1
Q
Malaria is a big obstacle to further global progress
A
- Still close to #1 infectious cause of child mortality
- Access to available interventions remains poor
- Drug and insecticide resistance rife
- Poor predictors of severe malaria
- No vaccine and desperate for new drugs
- malaria is considered one of the key drivers of poverty (countries cant get rich unless they get rid of malaria first)
2
Q
Taxinomic classification of Malaria
A
- Phylum: Apicomplexa
- Genus: Plasmodium
- 5 species infect Humans: P.falciparum (main one), and P. vivax
- Many other species infect animals
- single celled protozoan parasite, all apixomplexa invade cells like viruses
3
Q
Malaria is more common just ___ and ___ of the Equator
A
North and south
- where it becomes more and more tropical, malaria more common because their life cycle extends all year round, winters stop them breeding
4
Q
How important is Malaria now?
A
- 1 bil people worldwide with parasites in their blood but only 2-300mil clinical cases
(they’re not sick but the biomass of these parasites is a heavy burden) - 0.5mil deaths/year (mostly children)
- Malaria seriously hinders social and economic development
>est $12 bil in direct costs
>10% of yearly household spending in Africa
>work and school absenteeism (as high as 28% in some areas)
5
Q
The definitive host of the malaria parasite is the:
A
Anopheles mosquito
6
Q
RBCs stain ____ colour when they are infected with malaria parasites
A
Blue
7
Q
Life cycle of P. falciparum
A
Three stages:
- Mosquito stage (sexual reproduction)
- Liver stage (asexual reproduction)
- Blood stage (asexual reproduction, major amplification stage)
only in blood stage does it cause disease
8
Q
In the mosquito gut, there are ___ and ___ versions of the parasite
A
Male and female
-diploid organ, fertilisation
- in mosquito salivary glands, you get miosis into haploid organisms called sporozoites (which enter the human host)
Gamete>Zygote>Ookinete>Sporozoite
9
Q
Sporozoites enter the:
A
Human liver and infects hepatocytes (100 - 1000 sporozoites injected)
Doesnt cause disease for these 1-2 weeks in the liver
10
Q
Merozoites enter the:
A
RBCs where they start to replicate and keep amplifying
important: go from relative small numbers up to 1% of all of your blood cells
- started off with injection of 10-100 sporozoites but end up with 1% of all RBC about 10^12 cells infected
11
Q
Important aspects of lifecycle and spread
A
- Sexual stage in the female anopheles mosquito (1-2 weeks)
- Injected sporozoites enter hepatocytes via skin (~30 mins)
- Asexual liver stage (1-2 weeks)
- Asexual blood stage is relatively synchronous and takes 2-3 days
- Disease occurs a week to a month after infection
- Gametocytes form in the blood and are taken up by a feeding mosquito
12
Q
Malaria genome has 5200 genomes encoding for a lot of proteins, but the one we are interested in is:
A
PfEMP1
(Plasmodium falciparum Erythrocyte Membrane Protein 1)
Confers virulence and immune escape
13
Q
Disease only occurs in the ______
A
Blood-stage
- Fever, chills, anaemia
(hard to predict which individuals move on to develop more serious complications) - Most deaths (95%) caused by P.falciparum
>Cerebral malaria, coma
>Severe anaemia
>Placental malaria - P.vivax also results in significant morbidity but low mortality
>relapsing malaria (hypnozoites in liver)
14
Q
P. vivax has a _____ form
A
Latent
- can live as a form called a hypnozoite in the liver for life
- for reasons not understood, these hypnozoites can reactivate later in life and cause disease
15
Q
How does the malaria parasite avoid splenic clearance?
A
Cytoadherence/sequestration
- Infected RBC is stuck to BV wall, taken itself out of circulation
- Parasites are maturing inside, and across the course of 48h, parasites grown within there and burst out
16
Q
What is splenic clearance?
