8) Bacterial Toxins

Bacterial toxins are biologic virulence factors that prepare the host for colonization

by definition, a toxin triggers a destructive process

many bacterial pathogens produce various toxins that have different consequences for the host

• function as autonomous molecular devices

• targeting specific host cells and punching holes in their membranes, and/or modifying intracellular components

2 forms:

• Endotoxins = cell-associated

• Exotocins = secreted from the cell

LPS = Lipopolysaccharide -> example of an endotoxin

coats the surface of gram-negative bacteria

composed of lipids and sugars, 3 components:

• O antigen

• Core

• Lipid A -> toxic component

Human receptor for LPS: TLR4

• expressed on variety of cells including macrophages

• LPS-TLR4 binding induces a variety of responses -> pro-inflammatory responses —> endotoxic shock

• gram-negative sepsis = example of endotoxic shock

in contrast to bound endotoxins: bacterial exotoxins are soluble mediators located in the bacterial cytoplasm / periplasm, that are either excreted or released during bacterial cell lysis

classified in terms of the specific target cell or site affected:

• Enterotoxins: toxic to the intestinal tract, causing vomiting and diarrhea

• Neurotoxins: damage, destroy or impair the functioning of the central / peripheral nervous system

• Leukocidins: kill leukocytes, targets innate and adaptive immune cells

• Haemolysins: cause lysis of red blood cells by disrupting the cell membrane

Inhibiting protein synthesis (diphteria toxin)

activating second messengr pathways (cholera toxin)

activating immune responses (S. aureus superantigens)

Killing immune cells (leukocidins of S. aureus)

damaging cell membrane (E. coli haemolysin)

general action of metalloprotease activity (C. tetani tetanus toxin)

produces diphteria toxin

inhibits protein synthesis

A-B subunit toxins

Produces Cholera toxin: CTX, Ctx or CT

CT binds to ganglioside receptor and gets into the cell

causes increased levels of cyclic AMP within host cell

Results in electrolyte imbalance due to rapid efflux of chloride ions by the cystic fibrosis trans-membrane conductance regulator (CFTR) with decreased influx of sodium ions

-> leads to massive water efflux through intestinal cells

→ causes severe diarrhea and vomiting

produces enterotoxin B (SEP)

MOA: Superantigens

• short circuit the immune system and trigger uncontrolled production of inflammatory mediators leading to a lethal, cytokine storm

Produces Hemolysin (pore-forming toxin)

Hemolysin (HlyA) is a potent cytolysin

upon membrane binding, toxins concentrate and start oligomerization -> formation of a transmembrane pore

promoes influx or efflux of ions, small molecules, and proteins through the host membrane

may lead to host cell death/apoptosis

Produces TeNT (tetanus toxin)

extremly potent neurotoxin, on of the most toxic proteins known

initally binds to presynaptic terminals of neuromuscular junctions

transported by motor neuros to spinal cord

transferred to inhibitory presynaptic terminals surrounding those motor neurons

toxin then destroys vesicular synaptic membrane proteins, resulting in inactivation of inhibitory neurotransmission that normally suppresses motor neuron and muscle activity -> violent muscle spasms