The pathogenesis of necrotic enteritis in chickens: what we know and what we need to know: a review

Abstract

This review summarizes advances in understanding the pathogenesis of necrotic enteritis of chickens caused by netB-positive Clostridium perfringens. The discovery of NetB as the essential toxin trigger for the disease was followed by recognition that it forms part of a large plasmid-encoded 42 kb pathogenicity locus (NELoc-1). While the locus is critical for toxin production, it likely has additional functions related to colonization and degradation of the mucus barrier, which are essential both to multiplication and to bringing NetB close to the intestinal epithelium. Two "chitinases" (glycoside hydrolases (GHs)) present on NELoc-1 are predicted to be involved in mucin degradation, as is the large carbohydrate-binding metalloprotease, shown to be involved in mucinase activity in other clostridia. A second pathogenicity locus found in netB-positive C. perfringens, NELoc-2, also encodes a GH likely involved in mucin degradation. Upon reaching a sufficient cell density on the intestinal mucosa, the Agr-like quorum-sensing system is triggered, which in turn up-regulates the VirR/VirS regulon. This regulon includes NetB. Where NetB initiates damage is unresolved, but it may be deep in the intestinal mucosa, rather than superficially. As the disease progresses, C. perfringens line what remains of the intestinal epithelium in large numbers. This likely involves a number of different bacterial adhesins, including additional NELoc-1-encoded bacterial surface proteins, some of which may adhere to epithelial cell ligands exposed by bacterial sialidases. Further studies of the pathogenesis of necrotic enteritis should lead to development of novel ways to control the infection.

Recurring Necrotic Enteritis Outbreaks in Commercial Broiler Chicken Flocks Strongly Influence Toxin Gene Carriage and Species Richness in the Resident Clostridium perfringens Population

“…Although many studies have been conducted to better describe the role of C. perfringens in necrotic enteritis pathogenesis, little work has been done to better characterize this microorganism population structure in commercial broiler chicken farms, where the use of antimicrobials has been discontinued (Prescott et al, 2016; Rood et al, 2016). More importantly, much remains to be explained to better understand why raising drug-free birds would be more challenging on some farms in regard to digestive health management and NE issues (Brady et al, 2010; Smith, 2011).…”

“…It has been reported that C. perfringens strains associated with NE outbreaks would not only possess a chromosomal genetic background conferring them a selective advantage over the commensal strains (Chalmers et al, 2008; Hibberd et al, 2011; Lepp et al, 2013; Lacey et al, 2016), but that these strains would also harbor many plasmid-borne virulence genes organized in pathogenicity loci (Lepp et al, 2010; Lacey et al, 2016). Within these loci, some genes encoding toxins, antibiotic resistance, and adhesion factors might preferentially contribute to the ability of the virulent strains to persist over time and to colonize the birds (Lacey et al, 2016; Prescott et al, 2016; Zhou et al, 2017). Indeed, some genes found in these strains could be associated with a better adaptation to an environment where the disease is raging and where they will find the conditions to undergo positive selection and multiplication (Sawires and Songer, 2006; Prescott et al, 2016).…”

“…Within these loci, some genes encoding toxins, antibiotic resistance, and adhesion factors might preferentially contribute to the ability of the virulent strains to persist over time and to colonize the birds (Lacey et al, 2016; Prescott et al, 2016; Zhou et al, 2017). Indeed, some genes found in these strains could be associated with a better adaptation to an environment where the disease is raging and where they will find the conditions to undergo positive selection and multiplication (Sawires and Songer, 2006; Prescott et al, 2016). The increase in toxin gene carriage observed in the C. perfringens population found in NE-affected farms of our study could also be partially explained by the chromosomal background of these virulent strains, providing them with a heightened capacity of exchanging and carrying plasmids.…”

The Agr-Like Quorum Sensing System Is Required for Pathogenesis of Necrotic Enteritis Caused by Clostridium perfringens in Poultry

“…QS systems related to the S. aureus Agr system are widespread among Firmicutes (31) and typically act to regulate concerted, populationwide behaviors such as sporulation, biofilm formation, and virulence (32)(33)(34). The development of NE in poultry is generally attributed to the rapid overgrowth of C. perfringens in the gut and subsequent elaboration of virulence factors that induce damage to the host (35,36), a progression that is consistent with a QS-based regulatory mechanism. It follows that, by coordinating the production of extracellular toxins and enzymes to occur only once a sufficient population density is reached, a pathogen may inflict the greatest damage to the host while at the same time minimizing its expenditure of metabolic resources.…”

“…A third alternative explanation for the CP1⍀agrB attenuated in vivo virulence that does not involve NetB is the requirement of other agr-regulated genes for NE patho- genesis, although a more likely scenario is that additional agr-regulated genes contribute to virulence alongside NetB. Recent advances have made it clear that the onset of NE is a complex process involving multiple C. perfringens virulence factors related to colonization, adhesion, and acquisition of nutrients (35). Global gene expression analysis of CP1⍀agrB revealed 66 genes that were significantly differentially expressed compared to the wild-type CP1 control.…”