Escherichia Coli O157:H7—Clinical Aspects and Novel Treatment PDF

REVIEW ARTICLE published: 15 November 2012 CELLULAR AND INFECTION MICROBIOLOGY doi: 10.3389/fcimb.201...

REVIEW ARTICLE published: 15 November 2012 CELLULAR AND INFECTION MICROBIOLOGY doi: 10.3389/fcimb.2012.00138 Escherichia coli O157:H7—Clinical aspects and novel treatment approaches Elias A. Rahal † , Natalie Kazzi , Farah J. Nassar and Ghassan M. Matar * † Faculty of Medicine, Department of Experimental Pathology, Immunology and Microbiology, American University of Beirut, Beirut, Lebanon Edited by: Escherichia coli O157:H7 is a notorious pathogen often contracted by intake of Nora L. Padola, Universidad Nacional contaminated water or food. Infection with this agent is associated with a broad spectrum del Centro de la Provincia de Buenos Aires, Argentina of illness ranging from mild diarrhea and hemorrhagic colitis to the potentially fatal hemolytic uremic syndrome (HUS). Treating E. coli O157:H7 infection with antimicrobial Reviewed by: Charles M. Dozois, Institut National agents is associated with an increased risk of severe sequelae such as HUS. The de la Recherche Scientifique, difficulty in treating this bacterium using conventional modalities of antimicrobial agent Canada administration has sparked an interest in investigating new therapeutic approaches to Ramon A. Exeni, Hospital Niños San Justo, Argentina this bacterium. These approaches have included the use of probiotic agents and natural products with variable success rates. In addition, novel modalities and regimen of *Correspondence: Ghassan M. Matar, Faculty antimicrobial agent administration have been assessed in an attempt at decreasing their of Medicine, Department association with aggravating infection outcomes. of Experimental Pathology, Immunology and Microbiology, Keywords: Escherichia coli O157:H7, hemolytic uremic syndrome, hemorrhagic colitis, shiga toxins, antimicrobial American University of Beirut, Riad chemotherapy El-Solh, PO Box 11-0236, Beirut 1107 2020, Lebanon. e-mail: [email protected] † These authors equally contributed to this work. GENERAL CHARACTERISTICS OF E. coli O157:H7 of several countries including the USA, Canada, Germany, Spain, The identification of E. coli O157:H7 as the etiologic agent England, and Scotland (Armstrong et al., 1996). Outbreaks have of an outbreak of gastroenteritis that occurred in 1982 (Riley also occurred in these countries, as well as in Japan (Michino et al., 1983) has led to the recognition of a novel class of et al., 1999). E. coli, the Enterohemorrhagic E. coli (EHEC). This group of Cattle are considered to be the chief animal reservoir for E. coli pathogenic E. coli includes those that cause a clinical disease O157:H7, which is a temporary member of their normal gut similar to that caused by E. coli O157:H7 and that possess few micro flora (Caprioli et al., 2005). E. coli O157:H7 has been iso- other characteristics of this organism, namely producing one lated from many healthy cattle and has not been shown to be a or more phage-encoded Shiga toxins, possessing a hemolysin- pathogen in these animals. Cattle seem to lack vascular recep- encoding 60 MDa plasmid and that cause attaching and effac- tors for shiga-like toxins (Pruimboom-Brees et al., 2000). E. coli ing (A/E)lesions (Levine, 1987; Nataro and Kaper, 1998).E. coli O157:H7 has also been isolated from other animals including deer O157:H7 produces either or both of two toxins, one neutralized (Diaz et al., 2011), sheep (Urdahl et al., 2003), horses (Lengacher by antisera to shiga toxin produced by Shigella dysenteriae type 1 et al., 2010), goats (Mersha et al., 2010), and dogs (Kataoka et al., and referred to as Shiga toxin 1 (Stx1) while the other, Shiga toxin 2010). 2 (Stx2), is not neutralized by these antisera (Strockbine et al., The first outbreak of E. coli O157:H7 occurred in 1982 and 1986). Although E. coli O157:H7, like other E. coli ferments lac- was traced to contaminated hamburger meat (Riley et al., 1983). tose, it does not ferment sorbitol within 48 h, unlike 80–95% of Most outbreaks, particularly those that occurred during the 1980s E. coli isolated from human stools (March and Ratnam, 1986). were food borne with the main culprits being beef products On the other hand, it does not grow well at 44–45.5◦ C, which is particularly undercooked hamburgers in addition to unpasteur- the default incubation temperature for detection of E. coli in food ized milk (Griffin and Tauxe, 1991). During the past decade, and water sources (Raghubeer and Matches, 1990). however, marked changes in the epidemiology of human infec- Disease caused by E. coli O157:H7 has been reported from tions have taken place and outbreaks traced to vegetable and more than 30 countries on six continents (Doyle et al., 2001). fruit sources, in addition to other food sources are on the rise. In a 