Shiga toxin

Introduction

Shiga Toxins are a family of AB5 toxins (Stx1 and Stx2) which cause dysentery, hemolytic-uremic syndrome, and potentially renal failure in humans. They are primarily secreted by Shiga toxin-encoding Escherichia coli (STEC), notably by the 0157:H7 strain^[1] and shigella dysentarie. STECs are one of the major foodborne pathogens, affecting both developed and third-world countries. The stx gene is not endogenous to these strains, but is introduced through horizontal gene transfer from environmental prophages of the lambdoid bacteriophage family and incorporated into the E. Coli genome.^[1] Shiga Toxins are closely related to ricin, which is structurally and mechanistically similar. Shiga toxin acts to inhibit protein synthesis in eukaryotic cells and is the main virulence factor of STEC.

Human Interaction

0157:H7 STECs are spread to humans through a fecal-oral mechanism, primarily from ingestion of food contaminated with fecal material. Cattle, goats, and sheep are the primary reservoir of STECs and their close proximity to food sources as well as the use of animal feces for fertilizer makes them the main route of contamination.^[2] Inadequate sanitation and contamination of meat during slaughter can both lead to STEC contaminated food at the market. Once ingested the STEC can survive the high acid environment of the stomach and progress to the gut where they attach firmly to gut mucosa via the intimin adhesin protein.^[3] Secreted Stx then either attacks gut epithelia or passes into the bloodstream where it can damage kidney and brain tissue.

Treatments

Treatment with antibiotics is contraindicated as antibiotic treatment has been demonstrated to increase Stx production up to one hundred fold.^[2] This results from the link between Stx production (and phage induction) to the SOS response pathway.^[2] In the event of renal failure kidney dialysis may be employed. A number of potential treatments are under development including B subunit inhibitors, polysaccharides that promote macrophage uptake of Stx, blocking of the Gb₃ membrane receptor, and inhibition of retrograde transport.^[4]

Structure

Shiga Toxin consists consists of an AB₅ hexamer.^[5] The via a and .^[5]. The is located on the A subunit, but is blocked by the B subunit until they are cleaved and an active A subunit is released into the target cell.^[5]

Function

Shiga Toxin acts as an N-glycosidase, removing an adenine from the 60S ribosomal rRNA of a target cell leading to reduced protein synthesis.^[6] The B subunit is necessary for binding to globo series glycolipid globotriaosylceramide (Gb₃), a eukaryotic membrane receptor, where it is then endocytosed and proteolytically cleaved into two active A subunits and a B subunit.^[7] Once the A subunit is transported to the cytosol it acts by depurinating the 28S ribosomal RNA which leads to inhibition of protein elongation and ultimately cellular apoptosis. On the A subunit are all essential in glycosidic activity.^[6]