestinal infections in humans and animals. The major toxins involved in diseases are alpha (CPA), beta (CPB), epsilon (ETX), iota (ITX), enterotoxin (CPE), and necrotic B-like (NetB) toxins. CPA is the main virulence factor involved in gas gangrene in humans, whereas its role in animal diseases is limited and controversial. CPB is responsible for necrotizing enteritis and enterotoxemia, mostly in neonatal individuals of many animal species, including humans. ETX is the main toxin involved in enterotoxemia of sheep and goats. ITX has been implicated in cases of enteritis in rabbits and other animal species; however, its specific role in causing disease has not been proved. CPE is responsible for human food-poisoning and non-foodborne C. perfringens-mediated diarrhea. NetB is the cause of necrotic enteritis in chickens. In most cases, host–toxin interaction starts on the plasma membrane of target cells via specific receptors, resulting in the activation of intracellular pathways with a variety of effects, commonly including cell death. In general, the molecular mechanisms of cell death associated with C. perfringens toxins involve features of apoptosis, necrosis and/or necroptosis.

Amentoflavone Attenuates Clostridium perfringens Gas Gangrene by Targeting Alpha-Toxin and Perfringolysin O

“…Among them, two main toxins, alpha-toxin (CPA) and perfringolysin O (PFO), are thought to be responsible for gas gangrene pathology (Awad et al, 1995;Stevens et al, 1997). CPA (also known as phospholipase C), encoded by the cpa gene, is a typing toxin produced by all strains of C. perfringens, which can hydrolyze cell membrane phospholipids and eventually lead to cell death and immune-mediated pathology at infected sites (Navarro et al, 2018). CPA induces constriction of blood vessels, decreasing the blood supply to host tissues and producing an anaerobic environment that fosters the growth of C. perfringens (Titball et al, 1999).…”

Molecular structure and function of the carboxy‐terminus of the alpha‐toxin from Clostridium perfringens type A

“…As a single‐chain polypeptide, CPA is composed of 370 amino acids and its molecular weight is 43 kDa. It includes two functional regions, an amino‐terminus and a carboxy‐terminus, which have phospholipase C activity at the amino‐terminus (Navarro, McClane, & Uzal, ; Ochi, Oda, Nagahama, & Sakurai, ; Takehara et al, ; Verherstraeten et al, ).…”

“…As a single-chain polypeptide, CPA is composed of 370 amino acids and its molecular weight is 43 kDa. It includes two functional regions, an amino-terminus and a carboxy-terminus, which have phospholipase C activity at the amino-terminus (Navarro, McClane, & Uzal, 2018;Ochi, Oda, Nagahama, & Sakurai, 2003;Takehara et al, 2016;Verherstraeten et al, 2013). Titball, Leslie, Harvey, and Kelly (1991) and Nagahama, Mukai, Morimitsu, Ochi, and Sakurai (2002) studied the structure and function of the amino-terminus and carboxy-terminus of C. perfringens alpha-toxin, and they constructed a truncated alpha-toxin (CPA1-249).…”

Potential Therapeutic Effects of Mepacrine against Clostridium perfringens Enterotoxin in a Mouse Model of Enterotoxemia

“…␤-Hairpin loops from the N-terminal domain of CPE extend to form a ␤-barrel, which inserts into the lipid bilayer to create a pore (22). The resulting CPE oligomeric pore, named the CH-1 large complex, is cation permeable and creates a Ca 2ϩ influx into cells that triggers cell death (10,(23)(24)(25)(26)(27)(28).…”