Transcript WK11-RevApopt.

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
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
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.
Apoptosis vs Necrosis
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.
Pathogen manipulation of apoptosis

Viruses – often inhibit apoptosis
-

Protozoa – often inhibit apoptosis
-

Oncogenic viruses destroys p53 surveillance system
Inhibit extrinsic and intrinsic apoptosis pathways
Toxoplasma, Trypanosomes, Cryptosporidium
Heat shock proteins, NF-KB
Bacteria – often induce apoptosis
- Helicobacter, Shigella, Salmonella
- Toxins, protein synthesis inhibitors, TTSS
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
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.)
Chlamydial apoptosis manipulation

When to inhibit apoptosis?

When to induce apoptosis?
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
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 antiapoptotic proteins or inactivating pro-apoptotic
proteins. Type III Secretion Systems available.
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.
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.
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?
You have the keys to unlock
many of life’s mysteries