A
Spleen recognises RBCs that are not normal anymore
- has cross-hatched fenestrations like a little filter, RBCs go through spleen and are squeezing through these fenestrations
- Thought that the spleen is testing those cells (looking for cells that are getting too old and wants to get rid of them e.g. if a cell is getting too rigid)
Clearance mechanism
- Macrophage-like system will be activated and clear those red cells
- A plasmodium infected RBC wants to stay away from the spleen»_space; cytoadherence
17
Q
Cytoadherence is sometimes associated with ______ pathologies
A
Severe pathologies
- depending on which BVs they sequester to (not all BVs are the same, not all RBCs are the same)
e. g. Cerebral malaria - infected brain capillary
18
Q
What microscopic feature is diagnostic of malaria parasites?
A
BV full of cells with a gold particle in them - digested heme (haemozoan)
The parasite inside the RBC is digesting the haemoglobin, eating the protein partly because it is a nutrient source and partly because it needs to create space inside this RBC to grow
Heme - iron calated structure, very toxic for all cells including parasites
Malaria parasite polymerises that digested heme into this gold crystal called haemozoan
19
Q
Why are there different cytoadherence patterns and different clinical outcomes of Plasmodium infection?
A
Parasites can cytoadhere to BVs of different tissues
- BV in brain not same as BV in liver or fat, or kidneys, or skeletal muscle
- Those BV walls are all different and some p.falci parasites like BVs in one organ and others will like them in another organ
20
Q
Cytoadherence is caused by a single molecule:
A
PfEMP1
- responsible for binding a receptor on the endothelial cell wall
- can bind different receptors
- Parasite encode different PfEMP1s, 60 different copies of the gene encoding PfEMP1, and depending on which of those genes is expressed, will determine which receptor the parasite will bind to on the microvascular endothelium of BVs
21
Q
What does PfEMP1 bind to?
A
Receptors on the microvascular endothelium
- e.g. CD36, some tissues rich in this receptor, other receptors expressed on other tissues
- ICAM1 is thought to be enriched in the brain so if you had a parasite expressing PfEMP1 that liked ICAM1, it would sequester in the brain BVs (can cause cerebral malaria) and CD36 causes sequestering in the muscle BVs
22
Q
Knob structure?
A
PfEMP1 is exported all the way to the RBC cell surface for cytoadherence
23
Q
What causes antigenic distinct waves of parasitaemia seen in a single person infected with a single parasite?
A
With P.falci, after a week or so, you get another wave oi parasitaemia, that then gets cleared, then another wave, then clearance - why?
- each of these parasites, even though 100% genetically identical, are switching around the gene encoding for PfEMP1, using a different one each time
- What you get is immunity against the parasite expressing the PfEMP1 that causes antigenic wave A, then it switches to express B, then you develop immunity against B, then it switches to C and so on
24
Q
Different antigenic distinct waves of parasitaemia = different disease symptoms, why?
A
A and B might cause mild disease where the sequestering is to fat BV, but C maybe sequesters to brain BVs or another important organ then you get really severe disease
Other thing you can see is that this mechanism allows parasites to persist a long time
- P. falci doesnt have a latent form but it wants to hang around in the human host as long as possible so it can get taken up by a mosquito (then goes on to infect another person)
25
___ genes encode PfEMPs
Var genes
~60 copies per genome
- only one is expressed at any one time
- var genes are scattered around the 14 chromosomes, particularly clustered at the ends
26
Immune response against sequestered RBCs involve:
Antibodies directed against the PfEMP1 which stops them binding to BV walls (generated within a week or two)
27
In malaria endemic areas with lots of P. falciparum, children get infected with malaria a lot, then stop getting sick from the age of 5 onwards. They still get infected but wont get ill. Why?
Grow up, women start to have babies, all of a sudden become susceptible to malaria again
- get really sick, both themselves and their unborn baby
- parasites bound to walls of placental lining
- parasites packed full in the placenta where there is a problem
- turns out these parasites encode a PfEMP1 that binds to CSA and sequester to this point
Why do these women who have gotten infected hundreds of times before not gotten immunity?
