Mode of entry into the cell - Receptor mediated endocytosis

Dimeric exotoxin binds to a receptor-ligand complex that is internalized in a clathrin-coated pit that pinches off to become a coated vesicle. By the time, the molecule A and B are cleaved at protease sensitive site, but remains covalantly associated. Clathrin coat depolymerizes resulting in an uncoated vesicle (endosome). pH in the endosome decreases owing to the AT activity by reduction of disulphide bond. Low pH causes A and B component to separate, which is called as CURL ( Compartment of Uncoupling of Receptor and Ligand ). B domain is then recycled to cell surface. A domain moves through the cytosol, and inhibits protein synthesis.

Toxins - A Brief Introduction

Toxins are biological weapons and a specific soluble metabolic product of microorganisms directed at us, which causes deleterious effect on host. It is produced by Bacteria, Fungi, Protozoa and Worms. Their mode of action paves way to understand the pathophysiology of infection. Toxemia refers to the condition caused by toxins that have entered the blood of host.

Types of toxins – Exotoxin, Endotoxin.

Exotoxins

- Synthesized by specific pathogens that often has plasmids or prophages bearing the Exotoxin gene (mainly Gram +, sometimes Gram -). Ex: E.Coli, Vibrio, Shigella.
- Soluble protein, usually released in the surrounding as the pathogens grow.
- In many instances, they travel far from the site of infection to other target cells.
- Sometimes bound to Bacterial surfaces, released on cell lysis.
- Heat-labile proteins inactivated at 60-80c
- Mostly lethal – 1gm of tetanus, botulium or Shigella toxin is enough to kill 10 million people.
- Highly immunogenic and stimulate the production of neutralizing antibodies (antitoxins).
- Easily inactivated by formaldehyde, iodine to form immunogenic toxoids.
- Usually unable to produce fever.
- Categorized as neurotoxins, cytotoxins or enterotoxins based on their mechanism of action.

Structural Model

It occurs in many forms, the general structural model to which they frequently conform is AB model.
‘A’ Subunit – an enzymatic subunit, responsible for toxic effect in host cell
‘B’ Subunit – binding subunit, binds to target cells but non toxic and biologically inactive. Binds with specific receptors on target cells (or) tissue such as sialogangliosides.
Ex: Gm1 for Cholera toxin, GT1/GD1 for Tetanus toxin, GD1 for Botulinum toxin.

Entry of Subunits

Several mechanisms are proposed by the toxins. In one mechanism B subunit inserts into the membrane and creates a pore for the A subunit to enter. In another, entry is by receptor mediated endocytosis. The mode of entry is explained in the diagram given above.