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E. coli

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Toxic E.coli outbreaks are new in human history, emerging in the 1950s. The U.S. Centers for Disease Control made toxic E.coli a reportable pathogen in 1982. Since the mid-1980s, mostly small outbreaks of under 50 cases have cropped up in spurious fashion, however, the 1990s brought a distinctive change in the scope and severity of E.coli contamination.

A record-setting series of outbreaks over a 6 month period in 1996 Japan claimed over 17,800 victims.  A recent event in Germany, beginning May of 2011, reports over 4,200 with a high death toll and rate of further complication from a once-rare illness called hemolytic uremic syndrome (HUS). The toxin that these outbreaks have in common originally came from dysentery-causing bacteria called Shigella –its toxic genes are labeled “Stx” (stx1 and stx2) for Shiga toxin— and were discovered between 1896 and 1900. The Stx genes are carried on bacteriophages, or simply ‘phage’, the transferable viruses of bacteria. A microbe recombination event sometime in the 1950s inserted  Shiga toxin genes into the ‘lambda’ phage of the E.coli species which are now widening the spread of Shiga toxin-producing E.coli (STEC) and threatening human health.  This page is dedicated to the history and biology of toxic E.coli.

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To be posted: E.coli geographical spread, timeline, prominent E.coli researchers, scientific and medical citations describing how the Shiga toxin works, so-called “desirable” characteristics of the Shiga poison (stx), and the potential uses of Shiga toxin in pharmaceuticals and genetic engineering.

*http://en.wikipedia.org/wiki/Coliform_bacteria ; Escherichia coli (E. coli), a rod-shaped member of the coliform group*; “E.coli were discovered in the human colon in 1885 by German bacteriologist Theodor Escherich… E.coli can grow in the air using oxygen as a terminal electron acceptor (aerobically) or without air… The ability to grow both aerobically and anaerobically classifies the E.coli bacteria as a facultative anaerobe.” http://www.ecoliblog.com/2005/01/

 E.coli

 bacteriophage (heads with tailspikes)

 lambda phage  (transfers genes both to and from its host cell)

 phages in a cell

The lambda phage of E.coli (strain K-12) was discovered in 1950 by Esther Zimmer Lederberg, wife of science leader and Rockefeller University president Joshua Lederberg, after several years of observation with E.coli showed that genetic material was transferred by viral-like particles in a process of coinfection.  The original E.coli lambda phage and other lambdoid phages from various bacteria are capable of exchanging genetic material and altering the functions of the cells they infect. The similarity of these phages allows them to be considered as one gene pool although the type and functions are distinguished (or modified) as they interact with the host cell as endosymbionts. Esther Lederberg wrote “Lysogenicity, or latent virus [prophage], is of frequent occurrence in enteric bacteria..” http://www.estherlederberg.com/LMBD%20p2.html [scanned original 1950 paper]

Escherichia coli (strain K-12) was isolated in 1922 and became the “workhorse” of biotechnology. Modified E.coli have industrial uses in medicine and chemical production. They are highly adaptable bacteria, common (‘friendly’) and essential to the intestinal gut flora of mammals. Some of them just aren’t friendly any more. How and why did that happen?

The theory on the creation of toxic E.coli is generally held to be a bacterial ‘conjugation’ event between  Shigella dysenteriae and Escherichia coli. Bacterial conjugation as a method of gene transference was discovered in 1946 by Joshua Lederberg. http://en.wikipedia.org/wiki/Bacterial_conjugation ; http://denniskunkel.com/DK/Bacteria/71223E.html

“Inhibition of protein synthesis is a common mechanism by which bacterial and plant toxins injure human cells. Examples of toxin..include shiga toxins of [E.coli]..and the plant toxin ricin… Stx and ricin enzymically cleave an adenosine residue from 60S ribosomes, inactivating ribosome function. These toxins are..potential agents of bioterrorism. Consequently, there is considerable interest in understanding how these toxins interact with host cells, with the ultimate goal of developing [countermeasures].” http://jmm.sgmjournals.org/content/54/11/1023.full ;  ribosome definition http://www.absoluteastronomy.com/topics/Ribosome