- there has never been a selective force in most of these women to develop immunity against those CSA binding parasites
- Women with first pregnancy, and men always, have never had a placenta
28
How are most var genes 'silenced' while allowing just one to be expressed?
Chromosome ends cluster at the nuclear periphery and are in a 'silent' heterochromatic state
- if you look in the nucleus of a single parasite, and use a fluorescent probe for the ends of chromosomes, see just 3 or 4 spots
- 14 chromosomes so there should be 28 chromosome ends, but only see 3 or 4 spots
- Research showed that if you use stronger and stronger detergents, you start to see more of those spots
- Turns out that the ends of chromosomes are tightly clustered together so it looks like only have 3-4 ends
- Not only clustered, but at the outer edge periphery of the nucleus > wrapped up in heterochromatin > way to physically wrap up genes
- tight bundle of DNA
- limits accessibility of the DNA to be transcribed into RNA (hide RNA transcription binding sites)
29
Describe how the var2CSA gene gets activated
Silent var2CSA on Chr12 is bound up with other chromosomes in heterochromatin
If there is CSA selection, Chr12 gets separated from the heterochromatin bundle and move into an active zone to get transcribed
>active var2CSA
30
var gene silencing is caused by:
Epigenetic control of transcription (driven by physical histone modifications to DNA)
Histone modification at the nuclear periphery generally has genes inaccessible to transcription factors
A particular localisation is associated with a new histone modification that permits transcription
*stochastically (randomly), one of the 60 genes will move into active site for transcription, but selection allows a particular population to grow up
31
Summarise parasitic PfEMP1 and var gene expression
Parasites response to the development of immunity to PfEMP1
Clonal antigenic variation, parasites switches to use different var genes (which encode PfEMP1s)
Var genes are epigenetically-regulated, both histone modification and nuclear location important
Results in recrudescence - parasite persistence
(antigenic variation is about persistence, giving it max time for a mosquito to come and pick it up)
32
Different P. falciparum lines have a complement of var genes that are more different than you expect. Why?
Var genes 60 copies, but far more heterogeniety in var genes than for genes of other proteins.
This is due to ectopic recombination
33
Explain Ectopic recombination
Ectopid recombination leads to ehanced antigeneic diversity
- Recombination between heterologous chromosomes (i.e. recombination between different chromosomes - haploid organelle)
- Parasites way of generating rapid diversity in var genes
34
How does P. falciparum undergo ectopic recombination?
P. falciparum chromosome end clustering promotes recombination between aligned genes
- Similar higher order structure of chromosome ends
>virulence factor genes > TARE 16s > Telomeres
>common alignment of gene architecture of these ends
>seems to promote the recombination between different chromosomes
- wrapping up ends in heterochromatin not only silences various var genes but also aligns them for an unusual recombination event to occur
- end up with a far more heterogenous population of genes in this region that you would otherwise predict, had this ectopic recombination not gone on
haploid = no meiotic recombination going on here, just that during growth of parasites in the blood, there is a lot of diversity
35
What implications does ectopic recombinatioin give us?
We cannot just get immunity to 60 different PfEMP1s
| -> not an infinite number, but a far larger number of possible PfEMP1s than just 60
36
New drug targets for Malaria include:
other "exported" proteins and an Achilles' heel in the malaria parasite (PTEX)
37
What proteins are exported form the parasite to the RBC cytoplasm?
Plasmodium parasites export 100s of proteins into the RBC cytosol, playing crucial virulence and nutrient uptake roles
>parasite>bypass parasitophorous vacuole membrane > RBC cytosol > rbc surface
38
What is KAHRP?
Essential exported protein into RBC cytosol that is essential for 'knob' formation and adherence
- Genetic knockout in p. falciparum
- effectively the protein knockout of KAHRP - parasites grow fine in petri dish, knockout is smooth appearance compared to WT, cannot grow normally in vitro
39
Why are KHARP "knockout" parasites not infectious?
