Extraintestinal pathogenic E coli (ExPEC)

Extraintestinal pathogenic E. coli (ExPEC) are facultative pathogens which colonise the gastrointestinal tract of many healthy individuals, where they exist as commensals and do not cause enteric disease, contrary to the intestinal pathogenic E. coli (IPEC). ExPEC strains colonise sites outside of the intestinal tract, such as the urinary tract, bloodstream, and brain (Fig. 1.2). ExPEC are considered the primary aetiological agent of urinary tract infections (UTIs), as well as a common cause of bacteraemia and sepsis in the community. Other ExPEC strains are responsible for surgical wound infections, neonatal meningitis, and neonatal sepsis (Ron, 2010; Russo and Johnson, 2003). ExPEC strains which reside in the gastrointestinal tract differ from normal commensal strains, in that they possess virulence traits that allow them to colonise more

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inhospitable environments, such as the urogenital tract (Smith, Fratamico and Gunther, 2007). In addition to these bacteria-specific traits, host-specific factors are also required in order to cause disease. ExPEC is therefore considered a necessary but not sufficient cause for extraintestinal E. coli infection, and as a result, additional factors are required for an infection to occur (Singer, 2015). Consequently, ExPEC are considered opportunistic pathogens for causing ExPEC-associated disease. When provided with an opportunity in individuals who might be susceptible in some way (e.g., compromised immune system), or through the influence of specific risk factors, the bacterium can be transferred to the urogenital tract where it can cause a UTI (Foxman, 2014). Similar to the intestinal pathogenic E. coli described earlier, ExPEC strains are also categorised into pathotypes as defined by the anatomical location of the disease they cause and the molecular virulence-associated genes that they carry, although few traits appear to be exclusive to one specific ExPEC subgroup.

1.3.4.1. Avian pathogenic E. coli (APEC)

Avian pathogenic E. coli (APEC) are responsible for causing systemic extraintestinal infections such as aerosacculitis, polyserositis, and septicaemia in avian hosts such as chickens, turkeys, and other wild and domesticated birds (Manges, 2016). APEC are typically part of the intestinal microbiota of healthy birds and infections typically result from environmental exposures and increased host susceptibility. More recently, APEC are also thought to be responsible for infections in humans, due to similarities in virulence determinants found in APEC and human ExPEC strains (Johnson et al., 2008). For instance, it has been demonstrated that genome content, virulence gene profiles, phylogeny, biofilm formation, and in vivo transcriptional activation are shared by APEC strains and the human ExPEC serotypes O18:K1:H7, O78, and O2:K1:H7 (Bauchart et al., 2010). Other studies of pathogenesis in vivo and in vitro have shown that APEC can cause disease in mammalian hosts and conversely, ExPEC isolated from human infections can cause disease in avian models (Jakobsen et al., 2012; Tivendale et al., 2010). These findings have led to the supposition that APEC is a zoonotic pathogen contributing to the weight of ExPEC infections in humans, particularly UTIs, and that consumption of retail poultry may be a source of infection (Platell et al., 2011b; Tivendale et al., 2010).

1.3.4.2. Neonatal meningitis E. coli (NMEC)

Neonatal meningitis E. coli (NMEC) have the ability to cross the blood-brain barrier (BBB) and are the second-leading cause of neonatal meningitis (Heath, Nik Yusoff and Baker, 2003), causing high mortality and neurologic sequelae in affected neonates. NMEC commonly inhabit the lower gastrointestinal tract, but become niche pathogens upon entry to the bloodstream and central

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nervous system (CNS). NMEC are able to penetrate the BBB due to their ability to persist in the bloodstream by surviving engulfment by macrophages, multiplying in high numbers, and thus allowing successful invasion of the meninges of infants and causing meningitis (Kaper, Nataro and Mobley, 2004). NMEC are resistant to the host immune response, due to the possession of a KI capsule. This capsule is a thick polysialic acid layer that safeguards the bacterium from ingestion by phagocytic cells, and also from fusion with intracellular lytic vacuoles. As a consequence of the protection that the KI capsule provides, significant numbers of viable bacterial cells are transported across the BBB and into the CNS, where they can cause oedema and neural damage. It is most likely that these factors contribute to E. coli-associated neonatal meningitis carrying the significantly high mortality and morbidity rate (10–30%) associated with neonatal meningitis, caused by NMEC during the neonatal period (Kaper, Nataro and Mobley, 2004).

