Chlamydia trachomatis Flashcards
Describe the pathogenic burden of chlamydia
Widespread -
It is the most common bacterial STD with 90 million new cases each year
10% of sexually active adults aged 15-25 are infected.
It is highly infectious – and will infect in >50% of exposures – i.e. if you have intercourse with an infected individual on only one occasion, your risk of contracting chlamydia is >50%
Asymptomatic
It is asymptomatic in 80% of infections – these people can have the disease for months or even years before being diagnosed
No vaccine.
Harmful sequalae
If left untreated, it can progress to more serious conditions such as infertility. Worldwide it’s the leading cause of infertility.
Sequalae of chlamydia trachomatis infection include blindness, pelvic inflammatory disease, ectopic pregnancy and infertility.
Describe the disease trachoma
C. trachomatis also causes trachoma - infection that causes hardening of inner surface of the eyelids.
Can lead to pain in the eyes, breakdown of the outer surface or cornea of the eyes, and possibly to blindness.
Scarring is due to an inflammatory response.
Can be acquired through contact with infected individuals or objects carrying infectious particles.
Transmission is increased in areas of poor sanitation.
Endemic in Africa and other developing countries.
Treatment is usually a single dose of azithromycin (a macrolide) as chlamydia is resistant to penicillin and other beta-lactams.
Describe bacteriology of C.trachomatis
- It’s an obligate, aerobic bacterium
- Gram-negative bacteria and has a spherical shape.
- Intracellular bacterium - it require growing cells in order to remain viable since it cannot synthesize its own ATP – can only replicate in cell. Without a host organism, it can’t survive.
- It is thought that chlamydia trachomatis has undergone evolutionary genomic reduction, causing it to rely on the host for the majority of its nutrients.
- It lacks peptidoglycan - it instead has cytsteine-rich proteins which prevent phagolysosome formation and allow it to survive in phagocytes.
Describe the life cycle of C.trachomatis
It has a short, bi-phasic life cycle
- It infects epithelial cells –> the infectious form, the elementary body, will attach to receptors on host epithelial cells and enters by endocytosis.
- Once inside, the elementary body will interact with glycogen molecules to form the larger reticulate body – this is the non-infectious/replicative form which rapidly divides via binary fission, creating hundreds of new elementary bodies.
- The elementary bodies are very compact with slight metabolic activity.
- The host cell will lyse and release the elementary bodies, which are then able to infect more epithelial cells.
Explain the mechanisms C.trachomatis has developed to help its survival
Induce its own uptake –the chlamydial type III secreted effector protein - translocated actin recruiting phosphoprotein (TARP) is necessary for uptake of elementary bodies into the cells. TARP has distinct actin binding domains which recruits and causes the clustering of actin monomers to create filaments that will allow entry of EBs into the cell.
Avoids the endocytic pathway – the bacterium is carried and grows in a specialised vacuole which will avoid it being detected by the intracellular immune system in the host cell. The cost of this –> the vacuole will also segregate it from the nutrient rich cytosol.
Chlamydia nutrient acquisition –> it disguises itself as a recycling endosome and ‘steals’ the nutrient rich secretory vesicles. It interacts with Rab GTPases (trafficking proteins) to do this.
Persistence phenotype: in stressful conditions, the chlamydia bacteria will enter an alternative growth mode termed the persistent phenotype.
o Many different factors can trigger this phenotype including penicillin, interferon-gamma, iron/nutrient starvation.
Long-term persistence has been linked to the serious conditions caused by chlamydia infection.
o Involves Aberrant, enlarged RB with no elementary bodies being produced.
o Its transcriptional pattern is altered, e.g. the expression of the outermembrane proteins is increased.
o While genomic replication may continue, there’s lack of cytokinesis –> no new cells being produced.
o It’s a reversible state – once stressor is removed, it will go back to infectious EBs.
Antibiotics are ineffective against chlamydia in the persistent phenotype.
How does IFN-gamma induce the persistent phenotype?
it mediates persistence by depleting tryptophan levels – it does this by activating the tryptophan catabolising enzyme, indoleamine 2,3-dioxygenase IDO. Low levels of tryptophan will correlate with inhibited growth of the bacterium since it’s needed for replication.
Why does Chlamydia trachomatis need an iron homeostasis system?
Iron is essential for most organisms, in cellular processes such as electron transport and nucleotide biosynthesis and it’s often a limiting nutrient for a pathogen.
However excess iron can catalyse the generation of toxic free radicals which is why most organisms have some sort of homeostatic mechanism to regulates its levels.
Describe the mechanism of C.trachomatis iron regulation
No iron –>
Upon experiencing iron starvation in vitro, chlamydia trachomatis exhibits elevated expression of a putative iron-transport system encoded by the ytg operon.
- The operon encodes for a periplasmic metal substrate-binding protein (YtgA), a cytosolic ATPase (YtgB), and a membrane channel formed by two proteins (YtgC and YtgD) in complex.
- Iron binds to YtgA and is then transported through the C and D domains into the cytosol.
- ytgA transcription is elevated following iron starvation -> response
- This will increase intracellular levels of iron inside the bacterium.
o Ct069 domain, referred to as ytgC is interesting as it’s made up of two proteins of distinct domains and functions.
N terminus – integral protein ytgC
C terminus - DNA-binding transcriptional repressor, termed YtgR. It’s a member of diphtheria toxin repressor superfamily and is present on cytoplasmic side of the inner membrane.
Iron levels are high –>
When iron is sufficiently present, it binds to the ytgR and this complex binds upstream of ytg operon and represses transcription of iron – homeostasis.
Iron acts as the metal cofactor for the activation of ytgR.
Repressor recognizes cis-regulatory elements which blocks initiation of transcription of regulated genes
How does the YtgR domain affect transcription from a membrane-anchored localization?
YtgR is cleaved during the course of infection by proteases to produce functional repressor which can then bind upstream of ytg operon in presence of iron.