                                                              The deadly strains O157 and O104

“The toxic strain O157:H7 emerged in the United states during the 1980s, and has since caused illness and death globally. Ten years ago [c.2001], 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… 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… 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.” http://www.i-sis.org.uk/E_coli_O104_H4_Newly_Emergent_Pathogen.php; “Hemolytic uremic syndrome..was first described in 1955, and is now recognized as the most common cause of acute kidney failure in childhood.” http://www.marlerblog.com/legal-cases/three-suffering-kidney-failure-hus-from-alabama-e-coli-poisoning/
   It is equally legitimate to propose that genetic engineering is the sole reason for the emergence and spread of toxic E.coli. Nature, in all its wonder, has never combined the activating stx toxin with E.coli at any time before human ‘tinkering’ made it possible. Further analysis will prove the high unlikelihood of continent-hopping deadly strains under natural conditions, a situation ripe for sabotage and bioterror. If an unrevealed Public Enemy exists that would destroy only humans by attrition and stealth, toxic E.coli is an ideal weapon.
   The STEC (Shiga toxin E.coli) group of pathogenic E.coli bacteria currently have 100 or more member strains that cause illness, “although more than 200 STEC serotypes have been described..” http://aem.asm.org/cgi/content/full/75/19/6187. The subgroup of STEC that is now lethally epidemic, including O157:H7 and O104:H4, are enterohemorrhagic E.coli (EHEC): “Gastrointestinal infections with enterohemorrhagic Escherichia coli..usually manifest as acute, afebrile, painful, bloody diarrhea. EHEC are the leading precipitants of hemolytic uremic syndrome (HUS), an important [leading] cause of childhood renal failure. E.coli O157:H7 is the most common EHEC serotype associated with HUS, but several non-O157:H7 serotypes such as O26:H11, O103:H2, O111:H8, O145:H28 and O157:NM (nonmotile) have emerged as causes of this disease.” [2005] http://cid.oxfordjournals.org/content/41/6/785.full   E.coli O104:H4 is a newcomer to the expanding EHEC list as each outbreak raises the probabilty of even more emerging strains and the potential of toxigenic crossover to other bacterial species. For this reason, a separate description of the shiga toxin, the interest that it generates among scientists as a ‘tool’ in genetic engineering and as a bioweapon is of timely significance.
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“The Shiga toxin triggers a complex cascade of changes in the blood.. and there is disruption of the inherent clot-breaking mechanisms. The formation of micro-clots in the blood vessel-rich kidneys leads to impaired kidney function and can cause damage to other major organs. About ten percent of individuals with E.coli..infections (mostly young children) goes on to develop Hemolytic Uremic Syndrome.” http://www.marlerblog.com/legal-cases/three-suffering-kidney-failure-hus-from-alabama-e-coli-poisoning/
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“Approximately 110,000 cases of Shiga toxin-producing E.coli infections are reported annually in the United States..” http://ncbi.nlm.nih.gov/pmc/PMC1168570; Current CDC estimates for Stx-producing E.coli infections in the U.S. stand at 186,000 cases annually http://www.marlerblog.com/lawyer-oped/non-o157-e-coli-in-beef—how-does-fsis-justify-it/
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                                                               Hemolytic Uremic Syndrome
“The principle organ affected in STEC-mediated HUS is the kidney… The severity of renal injury varies in degree from urinary abnormalities such as hematuria and proteinuria to acute renal failure… The second most important organ affected in the disease is the brain… more serious cerebral complications, including seizures, cortical blindness, and thrombotic strokes, occur in 5 to 10% of patients… A similar percentage of patients may develop life-threatening cardiopulmonary sequelae, including adult [acute] respiratory distress syndrome [ARDS], congestive heart failure and myocarditis. The occurrance of neurological and cardiovascular complications is associated with more severe STEC-induced HUS and a higher risk of mortality during the acute illness. Other organs that are frequently involved in STEC-induced HUS are the endocrine and exocrine pancreas, liver, gall bladder, gastrointestinal tract, and skin. It is evident that STEC-induced HUS is a systemic illness potentially affecting every organ throughout the body.http://cmr.asm.org/cgi/content/full/17/4/926
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                                                                  Japan 1996
