Damage to the Host

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Damage to the Host
Bio 5392 Molecular Microbiology and
Pathogenesis Mondy April 6 Wednesday April 8,
2009
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Bacterial Damage to the Host

• I. Direct Damage to Tissues or Cells
• a) Byproducts of bacterial metabolism
• b) Degradative enzymes released by bacteria
• c) Secreted exotoxins
• II. Indirect damage
• stimulation of inflammatory response

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Bacterial Damage to the Host

• Direct Damage
• a) metabolic byproducts
• - secreted products that have adverse effects on
  host cell biology
• i) H2S
• ii) acetic acid
• iii) reactive oxygen species

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Bacterial Damage to the Host

• I. Direct Damage
• a) metabolic byproducts
• b) degradative enzymes
• c) secreted toxins

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Degradative enzymes

• allow tissue destruction and cellular damage
• no specificity for cell type (different from
  classic toxins)

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Bacterial Damage to the Host

• I. Direct Damage
• a) metabolic byproducts
• b) degradative enzymes
• c) secreted toxins
• II. Indirect damage
• inflammatory response

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Bacterial Toxins

• Practical definition and characteristics of an
  exotoxin
• comprised of one or more proteins
• secreted, generally acts at remote site
• bind specific receptor on target cells
• results in cellular injury or altered physiology

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Stages at which bacterial toxins may contribute
to pathogenesis
1. Acquisition (Encounter) 2. Colonization 3
. Invasion 4. Spread 5. Disease 6. Resolution
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Stages at which bacterial toxins may contribute
to pathogenesis
1. Acquisition (Encounter) 2. Colonization 3
. Invasion 4. Spread 5. Disease 6. Resolution
Toxins may result in disease without invasion or
spread
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Bacterial Exotoxins Contribution to Disease

• Inadvertent damage - contribution of toxin to
  pathogenesis fitness is not clear (e.g.
  staphylococcal enterotoxins cause diarrhea, even
  in absence of viable organism)
• 2. Selective advantage
• - access to nutrients
• - spread through tissues
• - immune evasion (kill PMN)
• - disease transmission (induce cough, diarrhea)

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Biologic Effects of Bacterial Toxins

• Damage membranes
• Inhibit protein synthesis
• Activate second messenger pathways
• Damage cytoskeleton
• Arrest cell cycle
• Inhibit neurotransmitter release
• Induce inflammation

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Bacterial Exotoxins Physiologic Effects

• Physiological and clinical effects depend on
• Host cell target determined by expression of
  toxin receptor
• Intracellular target determined by the enzymatic
  activity and substrate specificity of the toxin
• 3. Ability or inability of the toxin to spread
  systemically

-host cell specificity determined by presence of
receptor, and target
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Classification of Bacterial Exotoxins

• 1. Structure
• Enzymatic activity
• Host cell target

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Bacterial Exotoxins Structure

• 1. Single chain, multi-domain toxins
• most pore-forming toxins
• 2. A-B toxins
• - most toxins have A-B structure
• - A domain has enzymatic activity, generally
  released into cytosol in absence of B domain
• B domain responsible for receptor binding
• A and B domains may be translated as single
  peptide (then cleaved) or the two domains may be
  comprised of heterologous subunits (usually
  transcribed as an operon).

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Single chain, multi-domain pore-forming toxins
a-hemolysin
Perfringolysin O
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Ribbon structure of three classic A-B toxins
-A and B domains are separate, non-covalently
attached proteins
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Common A-B toxins
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Sites of toxin action on host cells

• Extracellular matrix
• not classic toxins, but damage occurs
• degradative enzymes, etc
• Cell membrane
• pore-forming toxins
• Intracellular
• membrane penetrating toxins (e.g. DT)
• toxin trafficked in retrograde direction through
  ER

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Insertion of pneumolysin into host cell membrane
Cell, Vol. 121, 247256, April 22, 2005
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Bacterial Exotoxins Mechanisms of Host Cell
Internalization
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Mechanisms of Shiga Toxin Internalization
Golgi
Endoplasmic Reticulum
Nucleus
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Mechanisms of Bacterial Toxin Action

• Pore formation
• ADP-ribosyltransferase activity
• N-glycosylase activity
• Adenyl cyclase activity
• Protease activity
• DNA damage
• Superantigen properties

A-B toxins

• Biological effect depends on target molecule.
• Clinical effect depends on target cell

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Biologic Effects of Bacterial Toxins

• Damage membranes
• Inhibit protein synthesis
• Activate second messenger pathways
• Damage cytoskeleton
• Arrest cell cycle
• Inhibit neurotransmitter release
• Induce inflammation

A-B toxins
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Bacterial Exotoxins Mechanisms of Host Cell
Damage
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ADP-ribosyltransferase activity
Target Protein

-also sometimes known as NAD glycohydrolases
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Bacterial Damage to the Host

• I. Direct Damage
• a) metabolic byproducts
• b) degradative enzymes
• c) secreted toxins
• II. Indirect damage
• inflammatory response

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