20-year surveillance period in the USA, 350 outbreaks were Infections traced to white radish sprouts (Michino et al., 1999), reported (Rangel et al., 2005). The Center for Disease Control and fresh spinach (Brandl, 2008), and lettuce (Hilborn et al., 1999). Prevention (CDC) estimates that E. coli O157: H7 causes 73,480 Consumption of tomatoes and apple juice has been frequently illnesses, 2168 hospitalizations and 61 deaths per year in the USA involved in outbreaks as well (McDowell and Sheridan, 2001). In alone (Mead et al., 1999). E. coli O157:H7 has been found in cattle addition, waterborne outbreaks have occurred (Swerdlow et al., Frontiers in Cellular and Infection Microbiology www.frontiersin.org November 2012 | Volume 2 | Article 138 | 1 Rahal et al. Escherichia coli O157:H7 1992; Olsen et al., 2002; Bopp et al., 2003). E. coli O157:H7 O’Brien, 1998; Schmidt et al., 2000; Melton-Celsa et al., 2002; appears to be capable of survival for prolonged times in water Zheng et al., 2008). Three functional properties characterize the particularly at lower temperatures (Wang and Doyle, 1998). This Shiga toxin family. These toxins are cytotoxic to HeLa and Vero microorganism was demonstrated to survive for more than eight cells. They lead to fluid accumulation in ligated rabbit illeal loops; months in a farm water gutter, and the surviving organisms were therefore, they are “enterotoxic” and they are capable of inducing able to colonize cattle (Kudva et al., 1998). Swimming in con- paralysis of the hind-legs and death in rabbit and mouse models taminated water has also resulted in outbreaks (Keene et al., (Jackson, 1990). 1994; Friedman et al., 1999; Paunio et al., 1999). Person-to- The binding moiety of these toxins, which aids them in person transmission has also been reported in day care centers binding to human and animal cells, consists of five B sub- and nursing homes as well (Panaro et al., 1990; Reida et al., units. These subunits are non-covalently associated with an A 1994). subunit, which in turn consists of an A1 and an A2 subunit The rather easy spreading of E. coli O157:H7 from one per- (Sandvig and Van Deurs, 1996). Shiga toxin and Stx1 differ son to another indicates that the infectious dose is rather low. only by a single amino acid in the B subunit (Calderwood Moreover, transmission by water, which would tend to dilute the et al., 1987; Hofmann, 1993). Thus, they are essentially identi- organisms, substantiates this suggestion. The estimated infectious cal; moreover, Stx1 is neutralized by antiserum to Shiga toxin dose from outbreak data is 10–100 CFU (Griffin et al., 1994). (O’Brien and Holmes, 1987; Qadri and Kayali, 1998). Stx2 is antigenically distinct and unrelated. It is approximately 55% VIRULENCE FACTORS OF E. coli O157:H7 homologous to Shiga toxin/Stx1 (Jackson, 1990) and is not The ability to produce one or more shiga toxins is a hallmark neutralized by antiserum to Shiga toxin (Qadri and Kayali, E. coli O157:H7 infection. However, toxin production is not 1998). sufficient to cause disease. Two other factors are indicted in con- The cellular receptors for the Shiga toxins are the neutral gly- tributing to the virulence of E. coli O157:H7. The first of these two colipids globotriosylceramide (Gb3) and globotetraosylceramide factors is harboring a 60 MDa virulence plasmid (pO157), which (Gb4) (Betz et al., 2011). Various cell types are sensitive to encodes a hemolysin (Schmidt et al., 1996; Mead and Griffin, Shiga toxins. These include enterocytes, renal, aortic, and brain 1998). The other factor is the locus of enterocyte effacement endothelial cells, mesangial cells, renal tubular and lung epithe- (LEE) (Kresse et al., 1998; Ogierman et al., 2000). lial cells, cells of the monocytic lineage, polymorphonuclear cells, in addition to platelets and erythrocytes among other cell types THE LOCUS OF ENTEROCYTE EFFACEMENT (LEE) (Meyers and Kaplan, 2000). The LEE contains all the genes necessary for inducing the A/E After the toxin binds its receptor on the cell membrane, a short lesions typical of E. coli O157: H7 infection (Louie et al., 1993; incubation leads to aggregation of toxin-receptor complexes in Vallance and Finlay, 2000). As E. coli O157:H7 attaches to the gut clathrin-coated pits. Next, the A fragment is endocytosed. The mucosa and interacts with it, histopathological changes are pro- toxin is transported through endosomes to the Trans Golgi net- duced in the epithelium. These changes are collectively known work (TGN). In the TGN, the toxin is cleaved by the enzyme as A/E lesions (Kresse et al., 2000). These lesions are character- furin into the A1 and A2 subunits. From the TGN, the toxin ized by effacement of the epithelial brush border microvilli and is transported to the endoplasmic reticulum where transloca- the formation of actin-rich pedestals within the host cell under- tion into the