Lecture 6: Toxoplama gondii Flashcards
True or false: T. gondii is an obligate extracellular pathogen?
False: it is an obligate intracellular pathogen
What phylum does T. gondii belong to?
Apicomplexa
What is the typical infective route for T. gondii?
oral
What disease does T. gondii cause?
Toxoplamosis
What is the end stage host of T. gondii?
warm blooded animals
What type of reproduction occurs in end stage hosts of T. gondii?
asexual reproduction only
What is the definitive host of T. gondii and what type of replication occurs here?
Cat
sexual reproduction
How is it that so many people are infected with T. gondii but not continuously ill?
Immune system controls infection - survives as a latent infection in the form of tissue cysts (such as brain)
How is toxoplasmosis transmitted?
- foodborne (undercooked meat)
- zoonosis (Cat litter trays)
- congenital (mother to child)
- transplantation
Under what conditions may toxoplasmosis cause serious complications?
in immunocompromised individuals (infants, elderly, HIV, immunosuppressed - cancer therapy, transplant)
What are the main symptoms following toxoplasmosis infection?
transient intestinal inflammation
flu-like symptoms
What is congenital toxoplasmosis and give three effects this can have on the foetus?
infection with toxoplasmosis during pregnancy that is transmitted to foetus
can result in hydrocephalus, epilepsy. hearing loss, learning disabilities, cerebral palsy
What is ocular toxoplasmosis?
cysts at the back of the eye can result in blurred vision, floaters, loss of vision
What is the most serious toxoplasmosis infection?
cerebral toxoplasmosis where cysts in brain but the infection is not controlled and can result in immune response and inflammation (serious and life-threatening as can result in confusion, seizures, loss of co-ordination)
Describe the life cycle of T. gondii
Tissue cysts contain bradyzoites
- in definitive cat host, the bradyzoites can differentiate into merozoites and allow sexual reproduction to produce gametocytes that form a zygote or differentiate into tachyzoites as part of asexual reproduction
- zygotes form oocysts that contain sporozoites
bradyzoites (from ingested cysts) and sporozoites (from ingested oocysts) differentiate into highly infective tachyzoites as part of the asexual reproductive cycle in the end-stage host
- tachyzoites invade cells and multiply until cell dies releasing more tachyzoites
- tachyzoites then differentiate back into bradyzoites and form cysts mainly in the brain, liver and muscle
how can an end-stage host become infected?
- ingesting oocysts containing sporozoites from cat faeces (sporozoites invade tissues and develop into tachyzoites then bradyzoites in cysts)
- ingesting meat infected with bradyzoite cysts (bradyzoites differentiate into tachyzoites)
How do we respond to T. gondii infection?
once recognition occurs, two key cytokines are produced:
IL-12 (produced by innate immune cell responses that trigger the activation of the adaptive immune response) and INF-gamma (produced by the adaptive immune cells)
how do we recognise T. gondii infection?
PRRs recognise PAMPs
- TLR1/2 and 4 potentially recognise GPI anchor of parasite
- once within the cell, TLR7 and TL9 potentially recognise RNA and DNA, respectively
- TLR11 and TLR12 recognise profilin during parasitophorous vacuole
Give two examples of transmembrane PRRs and two examples of Cytosolic PRRs
Transmembrane:
- TLRs (plasma membrane or endosomes)
- C-type lectin receptors (CTLs)
Cytosolic:
- Nod-like receptors (NLRs)
- RIG-1 like receptors (RLRs)
What is profilin, how is it recognised by our immune system?
Profilin is an actin binding protein in the parasite that is essential for motility and cellular invasion
recognised by TLR11 and TLR12
What is the significance of MyD88 in innate recognition of the parasite?
all the TLRs involved in recognition of T. gondii activate signalling pathways that all involve the protein MyD88 that ultimately activates transcription of IL-12
- k/o MyD88 mice fail to produce IL-12 and are susceptible to infection
What is the significance of UNC93B1 in innate recognition of the parasite?
UNC93B1 is attached to the N-terminal region of TLR7, 9, 11, and 12 (but not TLR1,2, or 4) and involved in signalling for these TLRs.
- k/o UNC93B1 mice are highly susceptible to infection
This indicates that perhaps the recognition of the GPR anchor by TLR1/2 and 4 is not as important in parasite recognition (not enough to produce effective immune response alone when the other TLRs are non-functional due to UNC93B1 k/o)
which cell does the innate recognition and IL-12 production largely occur in?
CD8 alpha dendritic cells
What does IL-12 do?
signals to naive helper CD4 T cells to drive the T-helper 1 response to make IFN-gamma
- Th1 response is good for intracellular parasites
What other immune cell is essential in the production of IFN-gamma?
NK cells
How does IFN-gamma result in parasite killing in immune cells?
Immune cells such as monocytes and macrophages that have phagocytosed parasites have IFN-gamma receptor
- binding of IFN-gamma to receptor results in STAT1 activation and toxicity-inducible reactive oxygen species and nitric oxide molecules that damage the parasitophorous vacuole
- STAT1 signalling also results in activation of GTPases (IRGs) and p67 guanylate-binding proteins (GBPs) that rupture the parasitophorous vacuole
How does IFN-gamma result in parasite killing in non-immune cells?
IFN-gamma receptor activation results in STAT1 signalling that results in activation of GTPases (IRGs) and p67 guanylate-binding proteins (GBPs) that rupture the parasitophorous vacuole
What is one of the big problems between the mouse model (from which a lot of the information about T. gondii infection has been found) and humans?
Humans have 3 stop codons on the TLR 11 gene and a complete absence of the TLR 12 gene = no ability to recognise profilin as a human
What is different about the human equivalent of the CD8alpha dendritic cells in mice?
The main human producers of IL-12 are the opposite dendritic cell population to that of the mouse model (i.e. the human equivalent of the mouse non-CD8alpha DCs)
How do human dendritic cells recognise the live parasites?
phagocytosis of the parasite possibly sensed by cytosolic PRRs such as RIG-1
How do infected rats/mice behave different around cat urine?
When infected, they lose their aversion to cat urine (which would normally promote their survival)
- parasite knows it is in an end stage host because it doesn’t have sexual reproduction
- to promote sexual reproduction and carry on the parasite lifecycle, it makes the mouse more likely to take risks and get killed by the cat
Describe the host cell invasion and manipulation by T. gondii
- actin-based motility and protein secretion from the Rhoptory bulb allows envagination to create a parasitophorous vacuole
- the protein secretion recruits mitochondria and host ER and avoids fusion with lysosomes and endosomes
- activation of anti-inflammatory pathways such as STAT3/6 (opposite of STAT1) and SOCS3
- GTPase inhibitors prevents non-immune cell breakdown of the parasite wall via STAT1 IFN-gamma signalling
A small study showed a significant correlation between toxoplasmosis infected humans and what type of behaviour?
risk-taking behaviour (although large studies have suggested this is unlikely in humans - although very clear in rats/mice)
Give two human diseases that toxoplasmosis infection has been linked to
Alzheimer’s disease
Schizophrenia