They cannot adhere to vascular endothelium
- can still invade RBCs, have PfEMP1, but has no Knob structures,. cannot bind to BV wall >>>> cannot avoid splenic clearance
- insertion of plasmid that physically disrupts the KAHRP gene
- Knobby structures in those KAHRP knockouts provide stability for the PfEMP1 to cling on to BV wall
*500 or so proteins exported to RBC cytoplasm have important functions -> if so much of the genome has to be exported and they have crucial functions, is there a way to understand the mechanism of export of those 500 proteins, block it and therefore simultaneously screw up 10% of the whole genome which will lead to the killing of parasites?
40
What allows parasite protein export into the RBC cytosol and beyond?
Exported proteins contain a conserved 'PEXEL' motif
2 components
1) ER signal sequence very close to the end terminals of the proteins
(allow uptake into ER and therefore into the endomembrane system, where you can go from vesicular trafficking into diff parts of the cell)
2) downstream of the ER signal sequence if a signal motif
- Asparagine-anything-Leucine-anything-Seemingly a restrictive group of AA, either E, Q or D
- RxLx(E/Q/D)
- Showed that you could take a random protein with this architecture, fuse it with gfp, and that gfp would get exported
- ~5% of p. falciparum proteome is predicted to be exported
41
A knockout screen of 51 exported proteins (46 PEXEL-containing) revealed:
revealed many proteins of virulence and survival roles
-~25% of exported genes are essential to growth in a petri dish (metabolic roles, not pathogenic roles)
42
What pathway do all these exported proteins follow?
The PEXEL protein-export translocon is a nexus through which many if not all of these functions are connected
- whole bunch of proteins going through the same export pathway
- if we can block that export pathway, we have a good new drug
43
Protein export is a major point of vulnerability: How do these proteins cross the parasitophorous vacuole membrane?
2 important sites in export:
1) the ER
2) the PV membrane (protein translocation)
44
What is the PEXEL sequence?
PEXEL = plasmodium export element
- is a cleavage site that is recognised in the ER by a protease enzyme known as Plasmepsin V (this is a potential drug target, in HIV there are drugs that target proteases, why not in malaria?)
Plasmepsin V
- Cleaves RxLx(E/Q/D) into RxL + xE/Q/D
- end terminus of all exported proteins have this xE/Q/D signal
>directs it to the translocon in the vacole space (goes across the parasite membrane by budding - vacuole)
45
The two important sites in protein export: the __ and __
ER and PV membrane
- ER: export protein recognition (PEXEL motif), processing (Plasmepsin V), vesicular targeting (xE/Q/D)
- PV membrane: Protein translocon
>molecular machinery that can physically take a protein from one side of the membrane and put it on the other side
>looks like a pore - has to be unfolded, pulled through
>molecular machinery (translocon)
>you can destroy the transporter activity with proteases so you know there is proteinacious activity
46
What is PTEX?
A putative Plasmodium Tanslocon of PEXEL proteins
Key criteria:
- plasmodium specific and in the correct location
- Essential to blood-stages
- Energy source (HSP101), an unfolding mechanism
- Binds transiting cargo PEXEL proteins
47
Where is PTEX found?
Found on Parasitophorous vacuole (transmembrane)
-The PTEX component EXP2 (pore) co-localises with a PEXEL protein at ~10 mins post invasion
48
How do we know PTEX is essential to the survival of plasmodium?
