E. coli O104:H4 A Newly Emergent Pathogen A deadly new strain that has picked up the Shiga toxin genes with the help of a virus that smuggles genes between bacteria
The outbreak of Shiga toxin-producing Escherichia coli O104:H4 (The "O" in the serological classification identifies the cell wall lipopolysaccharide antigen, and the "H" identifies the flagella antigen) began in Germany in May 2011 [1]. Between 2 May and 14 June 2011, 3,332 cases were reported, including 818 cases of HUS (haemolytic uremic syndrome, or bloody urine) were reported from 13 European Union Member States, and 36 patients died. Over 95 percent of the afflicted were from Germany and the vast majority live in, or have travelled to northern Germany [2]. Cases were also found in US and Canada [3]. Some 100 patients have such bad kidney damage in Germany that they need an organ transplant or will require dialysis treatment for the rest of their lives, according to Karl Lauterbach, health expert for the Social Democrats party. After several weeks of searching, German authorities said the source of the outbreak was vegetable sprouts from an organic farm in Lower Saxony in northern Germany.
E. coli O104:H4 is a new strain more threatening than E. coli O157:H7 that has killed many in North America and Europe during the past thirty years.
Shiga toxin
Shiga toxin-producing E. coli (STEC) was created by the transfer of DNA from another bacterium, Shigella dysenteriae type 1, to previously harmless E. coli by a bacteriophage (virus that infects bacteria), thereby providing the resultant STEC with the genes to produce one of the most potent toxins. HUS can also occur after S. dysenteriae type 1 infection. Convulsions may occur in children, related to a rapid rise in temperature or metabolic alterations associated with the production of the Shiga toxin. Although E. coli O157:H7 is responsible for the majority of cases in America, there are many additional STEC strains that can cause HUS [4], including O104:H4.
Shiga toxins are iron-regulated toxins that catalytically inactivate 60S ribosomal subunits of eukaryotic cells, blocking mRNA translation and causing cell death. STEC stains gained the ability to produce Shiga toxins by being infected with a prophage (phage genome integrated into the bacterial genome) containing the structural coding for the toxin, and nonproducing strains may become infected and produce Shiga toxins after incubation with Shiga toxin positive strains. The prophage responsible seems to have infected the outbreak strain fairly recently, as viral particles have been observed to replicate in the host if it is stressed, as for example, with antibiotics. That is why antibiotics are not recommended for treatment of infections with STEC.
Bacterial gene transfer
Bacteria employ a number of means of transferring genes between individuals of the same species and between widely divergent species and genera (horizontal gene transfer). Most bacteria have a single circular chromosome that may be transferred to a recipient during mating (conjugation). Genetic analysis of the complete DNA sequence of E coli O157:H7 showed that almost 20 percent of its chromosome consists of foreign DNA not present in the chromosome of E. coli K-12 (the common laboratory strain), probably acquired from other bacterial species through horizontal gene transfer [5, 6].
Prophages are copies of a virus genome inserted into a bacterial chromosome which may be activated by stress (the SOS response) to produce and release infectious virus. Prophages may incorporate bacterial genes such as the Shiga toxin genes and transmit them as infectious virus particles to be incorporated into recipient bacteria. In some cases the incorporated Shiga toxin genes are in defective prophages that are unable to produce infectious viruses {such Shiga toxin genes are flanked by insertion sequences) [7]. Shiga toxin and antibiotic resistance genes will transfer horizontally among bacteria in the house fly gut via plasmid transfer or phage transduction [8]. Plasmids are circular DNA molecules that replicate autonomously. The toxic HUS/STEC strains maintain one or more plasmids bearing virulence factors and antibiotic resistance genes. For example, E coli O157 possesses a large virulence plasmid pO157 of approximately 90 Kb. The nucleotide sequence of this plasmid shows that it encodes 35 proteins, some of which are presumably involved in the pathogenesis [9]. In conclusion, horizontal gene transfer is of utmost importance in the genesisand perpetuationof deadly E coli strains. The direct and immediate observation of horizontal gene transfer by plasmids and transduction in the gut of house flies reflects the similar transfers taking place in the guts of vertebrates and invertebrates. Horizontal gene transfer takes place also in soil and surface water containing faeces that has not been composted sufficiently to eliminate the Shiga toxin genes.