1.3.4.3. Uropathogenic E. coli (UPEC)

The pathotype of E. coli responsible for causing urinary tract infections (UTIs) is referred to as uropathogenic E. coli (UPEC). Among the common urinary pathogens associated with the development of UTIs, UPEC are the primary cause (Terlizzi, Gribaudo and Maffei, 2017). UPEC are defined by their ability to cause extraintestinal infections of the urinary tract (bladder, kidneys, ureter, and urethra), and are characterised by a plethora of both structural (fimbriae, pili, flagella, capsules) and secreted (toxins, iron-acquisition systems, proteins) virulence factors that contribute to their capacity to cause disease. UTIs are globally widespread and affect a large proportion of the human population. Approximately 150 million people worldwide develop a UTI each year (Flores-Mireles et al., 2015) and roughly 11% of women suffer an episode of UTI per year (Foxman, 2014). UPEC are thought to be responsible for up to 80% of uncomplicated UTIs in females (Flores-Mireles et al., 2015). UPEC are particularly well-adapted to surviving in the urinary tract and possess VAGs enabling them to scavenge iron from the environment and catabolise the amino acid D-serine, which is present in urine (Flores-Mireles et al., 2015). Additionally, UPEC are also notable for their ability to adhere to host epithelial cells in the urinary tract, and this represents the most important determinant of pathogenicity for UPEC. In severe cases where a UTI is left untreated, UPEC can ascend the urinary tract to cause infection of the kidneys and bloodstream.

UPEC strains that have invaded the bladder cells may be released and ascend to the kidneys via the ureters. Adherence to the kidney epithelial cells is mediated by binding of P-fimbriae to digalactoside receptors (Kaper, Nataro and Mobley, 2004). Upon colonisation of the kidney, UPEC virulence factors such as haemolysin and secreted autotransporter toxins (SAT) result in

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damage to the renal epithelium, leading to pyelonephritis. Bacteria that have made it to this stage are then able to penetrate the endothelial cells of the proximal tubes and gain access to the bloodstream, resulting in bacteraemia (Kaper, Nataro and Mobley, 2004). The process of ascending infection from UTI to bacteraemia, involving the bladder, kidneys, and bloodstreams is known as urosepsis. The incidence of bloodstream infection is becoming more prevalent and is associated with higher rates of mortality. Bacteraemia caused by E. coli infection, which can be community or hospital-acquired, is reported with increasing frequency worldwide (Ron, 2010), accounting for 17–37% of bacteraemia cases globally (Russo and Johnson, 2003). Studies have reported that E. coli is the most frequent organism isolated from septicaemia resulting from an initial UTI. A UK-based study revealed that E. coli accounts for ~75% of Gram-negative bacteraemia cases of urinary origin (Al-Hasan, Eckel-Passow and Baddour, 2010). The association of bacteraemia caused by E. coli and UTI origin is therefore significant in the UK.

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Figure 1.2. Sites of colonisation of the human body by pathogenic strains of Escherichia coli.

Pathogenic strains of E. coli are able to colonise various parts of the human body and cause subsequent disease, an ability that is attributed to the genome plasticity of the species and the carriage of specific virulence-associated genes (VAGs). The human extraintestinal pathogenic E. coli (ExPEC) develop infections at anatomical sites exterior to the gastrointestinal tract. Neonatal meningitis E. coli (NMEC) have the ability of crossing the blood-brain barrier (BBB) into the central nervous system and cause meningitis, whilst uropathogenic E. coli (UPEC) colonise and cause infection along various parts of the urinary tract, including the bladder and the kidneys, from which they can disseminate to the bloodstream and cause septicaemia. The intestinal pathogenic E. coli colonise various parts of the gastrointestinal tract. Enteroinvasive E. coli (EIEC), enteroaggregative E. coli (EAEC), and the particularly virulent entero-aggregative-haemorrhagic E.

coli (EAHEC) and enterohaemorrhagic E. coli (EHEC) colonise the large intestines, whereas

enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), diffusely adherent E. coli (DAEC), as well as adherent invasive E. coli (AIEC) colonise and cause infection in the small intestines. Enteroaggregative E.

coli (EAEC) have the ability to cause disease in both the large and small intestines. Figure adapted from

Croxen and Finlay (2010) to include the recently identified pathotypes, EAHEC and AIEC.

Brain: NMEC

Bladder: UPEC Kidneys: UPEC

Small intestines: EPEC, ETEC,

DAEC, EAEC, and AIEC

Large intestines: EHEC, EIEC,

EAEC, and EAHEC

Bloodstream:

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