ReviewAnimal models to study the pathogenesis of human and animal Clostridium perfringens infections
Introduction
Clostridium perfringens, an anaerobic, spore-forming Gram-positive rod, can produce ∼17 toxins (McClane et al., 2006, Li et al., 2013). Four of these toxins, alpha (CPA), beta (CPB), epsilon (ETX), and iota (ITX) are used to classify this microorganism into five toxinotypes A, B, C, D and E. Most C. perfringens isolates produce, in addition to at least one of the typing toxins, other toxins including, but not limited to, enterotoxin (CPE), beta2 toxin (CPB2), NetB and TpeL (McClane et al., 2006, Li et al., 2013).
The different toxinotypes of C. perfringens produce a wide variety of diseases in both humans and animals, ranging from C. perfringens type A gas gangrene to several enterotoxemias and enteritis syndromes. All of these diseases are mediated by one or more toxins of C. perfringens (Uzal et al., 2014).
Several animal models have been used to study the role of the different toxins of C. perfringens in the pathogenesis of the infections produced by this microorganism (McDonel, 1980, Sayeed et al., 2008, Garcia et al., 2013, Li et al., 2013, Uzal et al., 2014). In particular, over the past few years, some of these animal models have been used to fulfill molecular Koch's postulates for various diseases (Awad et al., 1995, Sarker et al., 1999, McClane et al., 2006, Keyburn et al., 2008, Sayeed et al., 2008, Garcia et al., 2013). We review here the information published on the main animal models used to study the pathogenesis of C. perfringens infections, with special emphasis on those used to fulfill molecular Koch's postulates.
Section snippets
Gas gangrene
Gas gangrene, or clostridial myonecrosis, is an invasive, anaerobic infection of muscle and is characterized by extensive tissue necrosis and the production of gas (MacLennan, 1962). In humans, this infection can be divided into two types: spontaneous gangrene and traumatic gangrene. The former type is commonly caused by Clostridium septicum, while approximately 80% of the latter is caused by C. perfringens. However, other clostridia have also been associated with clostridial myonecrosis (
C. perfringens type C
C. perfringens type C isolates must produce, at the minimum, CPA and CPB (McClane et al., 2006). These strains are responsible for highly lethal enteric diseases and enterotoxemias in humans (enteritis necroticans) and in many other mammalian species. Type C disease is mainly characterized by necrotizing enteritis or enterocolitis and systemic disease. It is currently accepted that most clinical manifestations and lesions observed in patients with type C disease are a direct consequence of the
C. perfringens type D
C. perfringens type D is responsible for a highly lethal enterotoxemia in sheep, goats and other ruminants. Type D isolates produce CPA and ETX, but several toxinotype D isolates also produce several other toxins (McClane et al., 2006).
ETX is produced in the form of a relatively inactive prototoxin, which becomes fully activated when a string of 14 amino acids from the C-terminus are proteolytically removed (Minami et al., 1997). Activation of ETX in the host intestine is mediated by serine
Concluding remarks
Although significant progress has been made over the last few decades toward the understanding of C. perfringens infections in humans and animals, it was not until relatively recently that the development of reverse genetics, combined with the use of several animal models, allowed researchers to determine the importance of individual toxins in the pathogenesis and virulence of different toxinotypes and strains of this microorganism. In addition, although several animal models have been
Conflict of interest
None.
Acknowledgements
This work was supported by Public Health Service grants R37 AI019844 and AI056177 from the National Institute of Allergy and Infectious Diseases. Grant CE0562063 from the Australian Research Council, Project Grant GNT10695985 from the Australian National Health and Medical Research Council and Grant 1.1.2 from the Poultry Cooperative Research Centre (Australia). We thank Ms. S. Fitisemanu for excellent secretarial help.
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