“In Japan during 1996, explosive outbreaks of STEC infection occurred, with 17,877 people infected and 12 fatalities” http://aac.asm.org/cgi/content/full/46/11/3478
Japan’s 1996 outbreak was documented as 22 separate outbreaks between May and October (there were a total of 7 E.coli outbreaks in the previous five years): “In July..a large outbreak of exclusively Stx-1 producingE.coli 0118:H2 occurred in a junior highschool in Komatsu city. This appears to be the first report in the world of clinical infection caused by this organism… 241[students and staff] were symptomatic… Although Stx-producing E.coli was not isolated from the samples of food and water, it was isolated from a dipper… No subjects developed infection at 11 other schools that had served the same..foods… the source of the primary infection was not identified..” One month after that another type of E.coli, O26:H11, that also anomalously produced only the Stx-1 variant of shiga-toxin (again a world’s first), caused a small outbreak. http://pediatrics.aappublications.org/content/103/1/e2.full
“May through August..approximately 10,000 cases..[were] associated with at least 14 clusters… One cluster was a large outbreak in Sakai City, Osaka Prefecture, involving more than 6,000 primary school children..started on July 13, 1996… An outbreak also occurred in a factory in Kyoto, approx. 50 km from Sakai City… Of the 3,155 employees of the factory, 74 reported gastrointestinal symptoms [47 had diarrhea]… the peak date of symptom onset was July 17… Three cases of HUS (6%) among 47 cases..is comparable to rates described in other outbreaks.” http://www.cdc.gov/ncidod/EID/vol5no3/watanabe.htm
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                                                                    Germany, 2011
[July 7, 2011]”The European Union reports 50 European deaths, 4,236 Ill with 898
suffering from hemolytic uremic syndrome” http://www.marlerblog.com/legal-cases/european-e-coli-o104h4-update—is-the-united-states-willing-to-pay-to-to-prevent-it-from-happening/
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“…the outbreak originating in Germany shows 87% of those hit by the disease were women over the age of 20…the..outbreak displayed ‘several intriguing microbiological characteristics’ and ‘several novel epidemiological and clinical features’… Among the ‘completely unexpected’ features was the development of severe neurological symptoms in half of patients…” http://www.irishexaminer.com/ireland/kfojidqlsney/rss2/
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   “German authorities have cleared Cheshire drug maker Alexion Pharmaceuticals Inc. to formally open a clinical trial..to aid victims stricken in what is called the worst E. coli outbreak in history…The Paul-Erhlich-Institut, Germany’s healthcare regulatory body, gave Alexion permission… On May 30 [2011], Alexion disclosed that it was donating thousands of doses of Soliris, also known as eculizumab, for use on some 800 confirmed cases of E. coli victims whose kidneys had been affected with STEC-HUS. The Soliris treatment can run into the hundreds of thousands of dollars a year per patient… Investigators suspect the E. coli outbreak stems from ingestion of tainted produce.” http://www.hartfordbusiness.com/news19085.html
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Soliris was U.S. FDA approved in March 2007: “The Aplastic Anemia & MDS International Foundation (AA&MDSIF) is extremely pleased that PNH patients now have a treatment..and for anyone with bone marrow failure”  http://www.drugs.com/news/fda-approves-alexion-s-soliris-all-patients-pnh-5516.html
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Alexion president Katherine Bowdish was one of five panelists from the pharmaceutical industry to address Congress during the ratification process of Project BioShield in 2003: “Our second panel includes industry and academic experts who will give us their views on this proposal. We have Frank Rapoport an attorney representing Aventis Pasteur. Next we will hear from Dr. Michael Friedman on behalf of the Pharmaceutical Research and Manufacturers Association of America. We also have Dr. Una Ryan, president of the AVANT Immuno-therapeutics located in Needham, MA. And Dr. Katherine Bowdish. She is president of the Alexion Antibody Technologies located in Cheshire, CT. And rounding out the panel is Dr. John Edwards, chief of infectious diseases at UCLA.”