cytosol takes place. If toxin was not cleaved by neath the attached bacterial cells. The presumed functions of furin, then the cytosolic enzyme caplain may cleave the molecule these pedestals are prevention of dislodgement of the bacterium (Hofmann, 1993; Sandvig and Van Deurs, 1996). The A1 subunit during the host diarrheal response and inhibition of bacterial is a 28S rRNA N-glycosidase (Jackson, 1990). The toxin cleaves an phagocytosis (DeVinney et al., 1999). adenine residue from a specific nucleotide of the 28S rRNA com- ponent of the 60S ribosomal subunit. This blocks tRNA binding PO157 to the 60S ribosomal subunit thus preventing peptide elonga- All isolates of E. coli O157:H7 harbor the 60 MDa pO157 plasmid. tion and disrupting protein synthesis. This leads to cell death This plasmid contains the hly operon encoding an enterohe- (Hofmann, 1993). molysin (Schmidt et al., 1996). This hemolysin, with the aid of Shiga toxins induce an increase in chemokine synthesis from specialized transport systems, may allow the bacterium to utilize intestinal epithelial cells. This augments host mucosal inflam- the blood released into the intestine as a source of iron (Mead and matory responses with release of interleukins, such as IL-8 and Griffin, 1998). IL-1, in addition to Tumor Necrosis Factor (TNF). Activation of human endothelium by TNF or IL-1 leads to an increase in toxin SHIGA TOXINS receptor synthesis and hence increased sensitivity of the cell lead- The Shiga toxin family comprises three members. Shiga toxin, ing to increased cell death after exposure to the toxins (Meyers produced by Shigella dysenteriae type 1, is the prototype Shiga and Kaplan, 2000). toxin. On the other hand, Stx1 and Stx2 are produced by the E. coli O157:H7 strains may produce either Stx1, Stx2, or both; EHEC. Several variants of Stx2 have been identified as well and however, most strains produce Stx2 (Mead and Griffin, 1998). these include Stx2c, Stx2d, Stx2e, Stx2f, and Stx2g. These share Stx1 remains mostly cell-associated and stored in the periplasmic 84–99% of the amino-acid sequence of Stx2 but differ in some space while Stx2 is released from bacterial cells. Therefore, Stx1 of its biological characteristics (Ito et al., 1990; Melton-Celsa and is typically predominantly detected in cell lysates, while Stx2 is Frontiers in Cellular and Infection Microbiology www.frontiersin.org November 2012 | Volume 2 | Article 138 | 2 Rahal et al. Escherichia coli O157:H7 found in higher titers in culture supernatants (Strockbine et al., elevated serum potassium, blood urea nitrogen, and uric acid 1986; Yoh et al., 1997; Sato et al., 2003; Shimizu et al., 2009). levels) may occur as well. A condition known as thrombotic thrombocytopenia purpura (TTP) strikes mostly the adult pop- OTHER VIRULENCE FACTORS ulation and is rarer than HUS. In TTP less marked renal damage While the LEE, pO157 and Shiga toxin production are defining is noted and fewer cases have a diarrheal prodrome. Both HUS virulence factors of E. coli O157:H7, other factors contribute to its and TTP can present with neurological abnormalities includ- pathogenicity. Some strains harbors EspP, which belongs to the ing seizures, coma and hemiparesis. These two conditions need family of serine protease autotransporters of Enterobacteriaceae not always be differentiated and may be referred to as HUS/TTP (SPATE). This protease cleaves pepsin A and human coagulation (Nauschuetz, 1998). factor V, which probably contributes to increased hemorrhage HUS and TTP are non-consumptive coagulopathies i.e., char- into the intestinal tract (Brunder et al., 1997). Moreover, EspP acterized by the consumption of platelets but not of clotting cleaves multiple complement system components hence protect- factors. They are regarded as variants of a single syndrome (Van ing the bacterium from immune system-mediated elimination Gorp et al., 1999). While fever and central nervous system (CNS) (Orth et al., 2010). On the other hand, in addition to LEE involvement are more frequent in TTP, renal dysfunction is less, members such as intimin and Tir, bacterial attachment to host and mortality and recurrences are greater. Although TTP can be intestinal cells is also mediated by a type IV pilus referred to as the initiated by E. coli O157:H7 infection, a diarrheal prodrome is hemorrhagic coli pilus (HCP) (Xicohtencatl-Cortes et al., 2007). uncommon (Siegler, 1995). Multiple fimbriae and fimbrial gene clusters have also been impli- Classical postdiarrheal HUS always involves the colon and the cated in contributing to adherence of this organism to host cells kidney; however, other organ systems may be affected. The brain (Low et al., 2006). is most commonly affected with an evidence of CNS dysfunc- tion in nearly one-third of HUS cases. Generalized seizures are CLINICAL ILLNESSES ASSOCIATED WITH E. coli O157:H7 common and occur in