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Flashcards in Gibson - Host/parasite arms race Deck (31):

why does a mutation inferring resistance get positively selected?

resistant individuals have a higher rep advantage.
susceptible individuals die before they reproduce/fewer offspring


describe malaria as a selection pressure

malaria has been widespread for thousands of years, so has selected for resistance in the human population.
res is heritable and innate.


what is the malaria lifecycle?

Mosquito bite infects human blood with sporoziotes which migrate to the liver.
proliferate and form merozoites.
Asexual lifecycle in RBC, feeding off Hb.
forms gametocytes whch are taken up by the mosquito again.


what is one component of genetic resistance to malaria?

where is this mutation common?

Duffy Antigen Receptor for Chemokines (DARC)
Major receptor on RBC that plasmodium vivax uses for invasion.
DARC negative RBC cannot be invaded.
Point mutation in binding site for a TF which activates the promotor.
95% W africans are DARC negative, and p. vivax is rare in w and c africa.


how does p. faciparum enter RBC?

Crosnier et al 2011
one main receptor - basigin.
it must have another beneficial function, or else it would be selected against, and is on many cell types, not just RBC.

stange as no equivaent receptir for p vivax.


what causes sickled RBC?

sickled RBC
haemoglobin mutation - HbS
in the B chain, glutamic acid changed to valine in position 6.
causes a Conformational change in haemoglobin molecule leads to reduction in oxygen-carrying capacity of blood – RBC’s become sickled in conditions of low oxygen.
fragile and stack up, clogging capillaries. if homozygous, phenotype has sickle cell anaemia and lethal if untreated. heterozygote has only mild symptoms and a survival advantage in malaria zones.


who showed benefit of heterozygotes for sickled RBC?

Aidoo et al 2002
study of Kenyan children in area of high malaria prevalence from birth to 3-5 years old.
Protective effect of HbAS on survival (2 – 16 months).
Protective effect of HbAS and HbSS against symptoms of severe malaria.


evolution of sickle cell mutation?

arose independently several times
4 types: Senegal, Benin, Cental African, Indian/Arabian


Sickle cell – mechanism of resistance?

Cyrklaff et al 2011
in vitro studies: p.falciparum survived in HbAA and HbAS equally well.
however under hypoxic conditions, eg blocked capillaries, infected HBAS: sickle more quickly, parasites slower growth, higher phagocytosis rate, compared to HbAA RBC.


one way malaria causes death?

mature schizonts bind to epithelium of capillaries and block in the brain causing cerebral malaria, coma and then death.


what causes infected RBC to adhere to blood vessels?

Via Knobs on infected RBC surface which carry adhesins (parasite proteins which recognise host endothelial cells surface proteins eg thrombospondin)


what is HbC, how can it help protect against malaria?

Fairhurst et al 2005 - abnormal display of PfEMP1 on RBC carrying HbC
HbC is mutation in which codon 6 glutamate is replaced with lysine.
HbAA has very even dustribution of PfEMP1 (surface protein), whereas HbCC has v scattered. causes abnormal non functioning knobs

P. falciparum uses host RBC actin to transport adhesins to RBC cell surface causing it to stick to capillary walls. disabledin HbAS, adhesins arent trafficked to the RBC surface.
in HbCC, actin filaments much shorter and less developed vesicles = abnormal knobs.


what is G6PD?

G6PD - glucose phosphate dehydrogenase.
first enzyme in the pentose phosphate pathway, which generates NADPH, used by RBC to protect from oxidative damage.


how can G6PD deficiency be beneficial?

most common enzyme defect in humans. x linked, mainly affects men. 400m ppl deficient, common in middle east and SE Asia. causes jaundice and haemolytic anaemia if ROS levels increase, otherwise asymptomatic.
aka Favism - adverse reaction to eating broad bean which contains oxidant.
anti malarial drugs can cause increase in ROS, and plasmodium v sensitive to oxidative damage.


distribution of G6PD deficiency?

common in men, x linked, especially in SE asia and middle east.
overlapping distribution with malaria.

even so, parasited can still infectand grow in G6PD deficient RBC.
perhaps increased or earlier phagocytosis of infected RBCs limits the parasitaemia.


what causes AIDS and how is it controlled?