Dr. Bowdish’s statement: “As we saw in the attacks against our Nation in 2001, inhalation anthrax is a highly fatal disease if not identified early enough for antibiotics to be of use. Death usually occurs within a few days of the onset of acute symptoms, primarily from the toxins produced by the anthrax bacteria, not the bacteria itself…successful anthrax defense will require agents against the toxins otherwise known as antitoxins… Monoclonal antibodies are among the most logical and natural antitoxins that could be developed… Alexion has successfully isolated human monoclonal antibodies with therapeutic potential for biodefense… the approach we are taking is a necessary and achievable component to U.S. biodefense initiatives.And most importantly, we have demonstrated that our approach works. It is our hope that Congress can help us ensure that the appropriate decisionmakers in our Federal Government are aware of our critical and highly relevant work for consideration for civilian and military defense.” [scroll approx. two-thirds down]  https://house.resource.org/108/org.c-span.175961-1.raw.txt
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…some people don’t think the Shiga toxic E.coli came from tainted produce at all.
Stx has been listed as an aerosol: “The [Stx] protein is robust, stable, relatively easy to manufacture and has been the subject of intense research over many years…This [body of] information..may also be used to develop novel variants of greater effectiveness. The protein does not act through the skin, and effective protection can probably be obtained with a gas mask with activated charcoal filters.” http://www.cbwinfo.com/Biological/Toxins/Verotox.html
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                                                              Other Toxic E.coli strains
“Escherichia coli serogroup O103 has been associated with gastrointestinal illness and hemolytic uremic syndrome [HUS]” http://www.rt-pcr.com/showabstract.php?pmid=16121232
[2001] “In some geographic areas, non-O157 strains are more commonly isolated from persons with diarrhea or HUS… From the epidemiologic point of view, the most important..have been O26.. O103.. and O111..strains… In Australia, infections caused by STEC O160..have been reported.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC88246/
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                                                                 E.coli Infection
“[In a] 1984 survey of nosocomial [hospital acquired] infections in the United States, E.coli was associated with 30.7% of the urinary tract infections, 11.5% of the surgical wound infections, 6.4% of the lower respiratory tract infections, 10.5% of the primary bacteremia cases, 7.0% of the cutaneous infections, and 7.4% of the other infections [reference, 1991 Manual of Clinical Microbiology] http://www.freepatentsonline.com/6080400.html
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Uropathogenic E.coli (UPEC), cause of UTI and bladder infection http://www.umich.edu/~hltmlab/research/coli/genomic.htm
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E.coli is a frequent cause of pneumonia http://www.ncbi.nlm.nih.gov/pubmed/6753779
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Emerging E.coli pathogens
“The new superbug” E.coli,  (‘extraintestinal’ strain)–  “ST131 is severely drug resistant and causing major concern. Now being referred to as “the new superbug”, ST131 has been found..all over the world and all over the United States… ” http://www.associatedcontent.com/article/5680656/new_e_coli_superbug_st131_causing_major.html?cat=5 ; “In the past, highly virulent E.coli strains usually have been susceptible to antibiotics, while highly resistant strains have been fairly weak in terms of their ability to cause disease. The susceptible strains were easily treated even though they caused serious infections, whilethe resistant ones tended mostly to affect only weakened or vulnerable individuals. Now..findings suggest, the ST131 strain has appeared with a high level of virulence and antimicrobial resistance.” http://www.news-medical.net/news/20100731/Study-finds-ST131-a-major-cause-of-antimicrobial-resistant-E-coli-infections.aspx
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                                                         E.coli in research and industry
Recombinant DNA technology using E.coli was ‘breakthrough’ science in the late 1960s. A very controversial line of pursuit that accomplished the combining of E.coli with a monkey virus called SV40 was announced in 1972 by Paul Berg. Researchers in the U.S. are said to have voluntarily restrained from experimentation with the human-adapted recombinant. http://polioforever.wordpress.com/sv40-monkey-virus/
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Recombinant E.coli makes human insulin: “In the 1980s, researchers used genetic engineering to manufacture a human insulin. In 1982, the Eli Lilly Corporation produced a human insulin that became the first approved genetically engineered pharmaceutical product …Human insulin is grown in the lab inside common bacteria. Escherichia coli is by far the most widely used type of bacterium, but yeast is also used… Manufacturers manipulate the biological precursor to insulin so that it grows inside simple bacteria.” http://www.enotes.com/how-products-encyclopedia/insulin