Origin of E coli O157:H7
The toxic strain O157:H7emerged in the United states during the1980s, and has since caused illness and death globally. Ten years ago, Mae-Wan Ho argued that genetic engineering may have contributed to the rapid evolution of E. coli 0157:H7, which has many genetic differences compared to the common harmless E. coli strain (see [10] E. coli 0157-H7 and Genetic Engineering, ISIS News 9/10). Indeed, it is legitimate to question whether genetic engineering over the past 40 years may have contributed to the accelerated rate at which new and recurrent strains of antibiotic and drug resistant pathogenic viruses and bacteria have been emerging during the same period (see [12] Gene Technology and Gene Ecology of Infectious Diseases, ISIS scientific publication). The horizontal mobility of the Shiga toxin genes and their associated virulence genes suggests that toxic strains may have been generated many times. Along with the toxin genes, the toxic strains contain plasmids bearing antibiotic resistance. For example, analysis of O157 strains from Nigeria showed that one or resistance plasmids were present and an aquatic O157 isolate containing two plasmids was resistant to seven drugs, including ampicillin, cefuroxime, ciprofloxacin, cotrimoxazole, nalidixic acid, nitrofurantoin and tetracycline [13]. A Greek study of milk from cows, goats and sheep showed that all 29 E. coli O157 isolates displayed resistance to a wide range of antimicrobials, with the Shiga toxin positive isolates being, on average, resistant to a higher number of antibiotics than those which were Shiga toxin negative. All E. coli O157 isolates were found to be resistant to ampicillin, an antibiotic used in human medicine for the treatment of coliform infections, and all but one isolate (isolate LFH13) were also resistant to streptomycin. Interestingly, not one of the 9 antimicrobials tested was found to be inhibitory against all isolates. Overall, tetracycline was found to be the most inhibitory antimicrobial in terms of the number of isolates that were inhibited (27 isolates), followed by gentamicin (26 isolates) and cefuroxime (22 isolates); these three antimicrobials are also used in practice to treat human infections [13] The spectrum of antibiotic resistance genes in isolates of E. coli O157 suggest that veterinary, human hospital and research laboratories may have contributed to the spread of the toxic bacterium and to have shaped its current development.
Origin of E. coli O104:H4
The first isolates of the E. coli O104:H4 with Shiga toxin date back to 2001, and were described by scientists as HUSEC41. It turned up again in 2006, in a woman who contracted HUS in Korea [14]. The current O104:H4 outbreak strain is a recombinant of two pathogenic E. coli types, enterohaemolytic E. coli (EHEC), causing haemolytic uremic syndrome HUS, and enteroaggregative E. coli (EAEC), a recognized cause of diarrhoea in children in developing countries. Recent outbreaks implicate EAEC as a cause of foodborne illness in industrialized countries. EAEC infection causes bacterial cells to form biofilms that adhere to the intestinal mucosa and elaborate enterotoxins and cytotoxins, which result in secretory diarrhoea and mucosal damage. EAEC's ability to stimulate the release of inflammatory mediators may also play a role in intestinal illness [15]. E. coli O104:H4 may have arisen through mating between male and female E. coli that produced recombinants bearing new and deadly gene combination or by repeated horizontal gene transfer, resulting in deadly strains.
E. coli O104:H4 also contains an array of antibiotic resistance genes conferring resistance to ampicillin amoxicillin/clavulanic acid, piperacillin/sulbactam, apiperacillin/tazobactam, cefuroxim, cefuroxim-zxetil, cefoxitin, cefotaxim, cetfazidim, streptomycin, nalidixinsäure, tetracyclin, trimethoprim and sulfamethoxazol [16], exceeding the numerous resistance genes found in previous lethal outbreaks. The antibiotics are predominantly available in medical applications. The convergence of multiple antibiotic resistance genes and novel toxins suggest that the lethal bacteria originated in a hospital or hospitals.
Any defence?
Is there any defence against the newly emergent toxic bacteria? Researchers found that children treated with antimicrobials had a relative risk of 14.3 of developing HUS. They concluded that antibiotic treatment of children with E coli O157:H7 gastroenteritis significantly increases the risk of developing HUS [18]. Some antibacterial drugs, including fluoroquinolones and trimethoprim–sulfamethoxazole, increase the induction of phage-mediated production of Shiga toxin and increase the risk of development of HUS. Most authorities recommend supportive treatment only in patients with Shiga toxin–producing E. coli infection [19]. Recent animal studies found that virulence was inhibited by zinc in Shiga-Toxigenic Escherichia coli in animals but that treatment has not yet been used with humans [20].
Composting manure may be enough to prevent the spread of toxic, foodborne E coli, if the strain is harboured by livestock. Composting manure is effective in destroying E coli as long as temperatures above 50 °C are achieved. Temperatures below 50 °C cause an initial decline in the pathogen but this is followed by a significant re-growth at lower temperatures. The pathogen was destroyed after 300 degree/days (say 6 days at 50 °C of heating). A study from Sweden showed that E coli 0157 could survive for as much as a year in manure treated soil and in manure that had not been composted. Different strains of E coli 0157 differed in environmental survival. Urea treatment of cattle manure minimized transfer of E coli from animal to animal and hence to humans. The gene for Shiga toxin in E. coli 0157 can be transferred to relatives of E coli 0157 and even to other bacterial genera, such as Citrobacter. Parsley infected with Shiga toxin-bearing Citrobacter caused a major outbreak among people consuming parsley butter. The gene is transferred among bacterial genera by a bacteriophage Stx2. Growth of the phage was supported on compost, but the phage can be eliminated by composting during which a temperature greater than 50 °C is maintained for at least 5 days.
However, E. coli O104:H4 does not appear to be harboured by livestock, but rather by human hosts [17]. So personal hygiene especially of food handlers are of primary importance in preventing infection; giving no substance to those who try to implicate organic farming in the recent outbreak. There is a further complication; to quote the editor of the British Food Journal [21] “A common misconception is that science and research are about facts”.
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