Endotoxins

Endotoxin is the lipopolysaccharide (LPS) of the outer membrane of gram negative bacteria. They are bound to bacterium and are released only when the organism lyses since it is a part of cell wall. In contrast to Exotoxin, they are
- heat stable
- toxin only at high dose
- weakly immunogenic
- generally similar, regardless of source
- cannot be toxoided
- Induces many and different pharmacological and immunological changes at low and high concentration.
- At low amounts, elicits a series of reaction : fever, activation of complement by alternative pathway, activation of macrophages and stimulation of B-cells
- In large amounts, it produces shock and hypotension and even death.

Chemistry of Endotoxin:

Bacterial LPS is composed of three parts:

è A glycophospholipid called lipid A
- is a complex array of lipid sources
- Water insoluble since it is hydrophobic
- Responsible for toxicity
- Even when paired with artificial carriers, its activity is restored.

è A Core Polysaccharide with ethanolamine and phosphate
- Common to all gram negative
- serve as carrier

è ‘O’ Antigen
- A long side chain of species specific
- Unusual polysaccharide
- serve as carriers for lipid A

Major effects of Endotoxin:

- At low concentration it sets of series of alarm reactions.
- At high range, it induces shock.
- Overlapping of these complex events depends on the amount of Endotoxin, route of infection and previous exposure of host to those substances.
- The primary target cells of Endotoxin are mono-nuclear phagocytes (monocytes, macrophages of spleen, bone marrow, lung alveoli, peritoneal cavity and kuffer cells), neutrophils, platelets and B- lymphocytes since they have specific Endotoxin receptor.

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.