Genetic "knockdown" of PTEX components kills parasites
- cannot knockout because if not you dont get parasite growth in vitro (essential protein for survival)
- use knock-down strategy
(grow plasmodium as per usual, then add compound to the media and the gene of interest targeted genetically will be knocked down - expression is reduced, not actually a knockout
When PTEX150 is knocked out in this conditional way, parasites die very quickly and in a dose dependent way
Uses Glucosamine which destabilises RNA
Knockdown parasites are not able to export protein anymore because translocon expression is destroyed
49
PTEX inhibitors allow for:
A new anti-malarial drug strategy
- an approach to block many essential proteins/processes via the one target
50
Recent 3D (CryEM) structure of PTEX allows for:
a big step forward for drug development
- atomic structure gives you the opportunity to make drugs by rational design
- EXP2 pore
- PTEX150 'meat' of the sandwich
- HSP101 energy source
- if we stop transport, we block 5-10% of protein translocation
51
What do we need to understand about working towards a blood-stage malaria vaccine?
Understand the molecules that define alternative invasion pathways
- P. falciparum invasion of human RBCs
- What are the molecules on the surface of tis parasite and RBC that mediate this entry?
- Merozoite forms in the blood are very short lived, 1 min or less, in free extracellular form
- Invade RBC and are inside for the next 48h, rupture out, and then invade another RBC very quickly
- we want to target the merozoite form as a vaccine
52
3 types of potential malaria vaccines:
1) Pre-erythrocytic (e.g. RTS, S, whole parasite)
1) Pre-erythrocytic (e.g. RTS, S, whole parasite)
- Upstream of the merozoite phase (in liver or mosquito)
- Pre-erythrocytic = blocking parasites entering or maturing in the liver, not an anti-disease vaccine per-se because at this stage, no disease yet, but it is anti-parasitic so it still works
- RTS,S > passed phase 3 trials
- Only candidate that has got to the target group, 10000 baby trial in africa
- RTS,S is a bit of surface protein of a sporazoa mixed up with adjuvant (hepatitis B) and it works, just doesnt work brilliantly, only about 30-50% effective, only lasts max 1 year, possibly only 3-6 months
- whole parasite vaccine gaining traction
- all 5200 genes, all proteins that are in a sporozoite, given in some attenuated form, parasite not actually dead but not viable either, can invade cell but so deficient that it cannot replicate properly or genetically modified so that we have parasites replicating in the liver, no disease, no progression to blood-stage, but good immunity developed against those parasites
53
3 types of potential malaria vaccines:
2) Transmission blocking
2) Transmission blocking
- vaccine that stops development in the mosquito, effectively a vaccine that people will have but produce antibodies that protect the mosquito from infection, not us
- we make a recombinant protein to a form of the parasite that exists in the mosquito e..g ookinete
- make ookinete antigens, the mosquito then drinks that blood, gets those antibodies, parasites cannot develop because the antibodies stop them
- used to be controversial because vaccine did not actually confer immunity for the person getting vaccinated, more of prevention of spread.
54
3 types of potential malaria vaccines:
3) Blood-stage (anti-merozoite)
3) Blood-stage (anti-merozoite)
- disease symptoms occur in this blood cycle, dont occur in the liver and not in the mosquito
- if we ever did have a magic bullet vaccine, it would be at the blood stage because natural immunity against malaria does work - it takes a while but it does work
- if a child is exposed to malaria, they do survive and by the age of 4-5 dont get sick anymore because immune system convers immunity - proof in nature that you can get robust immunity against the blood-stage
55
Describe merozoite invasion of RBCs
>Merozoite floats around
>finds a RBC
>reorients to apical end (apicomplexa parasite) and apical end is juxtaposed to RBC membrane and it enters
>enters in a way that wraps another membrane around itself (parasitophorous vacuole membrane)
56
What happens at the apical end of the parasite when it is juxataposed to the RBC?
Apical end - contains complex of a range of organelles which defines this phylum of apicomplexa parasites
- all of these parasites, whether plasmodium or other genus all have this apical complex with different proteins in it
- spew these ligands out at the right time to bind receptors and aid invasion
57
What happens at the tight junctions at the parasite/rbc interface?
