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Published Date: 2012-03-07 15:12:55
Subject: PRO/AH/EDR> E. coli EHEC - Europe (03): discussion
Archive Number: 20120307.1063524

E. COLI EHEC - EUROPE (03): DISCUSSION
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Date: Thu 1 Mar 2012
From: Eran Kopel <eran.kopel@mail.huji.ac.il> [edited]

[re: ProMED-mail EHEC E. coli - Germany: (HH) 20120229.1056769]
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I would like to offer the ProMED-mail readers a view on the possible evolution of emerging pathogens such as the Shiga toxin enterohemorrhagic/enteroaggregative _Escherichia coli_ O104:H4 that caused the large outbreak in Germany in 2011.

The outbreak strain was found to be similar, apart from the unexplained presence of its Stx genes (1), to a strain isolated and described phenotypically in the mid-1990s from an HIV-positive adult patient with chronic diarrhea in the Central African Republic (2). Genome analysis-only, however, as the authors admitted, could not discover "the true complexity of the evolutionary pathway" that has created this highly virulent and resistant outbreak strain (1).

By using a simple method (http://www.ncbi.nlm.nih.gov/pubmed/; accessed 3 Jun 2011), I have learned that Cunin at al (3) described a bloody diarrhea outbreak that occurred in Cameroon in 1997-98. That outbreak had a remarkable epidemiologic similarity with the 2011 outbreak (4). Of 298 patients, morbidity incidence, and case fatality rates were significantly higher in women. Notably, multidrug-resistant _Shigella dysenteriae_ type 1, _S. boydii_, and enterohemorrhagic _E. coli_ O157 were found to co-exist in patients. The _E. coli_ O157:H7 strains had Stx 1 and 2 genes.

Global trade routes could have potentially facilitated the introduction of similarly unrecognized pathogen to the epicenter of the 2011 outbreak, Hamburg, Germany, a major European seaport. This possibility should facilitate public health efforts, preferably by international collaboration, for tracing-back and preventing such outbreaks already at their origin; such is the frequent lack of proper sanitation and healthcare infrastructure in developing world regions.

References
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1. Rasko DA, Webster DR, Sahl JW, et al. Origins of the _E. coli_ strain causing an outbreak of hemolytic-uremic syndrome in Germany. N Engl J Med. 2011; 365(8): 709-17 [available at http://www.nejm.org/doi/full/10.1056/NEJMoa1106920#t=articleTop].
2. Germani Y, Minssart P, Vohito M, et al. Etiologies of acute, persistent, and dysenteric diarrheas in adults in Bangui, Central African Republic, in relation to human immunodeficiency virus serostatus. Am J Trop Med Hyg. 1998; 59(6): 1008-14 [available at http://www.ajtmh.org/content/59/6/1008.long].
3. Cunin P, Tedjouka E, Germani Y, et al. An epidemic of bloody diarrhea: _Escherichia coli_ O157 emerging in Cameroon? Emerg Infect Dis. 1999; 5(2): 285-90 [available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2640683].
4. Frank C, Werber D, Cramer JP, et al. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med. 2011; 365(19): 1771-80 [available at http://www.nejm.org/doi/full/10.1056/NEJMoa1106483].

--
Eran Kopel MD
Tel Aviv, Israel
<eran.kopel@mail.huji.ac.il>

[ProMED-mail thanks Dr Kopel for his comments on the possible origin and spread of the _E. coli_ O104:H4 epidemic centered in Germany in 2011.

Regarding similar organisms to this chimeric outbreak strain with characteristics of both enterohemorrhagic and enteroaggregative _E. coli_, on 5 Mar 2012 PLoS One published a comparison between DNA sequencing of a strain of _E. coli_ O103:H25 that contained a phage coding for stx2 that had 90 per cent homology with the German outbreak strain (L'Abee-Lund TM, Jorgensen HJ, O'Sullivan K, et al. The highly virulent 2006 Norwegian EHEC O103:H25 outbreak strain is related to the 2011 German O104:H4 outbreak strain. PLoS One 2012; 7(3): e31413; (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031413).

Abstract
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"In 2006, a severe foodborne EHEC outbreak occurred in Norway. Seventeen cases were recorded and the HUS frequency was 60 per cent. The causative strain, _Escherichia coli_ O103:H25, is considered to be particularly virulent. Sequencing of the outbreak strain revealed resemblance to the 2011 German outbreak strain _E. coli_ O104:H4, both in genome and Shiga toxin 2-encoding (Stx2) phage sequence. The nucleotide identity between the Stx2 phages from the Norwegian and German outbreak strains was 90 per cent. During the 2006 outbreak, stx2-positive O103:H25 _E. coli_ was isolated from 2 patients. All the other outbreak associated isolates, including all food isolates, were stx-negative, and carried a different phage replacing the Stx2 phage. This phage was of similar size to the Stx2 phage, but had a distinctive early phage region and no stx gene. The sequence of the early region of this phage was not retrieved from the bacterial host genome, and the origin of the phage is unknown. The contaminated food most likely contained a mixture of E. coli O103:H25 cells with either one of the phages."

One of the other issues with regard to the German outbreak was potential interventions. Of some note, in a report in the journal Science in January 2012, scientists from Carnegie Mellon University reported that the use of manganese, which appears to affect trafficking of the Shiga toxin, could protect tissue culture cells as well as mice against Shiga toxin (Mukhopadhyay S, Linstedt AD. Manganese blocks intracellular trafficking of Shiga toxin and protects against Shiga toxicosis. Science 2012; 335(6066): 332-5).

Abstract
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"Infections with Shiga toxin (STx)-producing bacteria cause more than a million deaths each year and have no definitive treatment. To exert its cytotoxic effect, STx invades cells through retrograde membrane trafficking, escaping the lysosomal degradative pathway. We found that the widely available metal manganese (Mn2+) blocked endosome-to-Golgi trafficking of STx and caused its degradation in lysosomes. Mn2+ targeted the cycling Golgi protein GPP130, which STx bound in control cells during sorting into Golgi-directed endosomal tubules that bypass lysosomes. In tissue culture cells, treatment with Mn2+ yielded a protection factor of 3800 against STx-induced cell death. Furthermore, mice injected with nontoxic doses of Mn2+ were completely resistant to a lethal STx challenge. Thus, Mn2+ may represent a low-cost therapeutic agent for the treatment of STx infections."

Given the potential morbidity and mortality related to this _E. coli_ pathotype, it will be quite instructive to see human studies. - Mod.LL]

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