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Although extraintestinal pathogenic (ExPEC) are designated by their isolation site and grouped based on the type of host and the disease they cause, most diarrheagenic (DEC) are subdivided into several pathotypes based on the presence of specific virulence traits directly related to disease development. This scenario of a well-categorized collapsed after the German outbreak of 2011, caused by one strain bearing the virulence factors of two different DEC pathotypes (enteroaggregative and Shiga toxin-producing ). Since the outbreak, many studies have shown that this phenomenon is more frequent than previously realized. Therefore, the terms hybrid- and hetero-pathogenic have been coined to describe new combinations of virulence factors among the classic pathotypes. In this review, we provide an overview of these classifications and highlight the genomic plasticity that results in some mixed pathotypes displaying novel pathogenic strategies, which lead to a new symptomatology related to diseases. In addition, as the capacity for genome interrogation has grown in the last few years, it is clear that genes encoding some virulence factors, such as Shiga toxin, are found among different pathotypes to which they have not traditionally been associated, perhaps foreshowing their emergence in new and severe outbreaks caused by such hybrid strains. Therefore, further studies regarding hetero-pathogenic and hybrid-pathogenic isolates are necessary to better understand and control the spread of these pathogens.

Escherichia coli sequence type 131 (ST131) has emerged rapidly to become the most prevalent extraintestinal pathogenic E. coli clones in circulation today. Previous investigations appeared to exonerate retail meat as a source of human exposure to ST131; however, these studies focused mainly on extensively multidrug-resistant ST131 strains, which typically carry allele 30 of the fimH type 1 fimbrial adhesin gene (ST131-H30). To estimate the frequency of extraintestinal human infections arising from foodborne ST131 strains without bias toward particular sublineages or phenotypes, we conducted a 1-year prospective study of E. coli from meat products and clinical cultures in Flagstaff, Arizona. We characterized all isolates by multilocus sequence typing, fimH typing, and core genome phylogenetic analyses, and we screened isolates for avian-associated ColV plasmids as an indication of poultry adaptation. E. coli was isolated from 79.8% of the 2,452 meat samples and 72.4% of the 1,735 culture-positive clinical samples. Twenty-seven meat isolates were ST131 and belonged almost exclusively (n = 25) to the ST131-H22 lineage. All but 1 of the 25 H22 meat isolates were from poultry products, and all but 2 carried poultry-associated ColV plasmids. Of the 1,188 contemporaneous human clinical E. coli isolates, 24 were ST131-H22, one-quarter of which occurred in the same high-resolution phylogenetic clades as the ST131-H22 meat isolates and carried ColV plasmids. Molecular clock analysis of an international ST131-H22 genome collection suggested that ColV plasmids have been acquired at least six times since the 1940s and that poultry-to-human transmission is not limited to the United States.IMPORTANCE E. coli ST131 is an important extraintestinal pathogen that can colonize the gastrointestinal tracts of humans and food animals. Here, we combined detection of accessory traits associated with avian adaptation (ColV plasmids) with high-resolution phylogenetics to quantify the portion of human infections caused by ST131 strains of food animal origin. Our results suggest that one ST131 sublineage—ST131-H22—has become established in poultry populations around the world and that meat may serve as a vehicle for human exposure and infection. ST131-H22 is just one of many E. coli lineages that may be transmitted from food animals to humans. Additional studies that combine detection of host-associated accessory elements with phylogenetics may allow us to quantify the total fraction of human extraintestinal infections attributable to food animal E. coli strains.

Extraintestinal pathogenic E . coli (ExPEC) are facultative pathogens that are part of the normal human intestinal flora. The ExPEC group includes uropathogenic E. coli (UPEC), neonatal meningitis E. coli (NMEC), sepsis-associated E. coli (SEPEC), and avian pathogenic E. coli (APEC). Virulence factors (VF) related to the pathogenicity of ExPEC are numerous and have a wide range of activities, from those related to bacteria colonization to those related to virulence, including adhesins, toxins, iron acquisition factors, lipopolysaccharides, polysaccharide capsules, and invasins, which are usually encoded on pathogenicity islands (PAIs), plasmids and other mobile genetic elements. Mechanisms underlying the dynamics of ExPEC transmission and the selection of virulent clones are still poorly understood and require further research. The time shift between colonization of ExPEC and the development of infection remains problematic in the context of establishing the relation between consumption of contaminated food and the appearance of first disease symptoms. What appears to be most difficult is to prove that ExPEC strains cause disease symptoms and to examine the mechanism of transition from the asymptomatic colonization of the intestines to the spreading of the bacteria outside the digestive system. A significant problem for researchers who are trying to ascribe ExPEC transmission to food, people or the environment is to draw the distinction between colonization of ExPEC and infection. Food safety is an important challenge for public health both at the production stage and in the course of its processing and distribution. Examination of the genetic similarity of ExPEC strains will allow to determine their origin from different sources. Many levels of genotyping have been proposed in which the typing of strains, plasmids and genes is compared in order to obtain a more complete picture of this complex problem. The aim of our study was to characterize E. coli strains isolated from humans, animals and food for the presence of bacterial genes encoding virulence factors such as toxins, and iron acquisition systems (siderophores) in the context of an increasing spread of ExPEC infections.

