Recent Progress of Shiga Toxin Neutralizer for Treatment of Infections by Shiga Toxin-Producing Escherichia coli

Nishikawa, Kiyotaka

doi:10.1007/s00005-011-0130-5

Cited by 36 publications

(26 citation statements)

References 56 publications

(69 reference statements)

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“…Inflammation caused by the toxins is believed to be the cause of 11C } the first manifestation of E. coli infection, which is characterized by sudden onset of abdominal pain and severe cramps, followed by diarrhea within 24 hours (Fratamico and Smith 2006), HC typically occurs within 2 to 5 days of ingestion ofSTEC and is often complicated by potentially fatal systemic sequelae such as neurological damage and I IDS, which occur within 2-14 days after the onset of diarrhea (Nishikawa 2011). MUS is defined by the triad of acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia and occurs in about one-tenth to one-fourth of cases {Karmali 2004).…”

Section: Stec Infectionmentioning

confidence: 99%

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Shiga toxin-producing Escherichia coli (STEC) food-borne outbreaks

Pexara

Angelidis

Govaris

2017

J Hellenic Vet Med Soc

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Escherichia coli (E. coli) are Gram negativo, non-sporulating bacteria, which belong to the normal intestinal flora of humans and animals. Shiga toxin-producing E. coli (STFC) arc a group of if. coli that is defined by the capacity to produce toxins called Shiga toxins (Stx). hollowing ingestion of STEC, the significant risk of two serious and potentially life-threatening complications of infection, hemorrhagic colitis and hemolytic uremic syndrome (HUS), makes STHC food poisoning a serious public health problem. Besides Stx, human pathogenic STFC harbor additional virulence factors that are important for their pathogenicity. Although human infection may also be acquired by direct transmission from person to person or by direct contact of humans with animal carriers, the majority of STFC infections are food-borne in origin.The gastrointestinal tract of healthy ruminants seems to be the foremost important reservoir for STFC and ingestion of undercooked beef one of the most likely routes of transmission to humans, Other important food sources include faecally contaminated vegetables and drinking water, The serogroup classification of STHC is based on the somatic (O) and flagellar (H) antigens, and, to date, more than 200 STFC serogroups have been identified, Human STFC infections are, however, associated with a minor subset of 0;H serotypes. Of these, the 0157:H7 or the 0157 :H- serogroups (STFC 0157) are the ones most frequently reported to be associated with food-borne outbreaks. However other non-0157 STFC serogroups such as E. coli 026, 0103, O l l i , 012I, 045 and 0145 have caused several outbreaks in recent years.Two outbreaks of gastroenteritis caused by E. coli 0157:117 were first reported in the US, following the consumption of undercooked hamburgers, in 1982. Since then several outbreaks were reported worldwide. A major E. coli 0157:117 outbreak occurred in Japan and contaminated radish sprouts was identified as the vehicle of infection. More than 6,000 school children were affected, 101 people were hospitalized with lILS and 12 deaths were recorded. The recent outbreak of STFC 0104:114 infection and HUS reported in Germany in the spring of 2011 was one of the largest outbreaks worldwide. As of 27 July, 3 126 cases of STFC infections, 773 cases of HUS including 46 deaths linked to the outbreak in Germany and occurring in the Furopean Union (FU) (including Norway), Outside the FU 8 cases of STFC and 5 cases of HUS, including 1 death have been reported in the USA, Canada and Switzerland, all with recent travel history to Germany.The present review on major STliC food-borne outbreaks recorded worldwide highlights the need for eontrol measures in order to prevent or at least minimize the occurrence of similar events in the future.

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Section: Stec Infectionmentioning

confidence: 99%

“…Stx are clas sified into two subgroups, Stxl and Stx2. A variant of Stx 1, named Stx 1 c, and several variants of Stx2, named Stx2c, Stx2d, Stx2e, and Stx2f, which differ in their biological activities and association with disease, have been reported (Nishikawa 2011, Thorpe 2004.…”

