Shiga Toxin - Two words: bloody diarrhea

Today's post is compliments of Toaster, who knows a whole lot about bacterial toxins. Check out his website, Mad Scientist, Jr.

Background:
Bad-ass hexameric molecule produced by some strains of your friendly neighborhood bacteria, most notably Shigella dysenteriae (named after Kiyoshi Shiga, who discovered them in 1898: "Hmm...I wonder what this bloody diarrhea looks like under my microscope?") and Escherichia coli.

Structure:
Once again, hexameric (although this a picture of SLT-1, which warrants a discussion on nomenclature)

Nomenclature:
This terminological mess once confused me, I hope this will make it clearer for you. True Shiga toxin is made by S. dysenteriae, although several strains of E. Coli (collectively termed STEC, which includes EHEC, the stuff that was on spinach recently) also make very closely
related toxins. Shiga-like toxin 1 is made by STECs and differs from S. dysenteriae by only 1 amino acid, while Shiga-like toxin 2, also made by STECs, has ~60% sequence homology with Shiga-like toxin 1. However, most microbiologists refer to Shiga toxins interchangeably,
and may call any of the above Shiga toxins (abb. Stx), verotoxins, or verocytotoxins, leading to a lot of people being very often confused and frustrated, which I think that microbiologists secretly enjoy.

Back to Structure:
So, Shiga toxins are hexameric, with 6 distinct subunits: 5 B subunits and 1 A subunit per molecule. The whole thing is shaped like a big hook (A subunit) with a fan at one end (the B subunits).

Genetics:
From what I understand, Shiga toxin generally isn't encoded in the genome of E. Coli strains that produce it (I don't know about Shigella strains), but is instead encoded in the genome of a bacteriophage that infects most of the bacteria in a population of STECs. So when the
bacteriophage is induced from its happy little quiet lysogenic phase to the lytic phase it fills the bacteria up with Shiga toxins until the bacteria bursts like a sticky balloon of kidney death.

Pathophysiology:
Shiga toxin will mess you up. Seriously. Like, no joke. The LD50 for Shiga-like toxin 2, calculated upwards from animal studies, for a 60kg person would be approximately 3 milligrams. Luckily, true Shiga toxin and Shiga-like toxin 1 are about 400 times less toxic.

In any event, playing pretend is a good way to learn. So let's say you eat some undercooked beef that's been contaminated with poop. The STECs manage to colonize your digestive system and start sticking to your intestinal epithelia. At this point, bloody diarrhea begins. But
as the bacteria pop and release Shiga toxin everywhere, some of it is going to wind up in your bloodstream. And, like anything that gets into your bloodstream, it winds up pretty much everywhere in your body. But Shiga toxin affects mostly renal tissue, hepatic tissue, endothelial cells, and the central nervous system, where it can wreak cellular havoc.

It's best understood how Shiga toxin affects renal tissue, which is to say, it targets distal tubules and the glomerular thingies because these tissues express an abnormally large amount of globotriaosylceramide, a lipid also known as Gb3, which Shiga toxin binds to very strongly. This is highly unusual because lipids don't normally function as receptors. No one knows why this is or why it happens here. Nonetheless, it is the B subunits of the Shiga toxin that bind Gb3
(interestingly, Stx-B subunits have been found to be very potent adjuvants) and somehow (once again, no one knows) get the Shiga toxin into the cell, where the A subunit dissociates from the B subunits and binds to one of the subunits of the ribosomes, essentially shutting all protein synthesis down, which is very, very bad for your cells.

It has been hypothesized, but not conclusively determined, that Shiga toxin plays a role in the development of HUS. HUS is not good. It stands for hemolytic uremic syndrome and involves your red blood cells being transformed from their normal fat happy selves into ragged hunks
of cellular detritus. This condition is associated with infection with STECs (e.g., H7:O157) and usually only happens in those who are very young, old, or immunocompromised.

Then come the complications of Stx interaction with LPS, but that is an entirely different post.

- Palermo M et al. Pretreatment of mice with lipopolysaccharide (LPS) or IL-1beta exerts dose-dependent opposite effects on Shiga toxin-2 lethality. Clin Exp Immunol. 2000 Jan;119(1):77-83.
- Warnier M et al. Trafficking of Shiga toxin/Shiga-like toxin-1 in human glomerular microvascular endothelial cells and human mesangial cells. Kidney Int. 2006 Dec;70(12):2085-91. Epub 2006 Oct 25.