8 Bacterial Toxins

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

• By definition, a toxin triggers a destructive process

• O antigen

  • non protein and unique to each bacterial species

• Core

• Lipid A

  • toxic component

TLR4

Pro-inflammatory responses → ENDOTOXIC SHOCK

• Inhibiting protein synthesis (C. diphtheriae diphtheria toxin)

• Activating second messenger pathways (B. anthracis edema factor or V. cholerae cholera toxin)

• Activating immune responses (S. aureus superantigens)

• Killing immune cells (e.g. leukocidins of S. aureus)

• Damaging cell membranes (E. coli haemolysin)

• General action of metalloprotease activity (C. tetani tetanus toxin

Member of the family of A -B, ADP - ribosylating bacterial toxins (bAREs )

Functions by transferring an ADP -Ribose moiety from cellular NAD + to intracellular host proteins

→ protein inactivation and subsequent cellular dysfunction/death

→ symptoms of diphtheria

• Cholera toxin (CTX, Ctx or CT) is AB5 multimeric protein complex secreted by Vibrio cholerae

• CT binds to ganglioside receptor on host epithelial cells → triggers endocytosis of the toxin

• Internalized CT moves from the endosome to the Golgi complex and endoplasmic reticulum (ER)

• leads to ADP-ribosylation of G protein, and constitutive activation of AC (adenylate cyclase)

  • 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

  → cardinal clinical signs of cholera

inds directly to specific Vβ regions of T-cell receptors (TCR) and major histocompatibility complex (MHC) class II on antigen -presenting cells

Results in hyperactivation of T lymphocytes and monocytes/macrophages

Activated host cells produce excessive amounts of proinflammatory cytokines and chemokines

• TNF-α, IL-1, IL-2, IFNγ, and MCP-1

→ Causing clinical symptoms of fever, hypotension, and (toxic) shock (i.e.,TSS)

→ Pore -forming toxins: exfoliative toxin s A/B/C/D (blister formation and skin separation: SSSS), leukocidins, hemolysins

• Uropathogenic E. coli (UPEC) isolates encode the pore-forming toxin α-hemolysin

• Hemolysin (HlyA) is a potent and ubiquitous cytolysin

• prototypical member of repeats-in-toxin (RTX) family

• Soluble pore-forming proteins (PFPs) are recruited to host membrane by protein receptors and/or specific interactions with lipids

• Upon membrane binding, toxins concentrate and start oligomerization

• Final result is formation of a transmembrane pore

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

→ may lead to host cell death/apoptosis

• Tetanus toxin (tetanospasmin) is an extremely potent neurotoxin produced by Clostridium tetani

  • TeNT one of most toxic proteins known!

→ TeNT initially bound at presynaptic terminals of neuromuscular junction

→ Transported by motor neurons to spinal cord

→ Transferred to inhibitory presynaptic terminals surrounding those motor neurons

→ Toxin then destroys a vesicular synaptic membrane protein (VAMP, or synaptobrevin), resulting in inactivation of inhibitory neurotransmission that normally suppresses motor neuron and muscle activity

→ Action results in enhanced excitability and activation of affected motor neurons

• First symptom is typically stiffness of the jaw (lockjaw)

• Violent muscle spasms in other parts of the body follow

• Typically culminates with respiratory failure and deat