Gibson - Host/parasite arms race

Question 1

why does a mutation inferring resistance get positively selected?

Answer 1

resistant individuals have a higher rep advantage.

susceptible individuals die before they reproduce/fewer offspring

Question 2

describe malaria as a selection pressure

Answer 2

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

Question 3

what is the malaria lifecycle?

Answer 3

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.

Question 4

what is one component of genetic resistance to malaria?

where is this mutation common?

Answer 4

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.

Question 5

how does p. faciparum enter RBC?

Answer 5

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.

Question 6

what causes sickled RBC?

Answer 6

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.

Question 7

who showed benefit of heterozygotes for sickled RBC?

Answer 7

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.

Question 8

evolution of sickle cell mutation?

Answer 8

arose independently several times

4 types: Senegal, Benin, Cental African, Indian/Arabian

Question 9

Sickle cell – mechanism of resistance?

Answer 9

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.

Question 10

one way malaria causes death?

Answer 10

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

Question 11

what causes infected RBC to adhere to blood vessels?

Answer 11

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

Question 12

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

Answer 12

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.

Question 13

what is G6PD?

Answer 13

G6PD - glucose phosphate dehydrogenase.

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

Question 14

how can G6PD deficiency be beneficial?

Answer 14

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.

Question 15

distribution of G6PD deficiency?

Answer 15

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.

Question 16

what causes AIDS and how is it controlled?

Answer 16

HIV-1, human immunodeficiency virus.

no cure or vaccine but controlled with anti-retroviral therapy

Question 17

how does HIV-1 act?

Answer 17

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.

Question 18

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

Answer 18

1996
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

Question 19

distribution of CCR5-Δ32?

hypothesies of its existence

Answer 19

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.

Question 20

what causes sleeping sickness

Answer 20

Trypanosoma brucei
Vector- tsetse flies, glossina
distributedacross C africa

Question 21

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

Answer 21

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

Question 22

why cant T. brucei brucei infect humans?

Answer 22

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.

Question 23

what is HDL?

which bits of it are TLF?

Answer 23

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)

Question 24

which species have TLF?

Answer 24

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.

Question 25

what is the Mechanism of trypanolysis by TLF?

Answer 25

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.

Question 26

what is the APOL-1 receptor?

Answer 26

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.

Question 27

what disease is trypanolytic APOL1 associated with?

Answer 27

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

Question 28

which variant of APOL1 is useful?

Answer 28

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)

Question 29

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

not in gambiense

Answer 29

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.

Question 30

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

Answer 30

T.b. rhodesiense - single gene is responsible

T.b. gambiense - multiple mechanisms

Question 31

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

Answer 31

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.