LT-IIc, a New Member of the Type II Heat-Labile Enterotoxin Family Encoded by an Escherichia coli Strain Obtained from a Nonmammalian Host

Abstract

Infections caused by enterotoxigenic Escherichia coli (ETEC)are the leading cause of traveler's diarrhea and the major cause of diarrheal disease in underdeveloped nations, especially among children. ETEC, which is usually transmitted by food or water contaminated with animal or human feces, is estimated to be responsible annually for more than 650 million cases of enteric infections and nearly 800,000 deaths (29). Infection begins with ingestion of bacteria, followed by elaboration of enterotoxin and bacterial colonization of the gut, and presents as a profuse watery diarrhea which disseminates the bacteria back into the environment (10).ETEC strains are lactose-fermenting E. coli strains that produce a heat-labile enterotoxin (LT, hereafter referred to as LT-I), heat-stable enterotoxins (ST), or both and colonization factors which enable ETEC to colonize the small intestine (22). The pathogenesis of ETEC is dependent on the strains' capacity to produce LT-I and/or ST (10, 29). LT-I is closely related functionally, antigenically, and structurally to cholera toxin (CT), the heat-labile enterotoxin produced by Vibrio cholerae. Antiserum against CT neutralizes the toxicity of LT-I, and antiserum against LT-I neutralizes the toxicity of CT (15). Structurally, LT-I and CT are oligomeric proteins composed of an A polypeptide which is noncovalently coupled to a pentameric array of B polypeptides (15). The A polypeptide of LT-I and CT is enzymatically active and catalyzes an ADP-ribosylation of the G s ␣ regulatory protein in the intoxicated cell. Ribosylation of this regulatory protein constitutively activates adenylate cyclase, the enzyme which catalyzes production of cyclic AMP (cAMP) (3,20). Accumulation of cAMP induces the intoxicated cell to secrete electrolytes and chloride ions, thus generating the watery diarrhea, which is symptomatic of intoxication. Intracellular accumulation of cAMP modulates other cellular processes such as protein kinase activity, activation of calcium channels, etc. (15). Binding of LT-I and CT to ganglioside receptors is mediated by the B polypeptides. Gangliosides are members of a heterogeneous family of sialylated glycosphingolipids expressed on the surface of eukaryotic cells (9). Based on these characteristics, LT-I and CT have been designated as members of the large family of toxins known as the A 1 B 5 ADP-ribosylating heat-labile enterotoxins (HLTs).LT-IIa and LT-IIb, two new members of the A 1 B 5 family of HLTs produced by E. coli, were recently described (11,12,27). While it is clear that LT-IIa and LT-IIb are evolutionarily related to LT-I and CT, there are major differences between the two groups of enterotoxins. LT-IIa and LT-IIb are antigenically distinguishable from LT-I and CT and from each other (12). These antigenic differences are reflected in the low amino acid sequence similarity of the A polypeptides and the virtual absence of amino acid sequence homology of the B polypeptides between the two groups (LT-I and CT versus LT-IIa and LT-IIb) (35). To distinguish betwee...

Diarrheagenic Escherichia coli

“…Initially, two LT-I variants, isolated from human or swine-derived ETECs (LTh and LTp, respectively), were described and shown to have high amino acid sequence identity and similar but not equal antigenicity and biochemical and receptor-binding properties 342, 343. The related LT-II variants (LT-IIa,-IIb,-IIc) have been isolated from human beings or other hosts and contaminated food and bind to different receptors 344, 345, 346, 347. The LT-IIa, LT-IIb and LT-IIc share 51, 52 and 49% or 15, 16 and 7% identity with LT-Ih regarding the A and B subunits, respectively 347, 348…”

“…The related LT-II variants (LT-IIa,-IIb,-IIc) have been isolated from human beings or other hosts and contaminated food and bind to different receptors 344, 345, 346, 347. The LT-IIa, LT-IIb and LT-IIc share 51, 52 and 49% or 15, 16 and 7% identity with LT-Ih regarding the A and B subunits, respectively 347, 348…”

Recent Advances in Understanding Enteric Pathogenic Escherichia coli

“…There are two classes of LTs, the prototypical LT-I (usually referred to as LT, which will be followed in this review) and LT-II, which has differences in its B subunit receptor affinity and immune properties (reviewed in reference 745). LT-II can also be subcategorized into LT-IIa, LT-IIb, and the more recently discovered LT-IIc (746). Generally, LT-I is more consequential in human illness, but LT-II has been isolated from human cases of ETEC diarrhea (747).…”

Type II Heat-Labile Enterotoxins from 50 Diverse Escherichia coli Isolates Belong Almost Exclusively to the LT-IIc Family and May Be Prophage Encoded

“…Most of the predicted LT-II toxins form a single group that we designate the LT-IIc family. One subgroup of this toxin family is identical to the recently described LT-IIc of Nawar et al [16] who, while this study was in progress, independently cloned and characterized a novel LT-II operon from an ETEC isolated from ostriches that had diarrhea and died suddenly [17]. Here we present an analysis of the toxin-encoding genetic loci and deduced protein sequences from a diverse group of ETEC isolates whose toxins now form the LT-IIc family of enterotoxins.…”