A single extra-intestinal pathogenic Escherichia coli (ExPEC) clone, named sequence type (ST) 131, is responsible for millions of global antimicrobial-resistant (AMR) infections annually. Population genetics indicate that ST131 consists of different clades (i.e. A, B, and C); however, clade C is the most dominant globally. A ST131 subclade, named C1-M27, is emerging in Japan and has been responsible for the recent increase in AMR ExPEC in that country. The sequential acquisition of several virulence and AMR genes associated with mobile genetic elements during the 1960s to 1980s primed clade C (and its subclades C1 and C2) for success in the 1990s to 2000s. IncF plasmids with F1:A2:B20 and F2:A1:B replicons have shaped the evolution of the C1 and C2 subclades. It is possible that ST131 is a host generalist with different accessory gene profiles. Compensatory mutations within the core genome of this clone have counterbalanced the fitness cost associated with IncF plasmids. ST131 clade C had dramatically changed the population structure of ExPEC, but it still remains unclear which features of this clade resulted in one of the most unprecedented AMR successes of the 2000s.

The One Health approach emphasizes the importance of antimicrobial resistance (AMR) as a major concern both in public health and in food animal production systems. As a general classification, E. coli can be distinguished based on the ability to cause infection of the gastrointestinal system (IPEC) or outside of it (ExPEC). Among the different pathogens, E. coli are becoming of great importance, and it has been suggested that ExPEC may harbor resistance genes that may be transferred to pathogenic or opportunistic bacteria. ExPEC strains are versatile bacteria that can cause urinary tract, bloodstream, prostate, and other infections at non-intestinal sites. In this context of rapidly increasing multidrug-resistance worldwide and a diminishingly effective antimicrobial arsenal to tackle resistant strains. ExPEC infections are now a serious public health threat worldwide. However, the clinical and economic impact of these infections and their optimal management are challenging, and consequently, there is an increasing awareness of the importance of ExPECs amongst healthcare professionals and the general public alike. This review aims to describe pathotype characteristics of ExPEC to increase our knowledge of these bacteria and, consequently, to increase our chances to control them and reduce the risk for AMR, following a One Health approach.

Abstract Background One-third of the 100 million travelers to the tropics annually acquire extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae (ESBL-PE), with undefined clinical consequences. Methods Symptoms suggesting Enterobacteriaceae infections were recorded prospectively among 430 Finnish travelers, 90 (21%) of whom acquired ESBL-PE abroad. ESBL-PE isolates underwent polymerase chain reaction–based detection of diarrheagenic Escherichia coli (DEC) pathotypes (enteroaggregative E. coli [EAEC], enteropathogenic E. coli [EPEC], enterotoxigenic E. coli [ETEC], enteroinvasive E. coli, and Shiga toxin–producing E. coli), and extraintestinal pathogenic/uropathogenic E. coli (ExPEC/UPEC). Laboratory-confirmed ESBL-PE infections were surveyed 5 years before and after travel. Results Among the 90 ESBL-PE carriers, manifestations of Enterobacteriaceae infection included travelers’ diarrhea (TD) (75/90 subjects) and urinary tract infection (UTI) (3/90). The carriers had 96 ESBL-producing E. coli isolates, 51% exhibiting a molecular pathotype: 13 (14%) were DEC (10 EAEC, 2 EPEC, 1 ETEC) (12 associated with TD) and 39 (41%) ExPEC/UPEC (none associated with UTI). Of ESBL-PE, 3 (3%) were ExPEC/UPEC-EAEC hybrids (2 associated with diarrhea, none with UTI). Potential ESBL-PE infections were detected in 15 of 90 subjects (17%). The 10-year medical record survey identified 4 laboratory-confirmed ESBL-PE infections among the 430 travelers, all in subjects who screened ESBL-PE negative after returning home from their index journeys but had traveled abroad before their infection episodes. Conclusions Half of all travel-acquired ESBL-producing E. coli strains qualified molecularly as pathogens. Extraintestinal and uropathogenic pathotypes outnumbered enteric pathotypes (41% vs 14%), yet the latter correlated more closely with symptomatic infection (0% vs 92%). Despite more ESBL-PE strains qualifying as ExPEC/UPEC than DEC, travel-acquired ESBL-PE are more often associated with TD than UTI. Of subjects with travel-acquired extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBL-PE), 87% contracted potential Enterobacteriaceae infections, mostly diarrhea. Although ESBL-PE isolates more commonly displayed extraintestinal/uropathogenic than enteric pathotypes, hosts more commonly had travelers’ diarrhea than urinary tract infection.

