Host cell-induced signaling causesClostridium perfringensto upregulate production of toxins important for intestinal infections

Abstract

These authors contributed equally to this work.Keywords: Clostridium perfringens, enterotoxin, beta toxin, epsilon toxin, quorum sensing, Agr, two component regulatory system, VirS/VirR, intestinal infectionClostridium perfringens causes enteritis and enterotoxemia in humans and livestock due to prolific toxin production. In broth culture, C. perfringens uses the agr-like quorum sensing (QS) system to regulate production of toxins important for enteritis/ enterotoxemia, including beta toxin (cPB), enterotoxin, and epsilon toxin (eTX). The VirS/Virr two-component regulatory system (TcrS) also controls cPB production in broth cultures. Both the agr-like QS and VirS/Virr systems are important when C. perfringens senses enterocyte-like caco-2 cells and responds by upregulating cPB production; however, only the agr-like QS system is needed for host cell-induced eTX production. These in vitro observations have pathophysiologic relevance since both the VirS/Virr and agr-like QS signaling systems are required for C. perfringens strain cN3685 to produce cPB in vivo and to cause enteritis or enterotoxemia. Thus, apparently upon sensing its presence in the intestines, C. perfringens utilizes QS and TcrS signaling to produce toxins necessary for intestinal virulence.

Structure-Function Analysis of Peptide Signaling in the Clostridium perfringens Agr-Like Quorum Sensing System

“…The accessory growth regulator (Agr)-like quorum sensing (QS) system was first discovered in Staphylococcus aureus, where it controls gene expression via population density-induced autoinducer signaling molecules (8,12,13). Within the past 5 years, an Agr-like QS system has also been identified in C. perfringens, where this QS system was first demonstrated to regulate the production of CPA and PFO by type A strain 13 (12, 13).…”

“…In some cases, regulatory RNAs are involved in VirS/VirR-mediated regulation, although production of perfringolysin O (PFO) is directly regulated by the binding of phosphorylated VirR to DNA sequences, named VirR boxes, that are located directly upstream of the pfoA gene (6, 9). In contrast, the production of the enterotoxin (CPE) during sporulation is mediated by sporulation-specific alternative sigma factors (4, 10, 11).The accessory growth regulator (Agr)-like quorum sensing (QS) system was first discovered in Staphylococcus aureus, where it controls gene expression via population density-induced autoinducer signaling molecules (8,12,13). Within the past 5 years, an Agr-like QS system has also been identified in C. perfringens, where this QS system was first demonstrated to regulate the production of CPA and PFO by type A strain 13 (12, 13).…”

“…Both similarities and differences exist between the Agr-like QS system of C. perfringens and the well-characterized, paradigm Agr system of Staphylococcus aureus (8,12,13,(19)(20)(21). For example, the C. perfringens Agr-like QS system includes an operon encoding AgrD and AgrB, where AgrD is the precursor peptide for the autoinducing peptide (AIP) that mediates Agr QS signaling and AgrB is the integral membrane endopeptidase that is involved in processing AgrD to the active AIP.…”

“…For example, the C. perfringens Agr-like QS system includes an operon encoding AgrD and AgrB, where AgrD is the precursor peptide for the autoinducing peptide (AIP) that mediates Agr QS signaling and AgrB is the integral membrane endopeptidase that is involved in processing AgrD to the active AIP. However, C. perfringens lacks the AgrA/AgrC two-component system that responds to the AIP in S. aureus (6,8,19,20). Some evidence suggests that the VirS/VirR two-component regulatory system may sometimes be the functional equivalent of AgrA/AgrC in C. perfringens, but this relationship has not yet been firmly proven and there appears to be exceptions since expression of the C. perfringens etx gene is regulated by the Agr-like QS system, yet etx expression is not affected by inactivation of the virS-virR operon (6,8,12,14).…”

Characterization of Clostridium perfringens TpeL Toxin Gene Carriage, Production, Cytotoxic Contributions, and Trypsin Sensitivity

“…C. perfringens virulence is due largely to its abundant toxin production, which varies by strain (2). Different C. perfringens isolates are assigned to one of five types (A to E) based upon their production of four typing toxins (alpha toxin [CPA], beta toxin [CPB], epsilon toxin [ETX], and iota toxin [ITX]) (3,4). Besides these four typing toxins, this bacterium can produce at least 13 other toxins, including the enterotoxin (CPE) (1,5), although no single strain produces all of these toxins.…”