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“In 2000, four independent studies hallmarked the beginning of the synthetic biology era by introducing the first synthetic gene circuits… together they launched the field of gene network engineering..” http://www.ncbi.nlm.gov/pmc/articles/PMC2704926/
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[2000 publication] “Construction of a genetic toggle switch in Escherichia coli” –“Here we present the construction of a genetic toggle switch..in Escerichia coli..[that] exhibits a nearly ideal switching threshold..and has implications for biotechnology, biocomputing and gene therapy.” http://www.ncbi.nlm.nih.gov/pubmed/10659857
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                                                                    Stx Vaccine//Treatment
2002— “Human Stx2-specific monoclonal antibodies prevent systemic complications of E.coli O157:H7 ” http://www.ncbi.nlm.nih.gov/pubmed/11796590
2004— “Currently, supportive nonspecific treatment is the only available option for..HUS… preclinical studies indicate that neutralizing specific antibodies directed against the A subunit of the toxin can be highly protective..even when administered well after exposure..and onset of diarrhea..” http://www.ncbi.nlm.nih.gov/pubmed/15489355
2005–“..several therapeutic agents have been developed based on the concept that if the toxin(s) can be absorbed or neutralized in either the gastrointestinal tract or in the circulation, the development of HUS can be prevented… One limitation of most of these therapeutic agents, with the exception of antibodies, is that they are orally administered, which considerably reduces their efficacy… large quantities of an antitoxin agent would also be required. In contrast, neutralization of the toxin in the blood circulation, close to the organ target, is much more efficient and requires only small quantities of an antitoxin agent, which in the case of antibody, has a relatively long half-life… The most efficacious of the Stx2-specific HuMabs [human monoclonal antibodies are those directed against the A subunit of Stx2, of which 5C12 is the most promising..” http://ncbi.nlm.nih.gov/pmc/PMC1168570
2006— “we sought to develop..a prototypic orally delivered, plant-based [transgenic tobacco] vaccine against Stx2..” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1459021
2007— patent filed on HuMab 5C12 http://www.freepatentsonline.com/y2009/0068176.html
2007— “…Stx subunit B vaccine delivered by a patch for a high-risk population may be a practical approachto prevent (and/or reduce) Stx-induced pathology… While there is indirect evidence that human vaccination against STEC may be effective in preventing illness in humans, at present,there are no human vaccines or therapeutics for human STEC infections” http://cvi.asm.org/cgi/content/full/15/2/359
2008— “Stx2 A-subunit-specific HuMab, 5C12, currently undergoing phase I clinical trials, was selected on the basis of its superior efficacy in protecting mice [and piglets] against lethal challenge with Stx2..” http://www.ncbi.nlm/nih/gov/pmc/articles/PMC2346683/ ;
 clinical trial phases>>> http://www.nlm.nih.gov/services/ctphases.html
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What’s taking so long for Stx treatment, in clinical trials since 2004, to be available?