Uropathogenic Escherichia coli (UPEC) strains cause most uncomplicated urinary tract infections (UTIs). These strains are a subgroup of extraintestinal pathogenic E. coli (ExPEC) strains that infect extraintestinal sites, including urinary tract, meninges, bloodstream, lungs, and surgical sites. Here, we hypothesize that UPEC isolates adapt to and grow more rapidly within the urinary tract than other E. coli isolates and survive in that niche. To date, there has not been a reliable method available to measure their growth rate in vivo . Here we used two methods: segregation of nonreplicating plasmid pGTR902, and peak-to-trough ratio (PTR), a sequencing-based method that enumerates bacterial chromosomal replication forks present during cell division. In the murine model of UTI, UPEC strain growth was robust in vivo , matching or exceeding in vitro growth rates and only slowing after reaching high CFU counts at 24 and 30 h postinoculation (hpi). In contrast, asymptomatic bacteriuria (ABU) strains tended to maintain high growth rates in vivo at 6, 24, and 30 hpi, and population densities did not increase, suggesting that host responses or elimination limited population growth. Fecal strains displayed moderate growth rates at 6 hpi but did not survive to later times. By PTR, E. coli in urine of human patients with UTIs displayed extraordinarily rapid growth during active infection, with a mean doubling time of 22.4 min. Thus, in addition to traditional virulence determinants, including adhesins, toxins, iron acquisition, and motility, very high growth rates in vivo and resistance to the innate immune response appear to be critical phenotypes of UPEC strains. IMPORTANCE Uropathogenic Escherichia coli (UPEC) strains cause most urinary tract infections in otherwise healthy women. While we understand numerous virulence factors are utilized by E. coli to colonize and persist within the urinary tract, these properties are inconsequential unless bacteria can divide rapidly and survive the host immune response. To determine the contribution of growth rate to successful colonization and persistence, we employed two methods: one involving the segregation of a nonreplicating plasmid in bacteria as they divide and the peak-to-trough ratio, a sequencing-based method that enumerates chromosomal replication forks present during cell division. We found that UPEC strains divide extraordinarily rapidly during human UTIs. These techniques will be broadly applicable to measure in vivo growth rates of other bacterial pathogens during host colonization. Uropathogenic Escherichia coli (UPEC) strains cause most urinary tract infections in otherwise healthy women. While we understand numerous virulence factors are utilized by E. coli to colonize and persist within the urinary tract, these properties are inconsequential unless bacteria can divide rapidly and survive the host immune response. To determine the contribution of growth rate to successful colonization and persistence, we employed two methods: one involving the segregation of a nonreplicating plasmid in bacteria as they divide and the peak-to-trough ratio, a sequencing-based method that enumerates chromosomal replication forks present during cell division. We found that UPEC strains divide extraordinarily rapidly during human UTIs. These techniques will be broadly applicable to measure in vivo growth rates of other bacterial pathogens during host colonization.

This study explores the role of the vaginal microbiota (VM) in the pathophysiology of asymptomatic bacteriuria (ASB) in a cohort of 1,553 pregnant women. Worldwide, E. coli remains the most common etiological agent of bacteriuria during pregnancy and also a major causative agent of newborn infections. A healthy VM is typically characterized by low diversity and is dominated by lactic acid-producing species, notably those from the Lactobacillus genus. Our results point to decreases in Lactobacillus spp associated with an increase of gut-microbiota-associated species from the Enterobacterales order. Escherichia coli exhibited the most pronounced increase in abundance within the VM during bacteriuria and was notably associated with ASB. Molecular typing and antimicrobial resistance characterization of 72 metagenome assembled E. coli genomes (MAGs) from these pregnant women revealed a genomic signature of extraintestinal pathogenic E. coli (“ExPEC”) strains, which are involved in various extraintestinal infections such as urinary tract infections, newborn infections and bacteremia. Microbial diversity within the vaginal samples from which an E. coli MAG was obtained showed a substantial variation, primarily marked by a decrease in abundance of Lactobacillus species. Overall, our study shows how disruption in key bacterial group within the VM can disrupt its stability, potentially leading to the colonization by opportunistic pathogens.

