Recent advances in understanding enteric pathogenic Escherichia coli

Abstract

Although Escherichia coli can be an innocuous resident of the gastrointestinal tract, it also has the pathogenic capacity to cause significant diarrheal and extraintestinal diseases. Pathogenic variants of E. coli (pathovars or pathotypes) cause much morbidity and mortality worldwide. Consequently, pathogenic E. coli is widely studied in humans, animals, food, and the environment. While there are many common features that these pathotypes employ to colonize the intestinal mucosa and cause disease, the course, onset, and complications vary significantly. Outbreaks are common in developed and developing countries, and they sometimes have fatal consequences. Many of these pathotypes are a major public health concern as they have low infectious doses and are transmitted through ubiquitous mediums, including food and water. The seriousness of pathogenic E. coli is exemplified by dedicated national and international surveillance programs that monitor and track outbreaks; unfortunately, this surveillance is often lacking in developing countries. While not all pathotypes carry the same public health profile, they all carry an enormous potential to cause disease and continue to present challenges to human health. This comprehensive review highlights recent advances in our understanding of the intestinal pathotypes of E. coli.

Fig 1

Global mortality from diarrhea in children under the age of 5 in 2010. Estimates of diarrhea-specific mortality among children under 5 for each country reflect high mortality in developing countries, with the highest tolls present in countries in sub-Saharan Africa and South Asia. Many etiological agents, including pathogenic E. coli, are responsible for diarrhea-related mortality in these children. Recent work published by GEMS found significant child mortality associated with EPEC and ETEC infections in developing countries (7). Source data for the map: World Health Organization (5).

Fig 2

Diagnostic tools for intestinal pathogenic E. coli. E. coli causes a variety of diarrheal diseases in humans owing to specific colonization and virulence factors associated with each pathotype. As no single method can be used to detect and diagnose all pathogenic E. coli strains, a number of biochemical tests, typing methods, and molecular approaches have been developed to isolate E. coli from other enteric bacteria as well as to differentiate between particular pathotypes. Prospective methods such as whole-genome sequencing or high-throughput sequencing are becoming fast and affordable, providing much information about the pathogen that may be useful to clinicians, epidemiologists, and public health workers.

Fig 3

Phylogenetic tree of intestinal pathogenic E. coli. E. coli strains can be grouped into 5 main phylogenetic groups: A (blue), B1 (green), B2 (brown), D (pink), and E (red). Shigella/EIEC also form additional phylogroups (black). Pathotypes do not always group together in the same phylogroup. The hybrid EAEC and STEC strains are denoted with both an open square and open circle. Unmarked strains are either commensal, extraintestinal pathogenic E. coli (ExPEC), or avian-pathogenic E. coli (APEC). ETEC strains are isolated from both humans and animals, while DAEC is not represented in the phylogenetic tree. (Adapted from reference , which was published under a Creative Commons license.)

Fig 4

General overview of pathogenic gene acquisition and loss for different pathotypes. Gene gain and loss afford pathogenic traits to E. coli and ultimately lead to the pathotypes discussed in this review. Acquisition of genes is generally from mobile elements such as transposons, prophages, and plasmids. Typical EPEC carries the LEE and bundle-forming pilus gene (bfp), while most LEE-positive STEC strains (such as EHEC) also carry the LEE as well as Shiga toxin genes (stx₁, stx₂, or a combination). ETEC isolates carry enterotoxins LT and ST solely or together on plasmids, as well as colonization factors (CFs). Some DAEC isolates have acquired fimbriae that enhance adherence, called the Afa/Dr, while many virulence determinants for EAEC for some isolates are found on the pAA plasmid. Additionally, the O104:H4 serotype of EAEC, which was involved in the recent outbreak in Germany, acquired the stx₂ gene. EIEC/Shigella gained the ability to invade cells mainly through the pINV plasmid and acquired additional virulence traits in the form of chromosomal pathogenicity islands (PAIs). Subsequent pathoadaptation, including loss of antivirulence factors and motility, potentiate its virulence. Genes involved in the pathogenesis of AIEC are unclear. For more details about these genetic determinants, see the text.

Fig 5

General overview of potential reservoirs and modes of transmission for pathogenic E. coli. Pathogenic E. coli strains can be found in various animal reservoirs and can spread between these and other animals. Fecal matter can contaminate food, irrigation water, or recreational/drinking water. Humans can become exposed following the ingestion of contaminated food or water or through direct contact with colonized animals. Secondary transmission can occur between humans, commonly in day care centers or nursing homes. Food can become contaminated through poor cooking practice, where, for example, uncooked meat could come in contact with other food. Additionally, symptomatic or asymptomatic food handlers can contaminate food, particularly when hand hygiene is inadequate. Contamination of recreational or drinking water can occur through exposure of human sewage.

Fig 6

Adherence patterns of enteric E. coli. Pathogenic E. coli requires adherence to the host epithelium. Enteropathogenic E. coli (EPEC) (represented in yellow) and LEE-positive Shiga toxin-producing E.coli (STEC) (represented in pink) are extracellular pathogens that attach to the intestinal epithelium and efface microvilli, forming characteristic A/E lesions. Due to the presence of bundle-forming pili, EPEC is capable of forming microcolonies, resulting in a localized adherence (LA) pattern. Enterotoxigenic E. coli (ETEC) (represented in orange) uses colonization factors (CFs) for attachment to host intestinal cells. Enteroaggregative E. coli (EAEC) (represented in green) forms biofilms on the intestinal mucosa, and bacteria adhere to each other as well as to the cell surface to form an aggregative adherence pattern (AA) known as “stacked brick.” Diffusely adherent E. coli (DAEC) (represented in blue) is dispersed over the surfaces of intestinal cells, resulting in a diffuse adherence (DA) pattern. Adherent invasive E. coli (AIEC) (represented in purple) colonizes the intestinal mucosae of patients with Crohn's disease and is capable of invading epithelial cells as well as replicating within macrophages. AIEC uses type I pili to adhere to intestinal cells and long polar fimbriae that contribute to invasion. Enteroinvasive E. coli (EIEC)/Shigella (represented in red) are intracellular pathogens that penetrate the intestinal epithelium through M cells to gain access to the submucosa. EIEC/Shigella escape submucosal macrophages by induction of macrophage cell death followed by basolateral invasion of colonocytes and lateral spread.

Fig 7

Adherence patterns of enteropathogenic E. coli (EPEC) on tissue culture cells. (a) Localized adherence (LA); (b) localized adherence like (LAL); (c) diffuse adherence (DA); (d) aggregative adherence (AA). (Reprinted from reference with permission [© 2009 Federation of European Microbiological Societies].)

Fig 8

Phylogenetic tree of Shigella, EIEC, and nonpathogenic E. coli strains, showing the evolutionary relationship between 32 EIEC strains, 46 Shigella strains, and 20 E. coli reference strains of the ECOR group (EcoR strains) based on comparison of selected housekeeping gene sequences. Shigella groups in 3 phylogenetic clusters (C1 to C3) and EIEC in 4 phylogenetic clusters (C4 to C7), with broad distribution of traditionally surface antigen profile-classified strains. EIEC and Shigella strains outside clusters C1 to C7 are depicted in bold. Both EIEC and Shigella arose several times from multiple ancestral origins. The EIEC strain in C2 is assumed to be misclassified. The number of strains in a cluster is shown in parentheses. The Salmonella LT2 strain serves as outgroup. (Adapted from reference with permission.)