Genomics and pathotypes of the many faces of Escherichia coli

Abstract

Escherichia coli is the most researched microbial organism in the world. Its varied impact on human health, consisting of commensalism, gastrointestinal disease, or extraintestinal pathologies, has generated a separation of the species into at least eleven pathotypes (also known as pathovars). These are broadly split into two groups, intestinal pathogenic E. coli (InPEC) and extraintestinal pathogenic E. coli (ExPEC). However, components of E. coli's infinite open accessory genome are horizontally transferred with substantial frequency, creating pathogenic hybrid strains that defy a clear pathotype designation. Here, we take a birds-eye view of the E. coli species, characterizing it from historical, clinical, and genetic perspectives. We examine the wide spectrum of human disease caused by E. coli, the genome content of the bacterium, and its propensity to acquire, exchange, and maintain antibiotic resistance genes and virulence traits. Our portrayal of the species also discusses elements that have shaped its overall population structure and summarizes the current state of vaccine development targeted at the most frequent E. coli pathovars. In our conclusions, we advocate streamlining efforts for clinical reporting of ExPEC, and emphasize the pathogenic potential that exists throughout the entire species.

Keywords: Escherichia coli pathotypes; accessory genome, antibiotic resistance; bacterial species; population dynamics; virulence factors.

Figure 1.

Selection of E. coli colonization loci in the human host. Intestinal and extraintestinal pathogenic E. coli can colonize and infect many tissue types in the human body. Specific E. coli pathotypes are indicated, where known. Intestinal pathogenic E. coli (InPEC) are shown in blue font, extraintestinal pathogenic E. coli (ExPEC) are in purple. Based on phylogeny and genetic markers, some DAEC bacteria associated with ulcerative colitis and AIEC linked to Crohn's disease may be classified as ExPEC.

Figure 2.

Schematic examples of Negative Frequency Dependent Selection (NFDS) in E. coli at (A), species population level, and (B), clonal lineage level. NFDS generates population diversity by maintaining uncommon phenotypes without maximizing population fitness in the current environment. A. Schematic phylogeny of key clonal lineages of E. coli. Every lineage is composed of highly successful pathogens, but each lineage is intimately associated with a single O-serotype. Note that ST73 and ST95 share an identical human ecology and yet have different O-serotypes—therefore, a successful immune response against O6 (present in ST73) would prevent ST73 from colonising, but not ST95 and other similar E. coli lineages. The presence of O1 in both ST95 and ST648 illustrates that an O-serotype is not restricted to a single lineage but can appear across the species. B. Presence of unique alleles of exemplar genes in the E. coli ST131 lineage. Each column denotes a gene, with its functional pathway indicated above. Unique alleles are represented by solid blocks, and are distributed across the entire phylogenetic tree at low frequency. These alleles help maintain diversity in the population and allow ‘bet-hedging’ within the lineage, should they confer a fitness advantage in a changing environment. If these alleles were present at a high frequency across the lineage, their benefit to the lineage would be lost.

Figure 3.

Selection of E. coli vaccine types in (pre-)clinical development. A. Live attenuated whole-cell vaccines (such as attenuated and engineered ETEC isolates (Harro et al. 2019), recombinant Lactococci (Sagi et al. 2020); or recombinant Salmonella (Oliveira et al. 2012)); B. Inactivated whole-cell formulations (for example, ETVAX (Qadri et al. 2020) and the commercially available Urovac); C. Glycoconjugates based on E. coli O antigen polysaccharides (for example, ExPEC4V (Frenck et al. 2019) and its expansion in current phase 3 clinical trials, ExPEC9V); D. Protein subunit vaccines, such as D1. Proteins involved in bacterial adherence to host cells (for example, CFA antigens (Maciel et al. 2019), fimbrial tip adhesin (Riddle et al. 2020), FimH (Eldridge et al. 2021), and SslE (Naili et al. 2019)), D2. Proteins with functions in iron acquisition (for example, IutA, Hma (Forsyth et al. 2020), and FyuA (Brumbaugh et al. 2015)), D3. Proteins required for immune evasion (for example, LpxR (Rojas-Lopez et al. 2019)); D4. Toxoid fusion proteins (such as CFA/ST/LT fusions (Nandre et al. 2018) and Stx fusions (Cai et al. 2011)); E. Bacterial ghosts/outer membrane vehicles (Cai et al. , Leitner et al. 2015); F. DNA-based vaccines using expression vectors (Riquelme-Neira et al. 2015).

Figure 4.

Suggested modifications for clinical reporting of pathogenic E. coli causing acute disease. Proposed alterations include (i), an exclusive use of the ExPEC acronym to delineate the E. coli pathogroup; and (ii), a potential categorization of pathotype EIEC with Shigella. For medical reporting of ExPEC, universal use of the pathogroup term rather than a separation into pathotypes may improve tracking consistency. For scientific and expert discourse, the focus may either stay on E. coli pathotypes or may migrate to a terminology that is based on whole-genome analyses. Novel ExPEC pathotype designations may improve precision of future scientific communication on ExPEC diseases where no current pathotype has yet been defined. See Table 1 for explanation of pathotype abbreviations. *Pathotype is associated with both intestinal and extraintestinal disease.