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Shiga toxin in enterohemorrhagic E.coli: regulation and novel anti-virulence strategies
Alline R. Pacheco and Vanessa Sperandio*
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Currently, there is no effective treatment or prophylaxis for HUS. Because antibiotics trigger Stx production and their use to treat EHEC infections is controversial, alternative therapeutic strategies have become the focus of intense research.

Annually in the United States, EHEC is responsible for an estimated 73,000 illnesses, 1800–3600 hospitalizations and from 61 to 541 deaths (Rangel et al., 2005) (www.cdc.gov). EHEC is a foodborne pathogen, and outbreaks occur through ingestion of contaminated food or water including: contaminated ground beef, steak, salami (Bell et al., 1994; Jay et al., 2004; Greig and Ravel, 2009), dairy products (raw milk, cheese, butter, cookie dough) (Jaeger and Acheson, 2000; Neil et al., 2009) and vegetables (spinach, lettuce, sprouts) (Rangel et al., 2005; Grant et al., 2006; Wendel et al., 2009; Sodha et al., 2011). A remarkable feature of EHEC infection is its low infectious dose; it is estimated that 50–100 colony forming units (CFUs) of EHEC is sufficient to cause disease in healthy individuals (Tilden et al., 1996).

Initially, Stx was called Verotoxin due to its cytotoxicity against Vero cells in culture. Upon the discovery that Verotoxin could be neutralized by an antitoxin against purified Stx from Shigella, the name Stx came into use and is the more common name to date (O'Brien et al., 1983b). Stx and Verotoxin are used interchangeably,


Mechanism of Action of Shiga Toxin
Stx inhibits protein synthesis and induces apoptosis. Stx is an AB5 toxin, constituted by a catalytic subunit A bound non-covalently to a pentamer of B subunits (Stein et al., 1992; Fraser et al., 1994). The A subunit has N-glycosidase activity that cleaves an adenosine residue from 28S ribosomal RNA of the 60S ribosomal subunit (Endo et al., 1988). As a result, it inhibits protein synthesis, causing cell death by apoptosis. The five B subunits form a structure that binds the globotriaosylceramide (Gb3) receptor on the surface of eukaryotic cells (Jacewicz et al., 1986; Lindberg et al., 1987). Gb3 is expressed by Paneth cells in the intestinal mucosa and by kidney epithelial cells [reviewed in (Tarr et al., 2005)] (Figure 1). Stx enters systemic circulation through absorption by the epithelium (Acheson et al., 1996), enabling its access to the kidneys. The damage of the GI epithelium caused by EHEC likely aids in Stx systemic absorption (Mukherjee et al., 2002). Upon receptor binding, Stx is endocytosed by the eukaryotic cell (Romer et al., 2007), bypasses the late endocytic pathway and undergo retrograde transport from the trans-Golgi network to the endoplasmic reticulum (ER) where it encounters its target (Sandvig et al., 1992; Mallard et al., 1998). These processes have been reviewed in detail elsewhere (Johannes and Romer, 2010).

 
Mechanism of action of Shiga toxin (Stx). Stx is constituted by a pentamer of B subunits bound to a catalytic A subunit. The B subunits bind to globotriaosylceramide (Gb3) expressed by some eukaryotic cells (1) Stx is internalized by endocytosis (2) Subsequently, Stx undergoes retrograde transport to the trans-Golgi network (TGN) (3) and then to the endoplasmic reticulum (ER) (4) In the ER, Stx encounters its target, the ribosome, inactivating it (4) As a consquence, Stx inhibits protein synthesis, causing cell death by apoptosis.

Antibiotics
The use of antibiotics for the treatment of STEC infection is controversial due to its effect on induction of the phage lytic cycle (Zhang et al., 2000). Many studies have shown that antibiotics such as quinolones and mitomycin C increase the production of Stx (Zhang et al., 2000; McGannon et al., 2010). Specifically, mitomycin C is commonly used in research for prophage induction for its ability to interfere with DNA replication, triggering an SOS response (Los et al., 2010).