Tight junctions on either side (or a ring, in 3d structure)
- parasite using actin-myosin motor to draw the merozoite into the RBC
- eventually the parasite will fully enter the RBC and the RBC membrane will close over
58
P. falciparum is ____ for the RBC receptors
Promiscuous
It doesnt mind whether its a young or adult or old RBC, will infect them all
59
P. vivax only infects _____ RBCS
Young RBCs (Duffy antigen positive)
Most of west africa - duffy antigen negative, p.vivax cannot invade RBCs
60
Anti-merozoite antibodies have very little time to act becuase ___
Egress stage is only about 90s max,
Phase 1 pre-invasion only about 10-20s long
Anti-merozoite antibodies have to act at either egress or phase 1 pre-invasion stages
Once the parasite has entered the RBC its too late for vaccine to work
If you're using ligands on the surface of the free merozoite form that you're interested in, then you might have a fair chance of the antibodies to work.
If you are using ligands against the apical organelles that only get released around phase 1, you dont get very long to act
61
___ and ___ Interactions are vaccine targets
Primary and Secondary intreractions
Primary contact = vaccines target the proteins on the parasite surface coat (parasite has polarity, apical and distal end)
Secondary interactions = ligands that are spewed out of the apical organelles
-turns out these ligands are better than primary ones in terms of biological activity, but the problem is that they are only released "just in time" because these antigens are protected until some sort of signal when these parasites touch a RBC that tells them to come out
(most likely a phospho-signal cascade)
62
You can develop _____ to malaria after repeated infections
Immunity
Immunity to severe malaria develops quickly (anti-PfEMP1 based immunity) kicks in earlier between 2-3 years, max 5 years old - dramatically cuts down on number of malaria episodes per year
Broad and robust immunity develops slowly (anti-merozoite, aka anti-parasitic immunity)
Pregnant women return to a susceptible state because they have a new organ, the placenta, that the parasite can sequester to.
63
Rationale for an anti-merozoite vaccine remains _____
strong, but the most effective approach is not obvious and there is little functional knowledge to help inform vaccine design
People become immune because of antibodies that develop to surface proteins or proteins that come out of the apical organelles, but its hard because of antigenic drift
64
Where are we towards a blood-stage vaccine?
Still some way off - empirical vaccine approaches not working (trial and error)
Most antigens identified (50-100) but which are the best?
Very little functional knowledge of individual antigens
New genomic technologies unraveling function (gene knockdowns, gene knockouts, that have been unveiling function of the receptors and antigens to allow for rational vaccine design)
Rational vaccine design becoming feasible
65
The RBC surface is highly ____-
Polymorphic
Lots of different proteins on it, lots of diff carbohydrates on those proteins, and other post-translational modifications.
Different depending on young and old RBC, and different in us depending on blood groups etc. - lots of diff proteins and antigens on the surface of all our RBCs -> this polymorphism is evolutionary driven by malaria
66
What is the EBA175 family?
Gene family that encodes different proteins that have to do with binding RBC receptors
Erythrocyte binding antigen 175 (EBA175) family
- look very similar, different lengths but same domains in them, all involved in invasion
P.vivax only has one of these, which binds duffy receptor, and is its strict way of getting into RBCs
P.falci has mroe alternates than just this EBA175 family so more ways of getting into RBC
67
What is the PfRh family?
P.falcipareum also has PfRh family (reticulocyte binding homologue family)
- Rh proteins e.g. Rh1
- now we have up to 10 differnt proteins that are invilved at 1 point in this invasion cycle
68
Selective pressure can ____ receptor ligand usage:
Alter
e.g. W2mef strain (uses EBA175 to bind to sialic acid on Glycophorin A (GlyA))
When cell culture is treated with neuraminidase, the W2mef strain hardly grows
If you culture it for a week or two, all of a sudden they grow pretty well
- clone them out, redo the test, can see that the clonal line invades RBCs well
- This w2mef strain used to use EBA175 to bind to sialic acid on GlyA
- Now the w2mef has switched away from that and probably used PfRh family to get in
- This revealed the importance of these families to invasion
- differnt parasite isolates -> differnt p.falci that are isolated from diff regions of the world -> all infect RBCs and grow at the same rate, all as efficient as each other at infecting,
- All have differnt ways of invading using different receptors, can test by treating RBCs in various ways
69
What happens if you delete the ligand (EBA175) used by W2mef?
