An amazing amount of genetic analysis has been rapidly published about the huge recent outbreak of foodborne illness in Germany caused by a pathogenic E. coli. Much of this has been discussed in previous posts at this blog (accessible using the tag EHEC EAEC STEC).
Adding to this, yet another paper decoding the genomes of germs isolated from this outbreak has just been published in New England Journal of Medicine. The full content of this publication is freely available at the New England Journal of Medicine website. The main conclusions of this paper are as follows:
Our findings suggest that horizontal genetic exchange allowed for the emergence of the highly virulent Shiga-toxin–producing enteroaggregative E. coli O104:H4 strain that caused the German outbreak. More broadly, these findings highlight the way in which the plasticity of bacterial genomes facilitates the emergence of new pathogens.
But there is a swag of discoveries in this paper that are medically important and which give rich insights into the way in which gene movement between different types of bacteria is responsible for the emergence of new pathogens. They are really worthy of some further explanation (as given below), particularly since this kind of natural evolution of pathogens is so readily and wrongly interpreted by crank-science conspiracy theorists as the deliberate laboratory creation of some evil drug company.
This new paper in presenting findings with numerous different natural strains of pathogenic E. coli provides no hint at all of laboratory interference with natural evolution of germs. The German outbreak strain is in fact incredibly similar to a whole family of other germs that have been isolated in widely different locations around the planet over the last several years.
EHEC or EAggEC?
The most distressing feature of the recent huge European outbreak of foodborne E. coli disease is the severe kidney damage occurring with many of the victims of infection. Features of severe kidney disease seen among the patients are given the medical term haemolytic uraemic syndrome (abbreviated to HUS). Another type of symptom seen in this foodborne disease epidemic is the occurrence of bloody diarrhoea. E. coli bacteria that cause these patterns of disease in the past have been called enterohaemorrhagic E. coli or EHEC.
Unusually for EHEC infections, the recent German HUS outbreak strain exhibited a distinctive pattern of bacterial cell attachment to the lining of the human gut that that had been previously noted in in another type of disease-causing E. coli found with distressing frequency in developing countries in cases of diarrhoea among children. This type of E. coli are referred to as enteroaggregative E. coli (EAggEC also called EAEC)
Most often in the past, such EAggEC have been distinct from EHEC in not being able to produce a potent toxin called Shiga toxin that is a major cause of the severe kidney damage in patients infected with EHEC. But a very unusual feature of the 2011 German outbreak strains is that they are also able to produce Shiga toxin, so the question comes up: are they modified forms of EHEC who have gained ability to produce the aggregate of pattern of attachment to human gut linings, or are they modified forms of aggregative E. coli that have gained ability to produce Shiga toxin?
German Shiga toxin producing enteroaggregative E. coli is not EHEC.
The investigation reported in this issue of the New England Journal of Medicine provides a clear cut answer to this question. It is able to provide answers because it examines the genetic make up of a wide collection of enteroaggregative E. coli and comprehensively compares their genetic content to the genetic code of the German outbreak strain.
This family comparison reveals that the major part of the genetic composition of the outbreak E. coli strain is very similar to a variety of other enteroaggregative E. coli and quite dissimilar the common pathogenic EHEC type E. coli .
This confirms yet again the strains are probably best called Shiga toxin producing EAggEC, and that it is misleading to call them EHEC.
Further analysis of the detailed argument presented in this report confirms that the German outbreak strain arose relatively recently from other enteroaggregative E. coli by addition of a block of genes that is part of a welland characterised an familarbacterial virus (repeatedly seen in nature) that has become inserted at a particular place in the main E. coli chromosome. This newly inherited bacterial virus — or prophage as it called — contains a gene that encodes ability to produce Shiga toxin. The authors say ” outbreak strain is not a prototypical enterohemorrhagic E. coli strain that has acquired the virulence features of enteroaggregative E. coli.”
The report also reveals that the Shiga toxin output from the German outbreak strain can be greatly increased by exposure of the germ to certain antibiotics, a finding that has also been seen with EHEC type bacteria. This underlines the common advice that antibiotic treatment can worsen the prognosis for patients suffering this particular type of infection.
The outbreak strain carries three SPATEs.
This report introduces one other possible explanation for the apparent extreme virulence of the German outbreak strain. It comments that there are three copies of particular virulence related genes that encode for a secreted toxin system that goes under the acronym SPATE. This is an unusually large number of SPATE toxin genes for enteroaggregative E. coli. It seems possible that part of the virulence capabilities that the outbreak strain has acquired is an increased range of SPATE toxins, adding to the damage that could be caused by Shiga toxin.
The bottom line is the German outbreak was caused by a horizontal gene movement of extra virulence genes into a enteroaggregative E. coli and this gene movement added to the virulence capabilities of the strain leading to the relatively recent emergence of a new form of HUS disease. The mechanisms by which this evolution occurred were very similar to genetic changes frequently seen in other strains of E. coli, and such horizontal gene movement in bacteria is wholly unsurprising from a biological point of view, despite the fact that the emergence of new forms of disease caused by new germs is a dreadful shock to the health system and the food supply.
Origins of the E. coli Strain Causing an Outbreak of Hemolytic–Uremic Syndrome in Germany
David A. Rasko, Ph.D., Dale R. Webster, Ph.D., Jason W. Sahl, Ph.D., Ali Bashir, Ph.D., Nadia Boisen, Ph.D., Flemming Scheutz, Ph.D., Ellen E. Paxinos, Ph.D., Robert Sebra, Ph.D., Chen-Shan Chin, Ph.D., Dimitris Iliopoulos, Ph.D., Aaron Klammer, Ph.D., Paul Peluso, Ph.D., Lawrence Lee, Ph.D., Andrey O. Kislyuk, Ph.D., James Bullard, Ph.D., Andrew Kasarskis, Ph.D., Susanna Wang, B.S., John Eid, Ph.D., David Rank, Ph.D., Julia C. Redman, Ph.D., Susan R. Steyert, Ph.D., Jakob Frimodt-Møller, M.Sc.Eng., Carsten Struve, Ph.D., Andreas M. Petersen, Ph.D., Karen A. Krogfelt, Ph.D., James P. Nataro, M.D., Ph.D., M.B.A., Eric E. Schadt, Ph.D., and Matthew K. Waldor, M.D., Ph.D.
July 27, 2011 (10.1056/NEJMoa1106920)