Section: Stec Infectionmentioning

confidence: 99%

Shiga toxin-producing Escherichia coli (STEC) food-borne outbreaks

Pexara

Angelidis

Govaris

2017

J Hellenic Vet Med Soc

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“…Accordingly, several compounds with clustered trisaccharides that can bind to the B subunit with high affinity have been developed and shown to effectively neutralize Stx both in vitro and in vivo (27)(28)(29)(30)(31)(32)(33). These compounds, however, cannot be customized to specific Stx subtypes, because all Stx subtypes recognize the trisaccharide as the natural binding unit.Previously, we developed a library of multivalent peptides exhibiting the clustering effect, from which we identified Stx-neutralizing tetravalent peptides by screening the library for highaffinity binding to the specific receptor-binding sites (33)(34)(35)(36). By targeting Stx2a receptor-binding site 3 or Stx1a site 1, we identified various tetravalent peptides demonstrating remarkable therapeutic potency in both a mouse model of EHEC infection (34, 36) and a nonhuman primate model (19).…”

mentioning

confidence: 99%

“…This type of interaction contributes to the highly selective and potent binding of Stx to target cells, sometimes referred to as the "clustering effect." Accordingly, several compounds with clustered trisaccharides that can bind to the B subunit with high affinity have been developed and shown to effectively neutralize Stx both in vitro and in vivo (27)(28)(29)(30)(31)(32)(33). These compounds, however, cannot be customized to specific Stx subtypes, because all Stx subtypes recognize the trisaccharide as the natural binding unit.…”

mentioning

confidence: 99%

“…Previously, we developed a library of multivalent peptides exhibiting the clustering effect, from which we identified Stx-neutralizing tetravalent peptides by screening the library for highaffinity binding to the specific receptor-binding sites (33)(34)(35)(36). By targeting Stx2a receptor-binding site 3 or Stx1a site 1, we identified various tetravalent peptides demonstrating remarkable therapeutic potency in both a mouse model of EHEC infection (34, 36) and a nonhuman primate model (19).…”

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confidence: 99%

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Affinity-Based Screening of Tetravalent Peptides Identifies Subtype-Selective Neutralizers of Shiga Toxin 2d, a Highly Virulent Subtype, by Targeting a Unique Amino Acid Involved in Its Receptor Recognition

et al. 2016

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c Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), can be classified into two subgroups, Stx1 and Stx2, each consisting of various closely related subtypes. Stx2 subtypes Stx2a and Stx2d are highly virulent and linked with serious human disorders, such as acute encephalopathy and hemolytic-uremic syndrome. Through affinity-based screening of a tetravalent peptide library, we previously developed peptide neutralizers of Stx2a in which the structure was optimized to bind to the B-subunit pentamer. In this study, we identified Stx2d-selective neutralizers by targeting Asn16 of the B subunit, an amino acid unique to Stx2d that plays an essential role in receptor binding. We synthesized a series of tetravalent peptides on a cellulose membrane in which the core structure was exactly the same as that of peptides in the tetravalent library. A total of nine candidate motifs were selected to synthesize tetravalent forms of the peptides by screening two series of the tetravalent peptides. Five of the tetravalent peptides effectively inhibited the cytotoxicity of Stx2a and Stx2d, and notably, two of the peptides selectively inhibited Stx2d. These two tetravalent peptides bound to the Stx2d B subunit with high affinity dependent on Asn16. The mechanism of binding to the Stx2d B subunit differed from that of binding to Stx2a in that the peptides covered a relatively wide region of the receptor-binding surface. Thus, this highly optimized screening technique enables the development of subtypeselective neutralizers, which may lead to more sophisticated treatments of infections by Stx-producing EHEC. Shiga toxin (Stx) is a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, hemorrhagic colitis, and sometimes life-threatening systemic complications such as acute encephalopathy and hemolytic-uremic syndrome (HUS) (1-6). To date, numerous EHEC strains that produce various Stx subtypes have been reported (7,8). These Stxs can be classified into two subgroups, Stx1 and Stx2, each consisting of various closely related subtypes, such as Stx1a,. Stx2a (10, 11) and Stx2d, which is activated by elastase derived from the intestinal mucosa (12-14), are highly virulent and have been linked with HUS, the most serious sequela of EHEC infection. The pathophysiologic importance of these subtypes was also confirmed by the finding that Stx2a and Stx2d are highly toxic when injected into mice (15, 16) or primates (17-19). Therefore, Stx neutralizers, particularly those customized to specifically neutralize Stx2a and Stx2d, would be highly valuable therapeutic agents for treating infections caused by various EHEC strains.Stx molecules consist of a catalytic A subunit, which has RNA N-glycosidase activity and inhibits eukaryotic protein synthesis (20,21), and a B-subunit pentamer. The B-subunit pentamer is responsible for high-affinity binding to the functional cell surface receptor Gb3 (Gal␣[1-4]-Gal␤[1-4]-Glc␤-ceramide) (4,22,23) or Gb4 (GalNAc␤[1-3]-Gal␣[1-4]-G...

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