27 - Pathogenesis (Part 3): Toxins

Endotoxins

Lipopolysaccharide of Gram Negative Bacteria

Exotoxins

Toxins released from bacteria (superantigens are a unique group)

General Characteristics of Endotoxins

Has Lipid A which is the actively toxic portion, toxicity is due to an immune reaction, integral part of the outer membrane, released only by lysis, heat stable (resists autoclaving), can’t be detoxified to make a vaccination 

Host Response to Low Concentrations of Lipopolysaccharide 

Produce “alarm” reaction including fever, complement activation (inflammation), and lymphocyte activation leading to antibody synthesis

Host Response to High Concentrations Of Lipopolysaccharide

Septic shock, severe hypotension, clotting factors released, disseminated intravascular coagulation (DIC), multi-organ systemic failure

General Characteristics of Exotoxins

Many different types produced (both by gram+ and gram-), benefit the pathogen (kills host defense cells, obtains nutrients from other host cells/tissues, help in dissemination), released from bacteria, act enzymatically, can be detoxified by heat, plasmid/phage encoded, production regulated by growth conditions/host signals, can be made into effective toxoids

Exotoxin Categories

A-B Toxins, Membrane-Disrupting Toxins, Proteolytic Toxins, Superantigens

A-B Toxins

Secreted by bacteria and become toxic once they are taken up by the host cells. Has 2 necessary portions: A (active portion) and B (binding portion)

A Portion in AB Toxin

Active portion that enters the cell to exert action (has the toxic/enzymatic activity) which causes damage to the host (cleavage releases A portion)

B Portion in AB Toxin

Binding portion (determines host species specificity) and determines host cell specificity

Diphtheria Toxin (AB Toxin)

Single A and Single B subunits, inactivates elongation factor-2 which stops protein synthesis

Diphtheria Pseudomembrane

Thick leathery membrane in throat that can obstruct a patient’s breathing

Cholera Toxin (AB Toxin)

Five B and 1 A (Only A1 goes in), modifies the protein regulated cAMP synthesis (this accumulates and causes loss of control of ion flow) which leads to massive watery diarrhea (24+ liters/day) treatable with IV fluids 

Shiga Toxin (AB Toxin)

Not excreted from bacteria (released when organisms are lysed and doesn’t work by ADP-ribosylation), stops host cell protein synthesis by cleaving host cell 60S rRNA preventing protein elongation and causing mucosal damage and bloody diarrhea

Tetanus Toxin

Rarely moves from site of infection, AB toxin causes the system acting from a distance (binds and take into alpha-motor neurons and travels up axon into spinal cord), blocks release of inhibitory neurotransmitters and the muscles are constantly stimulated

Membrane Disrupting Toxins  

Cytotoxins and Hemolysins (disrupt integrity of host cell plasma membranes), however some insert into membranes to form pores (not an enzymatic action

What do low concentrations of membrane disrupting toxins inhibits?

Target Cell Function

What do high concentrations of membrane disrupting toxins lyse?

Lyse target cells by osmotic shock (the lyse is caused by destabilization of membrane)

What is more cell type specific: AB Toxin or Membrane Disrupting Toxins?

AB Toxin (MBT are less cell type specific)

Proteolytic Toxins

Enzymes that facilitate invasion/provide nutrients, the “spreading factors” aid in tissue invasion. Contains immunoglobulin and complement proteases

Proteolytic Toxin Examples

Hyaluronidase and Collagenase

Hyaluronidase

Staphylococci and Streptococci (breaks down hyaluronic acid in connective tissue)

Collagenase

Clostridium Perfringens (breaks down collagen acting like a meat tenderizer) 

Superantigens

Non Enzymes that bind antigen presenting cells to T cells causing the overproduction of proinflammatory signals to the immune system

What does superantigens cause?

Excessive proinflammatory cytokine production leading to fever, vomiting, malaise and shock

T Cell Activation

Release of large amounts of cytokines = life threatening fever, shock, rash and autoimmune-like responses