Vl 4 - host cell remodelling Flashcards
what is PSAC
- plasodium surface anion channel (in erythrocyte membrane)
- infected RBC membrane is more permeable for:
sugar, AA purines, vitamines, cholines, fatty acids, anions
more Na+, less K+
what is Plasmodium CLAG3?
- crucial subunit of PSAC
- required for increased permeability
- CLAG3 doesn’t need PTEX to be transported
what is PFEMP1?
- associated with knobs: mediates adherence between RBC and endothelium cells ⇒ clustering in blood vessels (rosettery)
- infected erythrocytes leave blood circulation by cytoadhesion
- exported proteins to RBC surface interact with endothelial surface proteins (major protein CD36)
- var-genes encode PfEMP1 (~60 var gens) ⇒ antigen-variation (immune evasion)
what are TgMYR1/2/3 used for??
- c-Myc (transcriptional regulator) regulation proteins in Toxoplasma gondii
TgMYR1 required for:
- induction of c-Myc expression
- phosphorylation of p38 through GRA24
- nuclear translocation of PP2A through GRA16
- GRA24 localization to host cell nucleus (TgMYR2/3 also required)
- TgMYR1,2,3 localize in the parasitophorous vacuole.
Which cells/tissues/organs are infected by Plasmodium and why?
- immune-privileged cells are invaded
- liver/hepatocyte:
- immune-privileged (⇒ immune system avoidance), high nutrient availability.
- Blood cells: Immune bypass ⇒ don’t code for MHC molecules (no cell nucleus) ⇒ no antigen presentation
- high nutrient availability in blood vessels and rapid migration through the entire body
- RBCs have little compartmentation ⇒ quick access to various host metabolic pathways
- RBC infection causes adhesive knobs, deformation
⇒ increased permeability: import of nutrients, ion permeability
To what extent are RBCs altered by Plasmodium?
- infected RBC show:
increased adherence, deformation (knobs) and increased permeability, formation of intracellular structures (Maurer’s clefts in Pf) - Adherence: knob formation
- Plasmodium surface proteins (PfEMP1, KHARP) interact with RBC cytoskeleton
- Knobs associated with PfEMP1 (erythrocyte membrane protein)
- mediates cytoadherence ⇒ PfEMP1 binds to endothelial cells (group B PfEMP1 ⇒ CD36 - group A PfEMP1 ⇒ EPCR - both surface proteins) and other RBC (rosetting) ⇒ iRBC “leaves” the blood circulation ⇒ bypassing spleen filtration
- Permeability: incorporation of PSAC (Plasmodium surface anion channel) at the RBC surface, of PVM channel at TVN and PVM and Nutrient transporters
⇒ more permeability for sugars (e.g. sorbitol), AA purines, vitamins, cholines, fatty acids and anions (Cl-). - also: K+ excreted from RBC, Na+ taken in
- Maurer’s clefts: sorting compartments for e.g. export of PEXEL/HT proteins
How does Plasmodium in the blood vessels bypass the immune system?
- PfEMP1 protein has many slightly different variants (about 60 var-gene) ⇒ if antibodies are formed against one variant, a new variant is expressed ⇒ evasion via antigen variation
Name a Plasmodium protein that is encoded and expressed by all Plasmodium species. What is its function?
- SBP1 = skeleton-binding protein 1:
- essential for positioning of PfEMP1 on RBC surface
- localized in maurer’s cleft, might recruit them onto the RBC membrane
What is the function of Maurer’s clefts? Name a protein contained in Maurer’s clefts and its function.
- essential organelles for transport of virulent complex proteins
- serve as intermediate stations for proteins on their way to the host cell membrane
- motile in early infection ⇒ fixed in position and number later
- needed correct transport of virulent complex components including PfEMP1 (or PEXEL export signal containing proteins) to RBC surface
- PFE60 plays a role in the segmentation of MC lamellas.
Via which complex do the parasitic proteins around the parasitophore vacuole penetrate through out into the host cytosol?
- PTEX complex (forms pore in parasitophoric vacuole)
What is PEXEL and what is it used for?
Plasmodium export Element (PEXEL)
- PEXEL/HT (Host Targeting) signal helps transporting over 300 proteins via the PV into the RBC
Where is Plasmodium protein targeting determined for its export?
- In the parasitic ER
How are parasitic proteins transported from the PV into the RBC plasma membrane?
- pass PTEX from PV to RBC
- either go directly to target site or first go to maurer’s clefts (e.g. KHARP)
- From Maurer’s clefts to the surface of the RBC ⇒ vesicle-mediated transport to knobs or host cell surface (possibly along tethers or actin filaments)
Which organelles are necessary for the host cell invasion of Toxoplasma? How long do the processes take?
- micronemes, rhoptries and dense granules
1) microneme proteins (AMA1) secreted at apical end, attach to host cytoskeleton
2) moving junction formation
3) rhoptry RON/ROP proteins interact with ESCRT complex (RON - ALIX and TSG101 are recruited to moving junction) and block immune response (ROP)
4) parasite enters cell through moving junction, forms PV
5) dense granule proteins (GRA) manipulate host signaling/gene expression - enlarges PV
- takes 1 min to enters cell
- end of dense granules secretion 10 min after invasion start
Which components can RON4 (and RON5) interact with? What are these components normally used for and what happens when RON4 interacts with them?
- with ESCRT complex components (annular complex required for abscission of vesicles) ⇒ ALIX and TSG101
- ESCRT ⇒ for the invagination (einstülpen) of factors on the membrane of vesicles ⇒ factor inside of vesicle ⇒ can get disrupted by lysosome
- ESCRT ⇒ cytosolic material is invaginated (to the outside or to the inside).
- With Toxo: ALIX and TSG101 recruited into moving junction during invasion ⇒ possibly to close the parasitophoric vacuole after invasion of the host cell