Extraintestinal pathogenic (ExPEC) isolates are responsible for many bloodstream infections. The aim of this study was to characterize isolated from the bloodstreams of patients ( = 48) at the University Hospital in Brazil. Epidemiological data were obtained through the analysis of medical records and laboratory tests. By PCR analysis, we investigated the presence of virulence factors (VFs), pathogenicity islands (PAIs), extended-spectrum β-lactamase (ESBL), phylogenetic classifications (A, B1, B2, C, D, E, and F) and molecular genotype by enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR). The mortality analysis showed that 33.3% of the deaths were associated with bacteraemia due to infections; in addition, an age between 60 and 75 years ( < 0.001; OR = 6.3[2.1-18.9]) and bacteraemia with an abdominal origin ( = 0.02; OR = 5[1.2-20.5]) were risk factors for the severity of the infection. Additionally, the presence of the gene was associated with mortality due to bacteraemia ( = 0.027; OR = 11.4[1.5-85.7]). Immunosuppression (27.1%), intestinal diseases (25.0%) and diabetes (18.8%), were prevalent among patients, and most of the bacteraemia cases were secondary to urinary tract infections (50.0%). The serum resistance gene T was present in 77.1% of isolates, group capsular 2 ( II) was present in 45.8% and the K5 capsule was present in 20.8% of isolates. The isolates also showed a high prevalence for the siderophore yersiniabactina ( A) (70.8%) and PAI IV (77.1%). Phylogenetic analysis showed that group B2 (45.8%) was the most prevalent, and was the phylogroup that had a higher prevalence of VFs and PAIs. However, in this study, a considerable number of isolated bacteria were classified as group B1 (18.8%) and as group E (14.6%). Eight (16.7%) isolates were resistant to third and fourth generation cephalosporin and group CTX-M-1 (CTX-M-15) was the most prevalent ESBL type. The molecular genotyping showed two clonal lineages and several isolates that were not related to each other. This study provides additional information on the epidemiological and molecular characteristics of bloodstream infections in Brazil.

Background Classification of pathogenic Escherichia coli ( E. coli ) has traditionally relied on detecting specific virulence associated genes (VAGs) or combinations thereof. For E. coli isolated from faecal samples, the presence of specific genes associated with different intestinal pathogenic pathovars will determine their classification and further course of action. However, the E. coli genome is not a static entity, and hybrid strains are emerging that cross the pathovar definitions. Hybrid strains may show gene contents previously associated with several distinct pathovars making the correct diagnostic classification difficult. We extended the analysis of routinely submitted faecal isolates to include known virulence associated genes that are usually not examined in faecal isolates to detect the frequency of possible hybrid strains. Methods From September 2012 to February 2013, 168 faecal isolates of E. coli routinely submitted to the Norwegian Institute of Public Health (NIPH) from clinical microbiological laboratories throughout Norway were analysed for 33 VAGs using multiplex-PCR, including factors associated with extraintestinal pathogenic E. coli (ExPEC) strains. The strains were further typed by Multiple Locus Variable-Number Tandem-Repeat Analysis (MLVA), and the phylogenetic grouping was determined. One isolate from the study was selected for whole genome sequencing (WGS) with a combination of Oxford Nanopore’s MinION and Illumina’s MiSeq. Results The analysis showed a surprisingly high number of strains carrying ExPEC associated VAGs and strains carrying a combination of both intestinal pathogenic E. coli (IPEC) and ExPEC VAGs. In particular, 93.5% (101/108) of isolates classified as belonging to an IPEC pathovar additionally carried ExPEC VAGs. WGS analysis of a selected hybrid strain revealed that it could, with present classification criteria, be classified as belonging to all of the Enteropathogenic Escherichia coli (EPEC), Uropathogenic Escherichia coli (UPEC), Neonatal meningitis Escherichia coli (NMEC) and Avian pathogenic Escherichia coli (APEC) pathovars. Conclusion Hybrid ExPEC/IPEC E. coli strains were found at a very high frequency in faecal samples and were in fact the predominant species present. A sequenced hybrid isolate was confirmed to be a cross-pathovar strain possessing recognised hallmarks of several pathovars, and a genome heavily influenced by horizontal gene transfer.