Pathogenicity of enteric Gram-negative bacteria

The Enterobacteriaceae are a large family (>20 genera and 100 species) of facultatively anaerobic Gram-negative bacilli that are easily cultured, reduce nitrate and ferment glucose. The wide diversity of named species is in part because they are easy to grow and study in the laboratory, but also because they are capable of causing a wide variety of clinical syndromes.

Habitat and transmission
The Enterobacteriaceae are almost ubiquitous organisms. They are found in:

• the normal flora of animals and humans (forming a major component);
• water;
• soil.

Transmission is both from other animals or humans and from the inanimate environment. Many infections arise from the body's normal flora when opportunities are provided by medical, surgical or other therapy (see Innate immunity and normal flora).

Pathogenicity
Capsules
Many species produce extracellular capsular polysaccharides (e.g. Klebsiella spp., Escherichia coli and Salmonella typhi). S. typhi possesses a capsule or Vi (virulence) antigen and a vaccine containing the Vi antigen is protective against typhoid. E. coli K1 is the most common type of E. coli isolated from patients with neonatal meningitis and septicaemia. There are biochemical and structural similarities between E. coli K1 and N. meningitidis group B and human central nervous system antigens that may give these Pathogens an advantage.

Lipopolysaccharide
The lipopolysaccharide (LPS) molecule consists of a central lipid A and oligosaccharide core, and a long straight or branched polysaccharide 'O' antigen. It is located in the bacterial outer membrane and protects the organism against the bactericidal activity of complement. Lipid A stimulates host macrophages to produce cytokines, such as interleukin-1 and tumour necrosis factor (TNF), which mediate the fever, shock and metabolic acidosis associated with severe sepsis. Some clinical syndromes are associated with particular O antigens: for example, E. coli O157 may produce verotoxin, which causes haemolytic uraemic syndrome (HUS); other O types are associated with urinary tract infection or diarrhoea. However, these are merely temporal relationships between a variety of bacterial characteristics that include an O antigen and a particular virulence determinant.

Urease
Proteus spp. express a potent urease. In the urinary tract, urea lowers the pH, therefore infection with Proteus spp. allows calcium and phosphates to precipitate, with the formation of renal stones (see Urinary and genital infections).

Fimbriae
Fimbriae or pili are bacterial organelles that promote colonization, for example in the ureter. E. coli that express mannose- binding fimbriae are associated with lower urinary tract infections and cystitis, whereas those that express P fimbriae are associated with pyelonephritis and septicaemia. In the intestine, E. coli that express different fimbriae (colonization factor antigens, [CFAs]) have been associated with diarrhoea.

Toxins
Enterotoxigenic E. coli
Enterotoxigenic E. coli (ETEC) produce LT and ST toxins that act on the enterocyte to stimulate fluid secretion, resulting in diarrhoea. LT toxin, which is heat labile, shares 70% homology with cholera toxin and, like cholera toxin, increases local cyclic adenosine monophosphate (cAMP) in the enteric cell. ST toxin is heat stable and stimulates cyclic guanyl monophosphate (cGMP). E. coli that possess these enterotoxins are associated with travellers' diarrhoea, which is a short-lived, watery diarrhoeal disease.

Enteroaggregative E. coli
Some strains of E. coli, which are known as enteroaggregative E. coli (EAggEC), secrete plasmid-encoded toxin, a serine protease that binds α-fodrin and causes disruption of the actin cytoskeleton, and are able to cause chronic diarrhoea. Strains express an ST-like toxin or a haemolysin-like toxin.

Enteropathogenic E. coli
Enteropathogenic E. coli (EPEC) cause disease by colonizing the epithelial lining of the small intestine and injecting effector proteins that cause effacement of microvilli and intimate adherence. Isolates with this characteristic were the first E. coli recognized as primary pathogens, when they caused outbreaks of diarrhoea in preschool nurseries.

Enterohaemorrhagic E. coli
The enterohaemorrhagic E. coli (EHEC) strains produce a verotoxin named because of its in vitro activity on 'vero' cells. The haemorrhagic diarrhoea that they cause can be complicated by haemolysis and acute renal failure (HUS). This organism is commensal in cattle and is transmitted to humans through hygiene failure in abattoirs and food production. A similar toxin (Shiga toxin) is a major virulence determinant in Shigella dysenteriae.

Genetic exchange
The Enterobacteriaceae can gain DNA rapidly from other organisms through transposons, integrons or plasmids. This enables antibiotic-resistance genes to spread from one species to another. In the hospital environment the survival of antibiotic-resistant strains is favoured. In some hospitals there have been outbreaks of multidrug-resistant Klebsiella pneumoniae in intensive care units. The Enterobacteriaceae have also been able to gain Pathogenicity determinants by genetic exchange. Acquisition of a series of connected genes can occur and these are known as Pathogenicity islands. In this way Salmonella have gained a series of genes that enable them to invade intestinal cells.