Klausur 2. Termin Flashcards
in which compartment of the cell do leishmania reside? which mechanisms influence the development of this compartment?
- resides and replicates in phagolysosomal compartments of the host macrophage
- resides in early endosome and inhibits its transport to the host lysosome by e.g. Rab5a overexpression which blocks the processing of lysosomal enzymes (in general: all intracellular pathogens avoid targeting to lysosomes)
- insertion of LPG inhibits SytV, which is needed for V-ATPase recruitment (no pH drop ⇒ no phagosome maturing ⇒ no fusion with lysosome)
https: //www.ncbi.nlm.nih.gov/pmc/articles/PMC5501680/
what are the two major strategies in anti-parasite drug development and how do they work?
VL - 2
- Target-based approach:
Essential genes ⇒ Structure-guided inhibitor design ⇒
in vitro SAR optimization ⇒ Cell-based tests ⇒ Animal and clinical studies ⇒ approval
BUT: Very high drop-out rates, Expensive - Phenotypic screen-based approach:
Screen for parasiticial hits ⇒ hit-to-lead optimization ⇒
Further animal and clinical studies ⇒ approval
BUT: inefficient optimisation and high toxicity
which experiments can be used to detect nutrients that leishmania absorbs from the host cell and metabolizes. which experiment can be used to prove wether the nutrient is essential for the growth of leishmania?
VL - 1
by GC/MS (Gas chromatography–mass spectrometry), using heavy C13 (in heavy U 13C6-D-Glucose) and/or H(2+) Isotopes to measure nutrient paths and fluctuation rates
by starving them of one nutrient at a time and see which impair growth when missing
which functions have MYR1, MYR2, MYR3
VL - 4
- 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.
How do Plasmodium sporozoites move?
- have circular movement (cork screw) in the approximate diameter of blood vessels and have same gliding motility as Toxoplasma (actin-myosin mediated) -with CS-protein help
Circumsporozoite Protein (CS-protein)
- surface protein ⇒ secreted from rhoptries and micronemes
- essential for the gliding motility and adhesion to the epithelium of mosquito salivary glands
- also essential for hepatocyte binding
- helps surviving in macrophages by ribo-toxic activity to inhibit protein synthesis in host cells
which vaccination strategies work against merozoites. list three proteins suitable for vaccination against merozoites.
vacination strategies: live, attenuated vaccines (particularly WT+Chloroquine/WT+Azithromycine or genetically attenuated approach) -> both approaches would induce late arrest of merozoites (delayed death of parasite, suppressive treatment or genetically defined arrest)
- also possible: RAS = induce cell-mediated immunity via CD8+ T-cell response (TRMs in liver and CD8+ mediated killing of infected hepatocyte)
merozoite proteins: mTRAP, MSP1, MSP3, AMA1
which mechanism and effectors are there in priming against pre-erythrocytic plasmodium.
definition pre-erythrocytic: sporozoites in the skin/liver and merozoites in hepatocytes
natural immunity: humoral (skin, sporozoites) and cell-mediated immunity (liver stage, merozoites)
- in general: CD4+ and CD8+ T-effector mechanisms
- skin: antibody response and T-cell priming
- spleen: CD8+ T-cell priming (via crosspresentation, regulated via CD4+ T-cells and gd-T-cells)
- liver: patroling of CD8+ T-cells (from spleen) in hepatocyte sinusoides as TRM-cells, direct killing of infected hepatocytes via CD8+ and CD4+ T-cells OR indirect via secretion of IFN-g (iNOS and NO production)
What is naturally acquired immunity against plasmodium?
- long and constant exposure to all 60 PfEMP1 (blood-stage surface protein) ⇒ immune system can recognize and react to them all ⇒ not possible in young children
- natural immunity can be lost⇒ b-cell response vanishes after some time
