Heat-labile Enterotoxins (LT) and Heat-stable Enterotoxins (ST)

Heat-stable Enterotoxin (ST)

ETEC isolates can express two distinct heat-stable toxin families, STa, STA, STI, or ST1 and STb, STB, STII, or ST2 with significant differences in structure, function, antigenic cross-reactivity, methanol solubility and activity in infant mouse. STa found in human isolates is a small cysteine rich enterotoxin of 18-19 amino acids. STa is encoded on a plasmid by a transposon associated estA gene. Within STa, two variants associated with human disease have been described, STh and STp, originally found in human and pigs, respectively. STp and STh are synthetized as 72-amino acid residues including a pre-or signal peptide, a pro region and a mature ST region. ST is active even after 60 min of heating at 95°C. STa also has to go through different steps until it reaches the target and cause diarrhea.

Diarrhea induced by STa is of the secretory type with no signs of inflammation or colon involvement. It also probably induces more severe disease than LT among children in developing countries. A recent study demonstrated that ST is responsible for the rapid onset and shorter duration of ST-induced diarrhea, while if a LT+/ST+ ETEC strain is causing the diarrhea episode, a second phase with longer duration is due to LT-induced diarrhea.

Mechanisms of Synthesis and Secretion of LT and ST

Figure 2. Mechanisms of synthesis and secretion of LT and ST. (Joffré, 2015)

LT Production and Secretion Pathways

• Synthesis of LTA and LTB as precursors with signal peptides, which are transported across the cytoplasmic membrane to the periplasm.
• Periplasmatic proteolysis of the signal peptides of mature subunits.
• By releasing mature subunits into the periplasm, the holotoxin assembly is mediated by the pentamerization of LTB in a circular conformation, which embeds the C-terminal tail of the LTA2 domain. Pentamerization also can occur in either absence of LTA or preformed LTB pentamers. However, in presence of LTA the assembly process is three times faster promoting stability.
• Secretion of the assembled subunits by the type II secretion (T2SS) apparatus.

ST Production and Secretion Pathways

• Synthesis of STa as an intracellular pre-pro-STa with subsequent cleavage of the 19 amino acid signal sequence by a signal peptidase during or after translocation across the inner membrane. B.
• Translocation to the periplasm and formation of intracellular disulfide bonds by a SecA-dependent export pathway establishing the three-dimensional structure of the peptide. C.
• Inside the periplasm DsbA cleaves the 53-amino acid pro-STa leaving the mature STa to be secreted through the TolC channel.

Creative Diagnostics plays a key role in advancing ETEC research by providing Heat-stable Enterotoxin (ST) and Heat-labile Enterotoxins (LT) antibodies and antigens. Our high-quality tools support mechanistic studies of toxin-induced secretory diarrhea, facilitate the development of vaccines, and enable high-throughput screening of neutralizing antibodies.