…”the [2003] BioShield proposal includes provisions for public health emergencies, not just bioterrorism threats. The idea of including public health emergencies in a BioShield makes sense, because infectious diseases that occur in nature can claim many lives, can even become bioterrorist agents if intentionally spread..”..”Another provision permits products to be distributed without FDA approval.” https://house.resource.org/108/org.c-span.175961-1.raw.txt

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Microbe review
“All living organisms can be sorted into one of two groups depending on the fundamental structure of their cells. These are..the prokaryotes and the eukaryotes. Prokaryotes..lack a cell nucleus or any membrane-encased organelles. This means the genetic material DNA is not bound within a nucleus… DNA is a single loop. In eukaryotes, DNA is organized into chromosomes… Scientists have divided the prokaryotes into two groups, the Bacteria and the Archaea.” http://animals.about.com/od/animalswildlife101/a/diffprokareukar.htm
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   “DNA stores genetic information in base pairs of nucleotides. Long sequences of these base pairs form genes, which..provide the information to encode RNA and subsequently proteins… mobile DNA [called ‘jumping genes’, transposons, or modular DNA] is an important source of evolutionary innovation… whole sections of DNA can be deleted, duplicated, inserted, and moved to other parts of the chromosome  and even to other organisms via horizontal gene transfer [ed.–phage and viruses provide a natural vector for transferring DNA]…The DNA may [also] be modified through..point mutations [changes to any base pair] to provide another function in the organism…Variation in DNA is of two types: point mutations and ‘tinkering’, that is the creation of novel genes by random [or engineered] combinations of preexisting genes.” http://www.epicofevolution.com/velcroDNA.html
Barbara McClintock (1902-1992) discovered transposons, what she first called transposable elements in a 1951 paper. “[S]he confirmed that chromosomes physically exchange pieces during the phenomenon known as ‘crossing over’..” (Gale Encyclopedia) www.answers.com/topic/barbara-mcclintock
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“The [lambda] phage particle recognizes and binds to its host, E.coli, causing DNA in the head of the phage to be ejected through the tail into the cytoplasm of the bacterial cell. Usually, a ‘lytic cycle’ ensues, where the lambda DNA is replicated many times… This leads to assembly of multiple new phage particles within the cell and subsequent cell lysis, releasing the cell contents… However, under certain conditions the phage DNA may integrate..in the lysogenic pathway..[and] the lambda DNA is called a prophage and stays resident within the host’s genome..duplicated with every subsequet cell division of the host. The phage genes expressed in this dormant state code for proteins that repress expression of [or ‘downregulate’]other phage genes… These repressive proteins are broken down when the host cell is under stress, resulting in expression of the repressed phage genes [and the intiation of the ‘lytic cycle’]. Stress can be from starvation, poisons (like antibiotics), or other factors..” http://en.wikipedia.org/wiki/Lambda_phage
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   “According to the idea of modular evolution of bacteriophages all tailed phages with double-stranded DNA genomes may be seen as one gene pool, exchanging functionally related gene groups by recombination events with each other and with their respective host bacteria” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC427775/
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   “A major virulence factor of [toxic E.coli] bacteria are the Stxs, also called verotoxins, which comprise a family of heteromultimeric proteins belonging to the AB family [with two subunits, ‘A’ and ‘B’] of toxins and are part of the potent class 2 ribosome-inhibiting proteins [ed.–they stop the process of RNA gene transcription resulting in incomplete and dysfunctional gene fragments] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1065167
Verotoxins (VT) are the stx substances that react with Vero cells, a cell line used in research from African Green Monkey kidney. The terms ‘Shiga toxin'(Stx), ‘shiga-like toxin’ (SLT), ‘verotoxin’ (VT) and their numbered derivatives (i.e. stx1, SLT II, VT2, etc.) are all referencing the same basic entity.
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“Shiga toxin, produced by the microbe Shigella dysenteriae, was rediscovered as Verotoxin in E.coli by researchers in Ottawa in 1977…” http://www.wordiq.com/definition/Shiga-like_toxin ; there are four main types of Shigella bacteriae; S.dysenteriae, S.flexnerii, S.boydii and S.sonnei. The Shigella flexnerii, discovered in 1900 by Simon Flexner (director of the Rockefeller Institute) has infective sequelae that include neurological damage and arthritis.
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“Shigella is a bacterium that can cause sudden and severe diarrhea…Approximately 20% of the nearly 450,000 cases of shigellosis that occur annually in the U.S are foodborne-related.” http://www.marlerblog.com/shigella-information/
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   “The Shigella flexneri [stx-producing] phage Sf6 is morphologically similar to the Salmonella phage P22. Both are members of the class C bacteriophages..containing six tailspike proteins [TSP] responsible for the binding and hydrolysis of the receptor O-antigen..” http://www.jbc.org/content/278/3/1542.full   [ed.–demonstrating that other bacterial phages, e.g. Salmonella and Staphylococcus aureus phages, can potentially recombine with stx genes]