HIV-1, human immunodeficiency virus.
no cure or vaccine but controlled with anti-retroviral therapy


how does HIV-1 act?

virus targets WBC, specifically CD4 T cells.
progressive loss of cell mediated immunity.
victims succumb to infections which are normally mild/symptomless eg toxoplasmosis, pneumonia.


when was resistance to HIV-1 discovered and how is it similar to DARC for malaria?

some people free of infection despite repeated exposure.
resistance due to mutant cell surface receptor CCR5, called CCR5-Δ32.
HIV targets CCR5 as well as CD4 to enter helper T cells.
in CCR5 negative homozygote, HIV cannot enter.
similar resistance mech to DARC


distribution of CCR5-Δ32?
hypothesies of its existence

common in Europeans: 15-20% heterozygous, ~1% homozygous. in 1346-53 the black death killed many, 30-60% of europeans. maybe it selected for this mutation. however mice with CCR5-Δ32 arent resistant to plague. could be selected for by another disease like smallpox - 30% mortality rate in 11 and 12th C.
but then revised dates and could be up to 7000 years old.
alternatively - expansion of roman empire could have selected against a preexisting high prevalence of it.


what causes sleeping sickness

Trypanosoma brucei
Vector- tsetse flies, glossina
distributedacross C africa


what 3 morphologically distinct subspecies of trypanosoma brucei are found in wild and domestic mammals in tropical africa.

Trypanosoma brucei brucei, not in humans, tropical Africa
Trypanosoma brucei rhodesiense + east Africa
Trypanosoma brucei gambiense + west & central Africa


why cant T. brucei brucei infect humans?

Humans are innately resistant to infection with T. b. brucei because of a trypanolytic factor (TLF) in the serum. component of HDL - high density lipoproteins in blood.
T.b.rhodiense and T.b gambiense are resistant to lysis by TLF.


what is HDL?
which bits of it are TLF?

high density lipoproteins in blood, formed of 50 proteins.
main function is to transport lipids and involved in cholesterol transport and metabolism.
2 of the minor components have evolved recently and are identified as TLF: Haptoglobin related protein (HPR)
Apolipoprotein L-1 (APOL-1)


which species have TLF?

Hpr and APOL-1 genes only seen in primates and humans
humans, babboons,gorillas but not chimps have trypanolytic sera and not susceptible to infectiokn with T.b.brucei.


what is the Mechanism of trypanolysis by TLF?

1. High affinity binding to receptors in the trypanosome flagellar pocket.
2. Uptake and entry into the lysosome.
3. APOL-1 causes formation of pores in the lysosomal membrane.
4. Influx of chloride ions causes lysosomal swelling - lysis of trypanosome.


what is the APOL-1 receptor?

Vanhollebeke et al (2008)
- within trypanosome flagellar pocket
- protein takes up Hb complexed with HDL components such as Haptoglobin (Hp), Haptoglobin-related protein (Hpr) and APOL-1.
TbHpHbR = T. brucei haptoglobin, haemoglobin receptor
function is nutrient uptake, requires heme for growth.


what disease is trypanolytic APOL1 associated with?

Kidney disease highly prevalent in Afro-Americans
Found that 2 allelic variants of APOL-1 were strongly associated with kidney disease in this population
Despite this, APOL-1 variants were surprisingly common in Yoruba from Nigeria


which variant of APOL1 is useful?

some APOL-1 variants were more effective than the normal protein in trypanolysis.
G2 variant, but not G1 variant, is protective against human trypanosomiasis in Uganda (T.b.rhodiense) whereas in Guinea, G1 protects against severedisease but G2 is associated with more severedisease (T.b.gambiense)


what can confer resistance in T.b. rhodesiense to human serum resistance??

*not in gambiense*

Xong et al
Serum Resistance Associated gene (SRA gene) confers a human serum resistance phenotype on T. b. brucei.
if transformed into brucei can infect humans and is resistant to lysis.
in rhodesiense, SRA inactivates APOL1., so not lysed.

SRA is only transcribedif the VSG gene B is active, not A.


ho w does the mechanism of nfecrivity differ between T.b.gambrnse and T.b. rhodesiense?

T.b. rhodesiense - single gene is responsible
T.b. gambiense - multiple mechanisms


what 3 mechanisms does gabiense use to combat human resistance, as SRA is only in rhodesianse.

1. Inefficient take up of APOL1 from blood via TbHpHbR.
2. Makes a protein (TgsGP) that strengthens the lysosome wall against lysis by APOL1.
3. Increased activity of cysteine protease in lysosome degrades APOL-1 quickly.