 

Shiga Toxin 1 Induces Apoptosis in the Human Myelogenous Leukemia Cell Line THP-1 by a Caspase-8-Dependent, Tumor Necrosis Factor Receptor-Independent Mechanism

 


Shiga toxin
Shigella dysenteriae 1 ¶Ç´Â ´Ù¸¥ ÀÌÁú±ÕÀÌ »ý»êÇÏ´Â ´Ü¹éÁúµ¶¼ÒÀÇ ÀÏÁ¾. ÀÌÁúÀ» ÀÏÀ¸Å°´Â Áß¿äÇÑ º´¿øÀÎÀÚ·Î »ý°¢µÈ´Ù. µ¶¼Ò´Â ±ÕüÀÇ Æ丮ÇÁ¸®Áò¿¡ Á¸ÀçÇÏ¿© ±ÕüÀÇ ÀÚ±âÀ¶ÇØ¿¡ ÀÇÇØ ¹æÃâÇÏ°í, ±× »ý»êÀº öÀÌ¿Â °áÇÌ ¶Ç´Â È£±âÁ¶°Ç ÇÏ¿¡¼­ ÃËÁøµÈ´Ù. Á¤Á¦µ¶¼Ò´Â Á¶Á÷¹è¾ç HeLa¼¼Æ÷¿¡ ´ëÇÑ ¼¼Æ÷Ä¡»çµ¶, Åä³¢°áÂû(Ì¿óÏ) Àå°ü·çÇÁ¹ýÀ¸·Î ¾×üÀú·ù¸¦ ÇÏ´Â Àå°üµ¶, Áã ¡¤ Åä³¢ ¡¤ ¿ø¼þÀÌ¿¡ ´ëÇÑ Ä¡»ç¸¦ ³ªÅ¸³»´Â ½Å°æµ¶À¸·Î È°¼ºÀ» ÇÑ´Ù.

ºÐÀÚ·®Àº ¾à 68,000ÀÌ°í, ÇϳªÀÇ A¼Ò´ÜÀ§(ºÐÀÚ·® 30,000)¿Í 6~7ÀÇ B¼Ò´ÜÀ§(ºÐÀÚ·® 5,000)·Î ±¸¼ºµÈ´Ù. ÃÖ±Ù Escherichia coli °¡¿îµ¥ O157: H7026ÀÇ Ç÷ûÇüÀ» ³ªÅ¸³»´Â °ÍÀÌ Á¶Á÷¹è¾ç Vero¼¼Æ÷¿¡ ´ëÇØ Ä¡»çÈ°¼ºÀ» ³ªÅ¸³»´Â Shiga-like toxinÀ» »ý»êÇÏ´Â °ÍÀ¸·Î ¾Ë·ÁÁ® ´Ù¸¥ Àå³»¼¼±Õ¿¡¼­ÀÇ À¯»çµ¶¼ÒÀÇ Á¸À縦 ½Ã»çÇÏ°í ÀÖ´Ù.

Shiga toxins act to inhibit protein synthesis within target cells by a mechanism similar to that of ricin.[5] After entering a cell via a macropinosome,[6] the protein cleaves a specific adenine nucleobase from the 28S RNA of the 60S subunit of the ribosome, thereby halting protein synthesis.[7]
Interestingly, the bacterial Shiga toxin can be used for targeted therapy of gastric cancer, because this tumor entity expresses the receptor of the Shiga toxin. For this purpose an unspecific chemotherapeutical is conjungated to the B-subunit to make it specific. In this way only the tumor cells, but not healthy cells should be destroyed during therapy

Ricin is a highly toxic, naturally occurring lectin (a carbohydrate-binding protein) produced in the seeds of the castor oil plant, Ricinus communis. A dose of purified ricin powder the size of a few grains of table salt can kill an adult human.[1] The median lethal dose (LD50) of ricin is around 22 micrograms per kilogram of body weight if the exposure is from injection or inhalation (1.78 milligrams for an average adult).[2] Oral exposure to ricin is far less toxic as some of the poison is inactivated in the stomach. An estimated lethal oral dose in humans is approximately 1 milligram per kilogram





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