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“VT production has been observed in other members of the Enterobacteriaceae, including Enterobacter clocae and Citrobacter freundii, but was first described in Shigella dysenteriae as Shiga toxin. The localization of VT genes on a bacteriophage was first described by Smith et.al., but their acquisition by pathogenic E.coli remained anomalous because only nonpathogenic (rough) E.coli strains could apparently be infected with VT phage… It has been suggested previously that VT phages can infect only rough strains of E.coli and Shigella sonnei, inferring that the phage receptor(s) is masked by lipopolysaccharide O side chains. This can now be refuted, since a smooth strain, F172, was susceptible to lytic infection… [It was] found that VT genes could potentially be disseminated to different E.coli strains… lysogen formation [gene-transferring phage, also called prophage], and not just production of an observable plaque [in a lab dish, indicating active infection] is an important indicator of infectivity…” http://aem.asm.org/cgi/content/full/67/9/4335
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   “Use of the lambda..system to produce recombinant prophages..[and] to induce mutations in the genome of some temperate Shiga toxin encoding bacteriophages. When phage genes are in the prophage state, they behave like chromosomal genes. This enables marker genes, such as antibiotic resistance genes, to be incorporated into the stx gene. Once the phages’ lytic cycle is activated, recombinant Shiga toxin converting phages are produced. These phages can transfer the marker genes to the bacteria that they infect and convert.” http://www.ncbi.nlm.nih.gov/pubmed/16984631 [ed.–the bacteria compound their antibiotic-resistance profiles by incorporating antibiotic-resistant parts]
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   “The expression of both stx1 and stx2 was found to be coregulated with transcription of the late phage genes associated with the lytic cycle, and in the case of stx1, could also be induced by low-iron conditions… [The] production of Stxs is a virulence trait that can be easily transmitted horizontally in a process called lysogenic conversion…”
The lytic cycle, known to ‘turn on’ the stx gene, is one of two processes in viral replication that results in destruction of host cells: http://en.wikipedia.org/wiki/Lytic_cycle
Lysogenic conversion utilizes the alternate process, lysogeny, transference of genes in living cells: http://www.biology-online.org/dictionary/Lysogeny
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   “Stx is an unrecognized modulator of the innate immune response of human enterocytes” http://www.jimmunol.org/context/178/12/8168.abstract
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   “We have preliminary data showing that Stx1 specifically inhibits the hallmark spontaneous proliferation of bovine leukemia virus(BLV)-infected cells placed in culture..” http://www.reeis.usda.gov/web/crisprojectpages/194154.html
   “We show here that purified Stx1 induces TNF (tumor necrosis factor) secretion by a human monocyte cell line… Treatment of cells with both lipopolysaccharides (LPs) and Stx1 results in augmented TNF production.” http://bloodjournal.hematologylibrary.org/content29/2/558.full
lipopolysaccharides are molecules in the outer bacterial membrane http://en.wikipedia.org/wiki/Lipopolysaccharide
Tumor Necrosis Factors..”refers to a group of [the inflammatory] cytokines..that can cause cell death (apoptosis)…implicated in tumor regression, septic shock and cachexia [wasting]..” http://en.wikipedia.org/wiki/Tumor_necrosis_factors
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“The inflammatory cytokines..potentiate the..effects of Shiga toxins… There may be some analogies with the pathophysiology both of diarrhea-associated HUS.. and of sepsis/DIC/renal failure…” http://www.hemonctoday.com/article.aspx?rid=40810
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“The first response is commonly a bloody diarrhea. This is because Shiga toxin is usually taken in with contaminated food or water. The toxin is effective against small blood vessels, such as found in the digestive tract, the kidney and lungs but not against large vessels such as the arteries or major veins. A specific target for the toxin..[is] the vascular endothelium of the glomerulus. This is the filtering structure that is a key to the function of the kidney.” …”the toxin requires highly specific receptors [Gb3] on the cells’ surface in order to attach and enter the cell..” http://uk.ask.com/wiki/Shiga-like_toxin
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   [2007] “Demonstration of the ability of [ Stx phage] to form multiple lysogens has two potentially serious impacts. First, multiple integrated prophages will drive the evolution of bacterial pathogens as novel Stx-phages emerge following intracellular mutation/recombination events. Second, multiple copies of the Stx gene may lead to an increase in toxin production and consequently increased virulence…. there is considerable scope for Stx integration [into a host bacterium] directed by as yet uncharacterized factors… Clearly, the occurence of multiple lysogens in a single host is likely to enhance the evolution and dissemination of bacteriophage-encoded genes throughout bacterial populations, with particular applied relevance for Stx-phages responsible for increasing the pathogenic potential of Escherichia coli hosts.”  http://mic.sgmjournals.org/content/153/12/4098.full
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                                                              TIMELINE (posting in progress)
1885 – Theodor Escherich discovers colon bacteria, E.coli