Knockout of EBA175 gene to see if you can repeat this selection genetically
Turns out you get a parasite that doesn not use EBA175-GlyA to invade RBC anymore
Parasite now expresses 2 other ligands, Rh4 (10,000x more expressed) and EBA165 (pseudogene, mutation that doesnt encode for an active protein. we dont know why it gets expressed, best guess is that its physically close on the chromosome to Rh4)
70
SA-dependent vs SA-independent P.falciparum strains
Wild type W2mef = uses EBA175 to bind to Sialic Acid on GlyA
W2mef/N = select for neurominidase treated cells, yous till have EBA175 but now you also get Rh4 expressed, and can enter RBC by other ways
W2mef/Δ175 = only Rh4 expressed
71
There are multiple red cell receptors and invasion ligands
P.falciparum can enter RBC by using different receptor-ligand interactions and do so efficiently
- no wonder its so hard to make vaccines
- just showed 8-10 different ligand interactions
- in nature, its good for the parasite to have all this diversity so its an evolutionary arms race for the parasite
- if humans are going to evolve differnt GlyA carbohydrates, parasite will evolve diff ways of invading
- stochastic mutation in darwinian evolution
- mutations and genetic rearrangements and gene duplications and divergernce that are advantageous get selected for
- can see why p.falci survives and why it is so hard to make a vaccine
72
Alternate invasion pathways allow parasite to invade via a ____
range of RBC receptors AND to avoid immunity
-showed that immune system also drove this swithcing around of the ligand that a particular parasite used to invade
73
Invasion pathway use and inhibitory antibodies
In experiment with diff serum samples
- showed that when a person has antibodies against EBA175, the W2mefΔ175 dominated (Rh4, SA-independent)
- when person has antibodies against PfRh proteins, the W2mef dominated (EBA175 pathway, SA-dependent)
- showed that variation in ligand usage is a mechanism of immune evasion
- EBA and Rh proteins are important targets of inhibitory antibodies
74
Alternate invasion pathways:
- accomodate RBC polymorphism
- immune avoidance
- at least 3 major pathways now identified
(parasites seem to prefer only 3-4 ways of getting into RBCs, research is trying to define those pathways well. Can see why old vaccine ideas didnt work because if you block 1 pathway, the parasite just switches to another pathway. If you can cover all 3 major pathways, maybe vaccine can work)
- Vaccine must cover all major pathways
75
Antigenic diversity remains a problem
Even if you cover the 3 major pathways, individual genes are also under selection pressure as well.
Antigenic drift
EBA175 for e.g. doesnt look exactly the same in every isolate even though theyt all bind to GlyA, they have different point mutations that make antibodies more or less effective.
But we can see how all this knowledge is leading to a more rational approach to malaria vaccine
BIOM30002
flashcards
Decks in class (20)
# Cards
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Pandemics (A)145
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Pandemics (B)75
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Type 1 Diabetes (1)31
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Type 1 Diabetes (2)29
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Type 1 Diabetes (3)50
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Type 1 Diabetes (4)26
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Type 1 Diabetes (5)36
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Type 1 Diabetes (6)42
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Cystic Fibrosis: Personal Perspectives12
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Cystic Fibrosis: Molecular Basis49
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Cystic Fibrosis: Clinical Genetics41
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The Respiratory System and CF46
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Cystic Fibrosis: A Multisystem Disorder35
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Current and future therapies in CF37
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Cancer Biology38
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Cancer Immunology32
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Skin Physiology and immunity3
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Patient interview and therapeutics0
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Immunotherapy for cancer0
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Clinical Skin Cancer Overview0
