Colonization factors among enterotoxigenic Escherichia coli isolates from children with moderate-to-severe diarrhea and from matched controls in the Global Enteric Multicenter Study (GEMS)

Abstract

BackgroundEnterotoxigenic Escherichia coli (ETEC) encoding heat-stable enterotoxin (ST) alone or with heat-labile enterotoxin (LT) cause moderate-to-severe diarrhea (MSD) in developing country children. The Global Enteric Multicenter Study (GEMS) identified ETEC encoding ST among the top four enteropathogens. Since the GEMS objective was to provide evidence to guide development and implementation of enteric vaccines and other interventions to diminish diarrheal disease morbidity and mortality, we examined colonization factor (CF) prevalence among ETEC isolates from children age <5 years with MSD and from matched controls in four African and three Asian sites. We also assessed strength of association of specific CFs with MSD.Methodology/Principal findingsMSD cases enrolled at healthcare facilities over three years and matched controls were tested in a standardized manner for many enteropathogens. To identify ETEC, three E. coli colonies per child were tested by polymerase chain reaction (PCR) to detect genes encoding LT, ST; confirmed ETEC were examined by PCR for major CFs (Colonization Factor Antigen I [CFA/I] or Coli Surface [CS] antigens CS1-CS6) and minor CFs (CS7, CS12, CS13, CS14, CS17, CS18, CS19, CS20, CS21, CS30). ETEC from 806 cases had a single toxin/CF profile in three tested strains per child. Major CFs, components of multiple ETEC vaccine candidates, were detected in 66.0% of LT/ST and ST-only cases and were associated with MSD versus matched controls by conditional logistic regression (p≤0.006); major CFs detected in only 25.0% of LT-only cases weren’t associated with MSD. ETEC encoding exclusively CS14, identified among 19.9% of 291 ST-only and 1.5% of 259 LT/ST strains, were associated with MSD (p = 0.0011). No other minor CF exhibited prevalence ≥5% and significant association with MSD.Conclusions/SignificanceMajor CF-based efficacious ETEC vaccines could potentially prevent up to 66% of pediatric MSD cases due to ST-encoding ETEC in developing countries; adding CS14 extends coverage to ~77%.

Enterotoxigenic Escherichia coli Heat-Stable Toxin Increases the Rate of Zinc Release from Metallothionein and Is a Zinc- and Iron-Binding Peptide

“…Under the same conditions of iron limitation, LT secretion was inhibited, while transcription of sta1 was roughly unchanged (26). Indeed, according to recent global data, Ͼ65% of the wild ETEC isolates maintain ST, either alone or in combination with LT (64), and in a study surveying pediatric patients with environmental enteric dysfunction, ETEC was the only pathogen to induce elevated fecal calprotectin, a fecal maker of environmental enteropathy and a zinc-and iron-binding protein (65)(66)(67). In a recently developed ETEC colonization model using dietary zinc restriction, ETEC colonization was associated with higher intestinal titers of the inflammatory markers myeloperoxidase and lipocalin-2 (42).…”

Oral Immunogenicity in Mice and Sows of Enterotoxigenic Escherichia Coli Outer-Membrane Vesicles Incorporated into Zein-Based Nanoparticles

“…The genetic plasticity of ETEC strains, their many different virulence factors, and the limited knowledge of the immunological mechanisms involved in protection makes the development of an effective vaccine against ETEC a real challenge [15,16]. Consequently, this antigenic complexity requires the use of multiple epitopes in order to protect against ETEC, with the aim of inhibiting bacterial adherence to receptors on the intestinal cells and neutralizing enterotoxins [11].…”

Immunizations with Enterotoxigenic Escherichia coli Heat-Stable Toxin Conjugates Engender Toxin-Neutralizing Antibodies in Mice That Also Cross-React with Guanylin and Uroguanylin

“…Importantly, ETEC strains that produce ST, with or without LT, have recently been identified as among the most important causes of moderate and severe diarrhea in children (10). Moreover, ETEC strains that produce STh are more closely associated with childhood diarrhea than those that produce STp (8,11,12). This implies that the STs in general, and STh specifically, are attractive targets for ETEC vaccine development, and ST-based vaccine antigens could be added to other ETEC vaccine candidate formulations to create vaccines with broad coverage (7).…”