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1896 – Kiyoshi Shiga discovers E.coli-like dysentery
bacterium, Shigella
         – Simon Flexner learns that colon bacteria “wander” through intestinal wall lesions, circulating and colonizing in other organs such as the lungs (causing pneumonia). Subsequent experimentation proves that ‘treatment’ with chemicals and x-rays turns the bacteria virulent.
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1900 – Simon Flexner isolates Shigella flexnerii in the Philippines, becomes director of New York’s Rockefeller Institute for Medical Research 1901 http://polioforever.wordpress.com/the-rockefeller-institute/; https://citizen2009.wordpress.com/the-flexners/
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1915 – discovery of bacteriophage (‘phage’) http://jenniferlake.wordpress.com/influenza-special/
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1918 – deadliest “influenza” in history, the Spanish Flu,  erupted near the end of WWI. Between 30 and 100 million died, though no one knows the approximate death toll. 500,000 Americans perished.
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1922 – isolation of E.coli, strain K-12; emergence of the research field of genetics
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1946 – discovery of bacterial conjugation, Joshua Lederberg and Edward Tatum. “Bacterial conjugation is the ability to transfer DNA between strains of bacteria (via a pilus). It allows a new mutation to spread through an existing population. It is believed that this process led to the spread of toxin synthesis from Shigella to E.coli (O157:H7).” http://denniskunkel.com/DK/Bacteria/71223E.html ; http://en.wikipedia.org/wiki/Joshua_Lederberg
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1950 – discovery of lambda bacteriophage, Esther Lederberg
http://www.estherlederberg.com/LambdaP.html
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1955 – first medical description of HUS, hemolytic uremic syndrome
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1977 – rediscovery of Shiga toxin, stx, (from Shigella dysenteriae) in E.coli http://www.wordiq.com/definition/Shiga-like_toxin
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1982 – CDC declares toxic E.coli a reportable pathogen in the U.S.
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1983 – “It was not until the breakthrough discoveries of Karmali et.al. in 1983 that HUS was definitively linked with ..STEC… when it was first identified, the mortality of STEC-induced HUS was in excess of 25%.” http://cmr.asm.org/cgi/content/full/17/4/926
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1996LARGEST OUTBREAK (22 outbreak clusters) May-October in Japan; 17,877 cases http://aac.asm.org/cgi/content/full/46/11/3478; http://pediatrics.aappublications.org/content/103/1/e2.full
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1999 – “Despite impressive advances in the biochemistry of SLTs [Shiga-like toxins], the precise roles of SLTs and host immune response..remain to be elucidated… the concept emerged that SLTs specifically target microvascular endothelial cells [in the lining of small blood vessels]…  experimental evaluation of these hypotheses is hampered by the lack of experience with a subhuman primate model. Studies..using mice, rabbits, and pigs have supported the concept that sites of..toxin receptor expression coincide with..tissue damage.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1866558/
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2001 –  “Expanding the Genetic Code of Escherichia coli” [Scripps Research Institute laboratory of Peter Schultz and Salk Institute fellow Lei Wang] http://www.sciencemag.org/content/292/5516/498.abstract; “unnatural amino acids could make existing proteins more potent in their actions, or even endow them with entirely new properties that might be useful for industry or medicine. Dr. Schultz’s [E.coli] bacteria, for example, look and act entirely like normal creatures until they are placed in contact with a certain sort of poison. Then, because they are producing an unnatural protein, they survive while all the others die.” http://www.economist.com/node/987697?story_id=987697
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2004 – “Currently there are approximately 10 Stx2 variants… and Stx2c is the most common Stx2 variant associated with HUS”… STEC-induced HUS is at a “current level of 3 to 5%.” http://cmr.asm.org/cgi/content/full/17/4/926
            – “Free Stx2-encoding bacteriophages have been found in aquatic environments, but there is limited information about the lysogenic strains and bacteria..that are susceptible to phage infection… this work was to study the..distribution of the stx2 gene..in sewage..of different origins..” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC427775/
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2009 – Stx1 used to treat breast cancer http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650710/
         – “On March 13, 2009, the USDA granted a conditional license for a new tool in the battle against foodborne illness –a vaccine for cows to prevent infection with E.coli bacteria..” http://www.dmaonline.org/CE/food_protection/2009_05.shtml
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2011DEADLIEST OUTBREAK in Germany, over 4,200 cases, 50 deaths, and 898 patients with Hemolytic Uremic Syndrome sequelae
         – Stx-producing E.coli infections in the U.S. stand at
186,000 http://www.marlerblog.com/lawyer-oped/non-o157-e-coli-in-beef—how-does-fsis-justify-it/
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Written by citizen2009

July 9, 2011 at 4:12 pm

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