Chlamydiae

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Chlamydiae

• Obligate intracellular pathogens.
• Acute and/or persistent infections.
• C. trachomatis mucosal surfaces
• Ocular infections - trachoma
• Genital infections - pelvic inflammation,
  infertility
• Reactive arthritis
• C. pneumoniae
• Pneumonia
• Atherosclerosis

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Chlamydia Life Cycle

• Elementary body (EB)
• -metabolically inactive
• -highly infective stage
• Reticulate body (RB)
• -metabolically active
• -intracellular growth stage
• Persistent body (PB)
• -life cycle pause between EB and RB stages
• -stable association with host cell

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Apoptosis vs Necrosis

• Apoptosis programmed cell death.
• -eliminate and phagocytose cells in an orderly
  fashion.
• -phosphatidylserine (PS) receptor on phagocytes
  increases anti-inflammatory cytokines TGF-beta
  and IL-10.
• -needed for embryogenesis, immune system
  maintenance.
• Necrosis non-programmed cell death.
• -cellular debris is a danger signal in the
  cell, so inflammatory response follows DSR
  interaction with phagocytic cells.

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Apoptosis vs Necrosis
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How might apoptosis help pathogens?

• Facilitating pathogen propagation
• -pathogens within apoptotic cells can be taken up
  by other phagocytic cells without the pathogen
  having to navigate the extracellular environment.
• Avoiding inflammatory responses
• -apoptosis can release anti-inflammatory
  cytokines that down regulate the immune response.

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Pathogen manipulation of apoptosis

• Viruses often inhibit apoptosis
• Oncogenic viruses destroys p53 surveillance
  system
• Inhibit extrinsic and intrinsic apoptosis
  pathways
• Protozoa often inhibit apoptosis
• Toxoplasma, Trypanosomes, Cryptosporidium
• Heat shock proteins, NF-KB
• Bacteria often induce apoptosis
• - Helicobacter, Shigella, Salmonella
• - Toxins, protein synthesis inhibitors, TTSS

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Mechanisms of Apoptosis

• Extrinsic pathway Receptor mediated
• FasL-death receptor interactions
• Initiator caspases caspases 8, 9
• Effector caspases caspases 3, 6, 7
• Intrinsic pathway Intracellular origin
• Caspase activation or intracellular stress
  signals
• Mitochondrial release of cytochrome c
• Apoptosome formation

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Extrinsic pathway

• Type I cells activate initiator caspase 8, then
  effector caspase 3, then apoptosis commenses.
• Type II cells require mitochondrial
  amplification. BAX, BAK stop being inhibited by
  BCL-2, BCL-X and cause mitochondrial release of
  cytochrome c, then apoptosome forms, activates
  caspase 3, and commenses apoptosis (DNA
  fragmentation, nuclear condensation, membrane
  blebbing, etc.)

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Chlamydial apoptosis manipulation

• When to inhibit apoptosis?
• When to induce apoptosis?

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Chlamydial apoptosis manipulation

• When to inhibit apoptosis?
• - for chronic or persistent infections
• - when intracellular growth stages dominate
• When to induce apoptosis?
• for acute infections
• when infectious Elementary Body stages dominate

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How to manipulate apoptosis?

• Chlamydia protein associating with death
  domains CADD, is an oxidoreductase, so
  accumulation of reactive oxygen species could
  lead to necrosis, while interactions with Fas
  could inhibit apoptosis.
• Chlamydia interferes with mitochondrial apoptosis
  signals, perhaps by secreting Bcl-2
  anti-apoptotic proteins or inactivating
  pro-apoptotic proteins. Type III Secretion
  Systems available.

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How to induce apoptosis?

• Caspase-independent apoptosis occurs.
• Necrosis occurs in some cases by design or
  accident?
• Cell type specific interactions.
• Over-expression of BAX, BAK cause cell death.
• BAX deficient cells and mice had fewer Chlamydial
  organisms, so perhaps BAX-induced apoptosis is
  important for propagation of the infection.
• Increased mitochondrial metabolism and oxidative
  stress observed in infected cells.

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How to inhibit apoptosis?

• Inhibit cytochrome c release from mitochondria.
• MEK/ERK MAPK signalling pathways.
• NF-KB as with MEK/ERK, upregulate transcription
  of anti-apoptotic genes.
• IAP upregulate Inhibitors of Apoptosis Proteins.

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Future Work

• No methods exist for genetic transfer (yet),
• so much is unknown about virulence and
  pathogenesis!
• Is Chlamydiae-induced apoptosis associated with
  acute disease while Chlamydiae-inhibited
  apoptosis is associated with chronic disease?

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