parasite-vector molecular interactions Flashcards
1
Q
malaria lifecycle
A
- bloodstream gametocytes in bloodmeal
- exit RBCs and flagellate → gametes
- male and female gametes fertilised → diploid zygote
- → ookinete → invade midgut epithelium
- reach basal lamina → oocyst → rounds of replication
- cell division → bursting → sporozoite release
- migrate to salivary glands → inject into human
- infect liver cell → schizont → rupture and merozoite release
- invasion of RBC → trophozoite
- reinfects RBCs or forms gametocytes
2
Q
incompatible vectors
A
- some stages of plasmodium life cycle lived
- no invasion of midgut epithelium
- specific receptor-ligand interaction
3
Q
vaccine targets
A
- TBVs only prevent transmission
- provides herd immunity but not individual immunity
- theoretically can target any stage
- best stage to target is pre-midgut invasion
- higher levels of parasite targets (if using antibodies/immune based cells)
- more susceptible before reaching midgut
4
Q
TBV targets
A
- gametocyte to ookinete transmission
- lower numbers
- little antigenic variation of plasmodium in mosquito
- only innate immunity - less selection pressure
5
Q
drawbacks of TBVs
A
- lack of host immune boosting
- antibody titres wane over time
- anitgens specific to mosquito stage of parasite
- human will not encounter these again after vaccination
- titres may become insufficient
6
Q
events required for full malaria transmission
A
- parasite devlopment
- gametogenesis, sporogonic development
- cell adhesion, entry, exit
- midgut entry
- salivary gland entry
- evasion of mosquito innate immune system
7
Q
male plasmodium gametogenesis
A
- rounding up (condensation)
- emergence from RBC membrane
- DNA replication (x3)
- mitosis (x3)
- axoneme assembly
- exflagellation
8
Q
female plasmodium gametogenesis
A
- rounding up
- emergence
- expression of P25/P28
- fewer morphological changes but slower
9
Q
P28 transcripts in females
A
- strong localisation to ookinete
- transcripts found from gametocyte to ookinete stages
- FISH
- but protein found gamete stage onwards
- western blotting
- parasite stores up transcript until needed on the surface
- immunisation with P28 produces potent TB antibodies
10
Q
control of gametogenesis
A
- strict control by mosquito midgut conditions
- maximal efficiency of sexual reproduction and transmission
- prevent TB immune response to prematurely produced mosquito stage antigen (in human host)
- parasite won’t risk exposing antigen to human host immune system if not needed at this stage
11
Q
factors regulating gametogenesis
A
- originally thought to be:
- temperature drop (5 degrees)
- pH increase in midgut to pH8
- pH alone actually not enough
- HPLC identifies chemicals present to induce exflagellation and gametocyte activation
- xanthurenic acid
- probably 2nd messengers and protein kinase cascades involved in triggering gametogenesis
- potentia targets
12
Q
xanthurenic acid
A
- sufficient to produce 100% exflagellation in male parasites in combination with pH increase
- specific mosquito-derived molecule
- triggers gametogenesis
- highly specific downstream signalling pathways likely
- potential for intervention
13
Q
protein kinases in gametogenesis induction
A
- identify differential expression in presence of XA
- knockout
- MAP2K knockout downstream of XA
- DNA aligns at equator, axoneme separation, cell polarisation but no exflagellation
- CDPK4 knockout
- almost no activity
- plant-like → potential herbicide use
- 2 kinases acting at different stages of the pathway
- activated by second messengers
14
Q
antibodies in bloodmeal
A
- can block transmission
- can agglutinate microgametes with e.g. ANTI-230
15
Q
male gamete targets
A
- P45 and P48
- target for blocking fertilisation and zygote formation
- knockout stuides identified as likely receptor for TBVs
