Lecture 16 + 17 - Malaria Flashcards Preview

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Flashcards in Lecture 16 + 17 - Malaria Deck (70):
1

Age group most represented in malaria deaths

Children under 5

2

Phylum of malaria

Apicomplexia

3

Genus of malaria

Plasmodium

4

Plasmodium species that infect humans
1)
2)
3)
4)

1) Falciparum
2) Vivax
3) Ovalae
4) Malariae

5

Primate - human plasmodium pathogen

Plasmodium knowlesi

6

How does plasmodium gain access to hepatocytes?

Kupfer cell

7

3 places where plasmodium live

Mosquito, human hepatocytes, human erythrocytes

8

Example of the strength of anti-malarial selective pressure

Sickle-cell anaemia alleles are maintained in sub-Saharan Africa, as being heterozygous for this reduces susceptibility to malaria

9

Difference in P. vivax and P. falciparum infection

Vivax causes more severe morbidity, but is less likely to kill

10

Number of malaria deaths per year

~650,000

11

What are the gold crystals observed in malaria-infected erythrocytes?

Haemozin
Parasite eats haemoglobin, but haem is toxic.
Crystallises haem to haemozoin

12

Malaria definitive host

Mosquito (where sexual reproduction of gametocytes occurs)

13

Why are malarial infections comparable between Latin America and sub-Saharan Africa, but sub-Saharan Africa has much higher mortality rates?

P. vivax more common in Latin America.
P. falciparum more common in sub-Saharan Africa

14

Estimated number of malaria cases per year

300 - 500 million

15

Amount of household spending on malaria in Africa

Estimated 10% of household spending (mosquito nets, medication ,etc)

16

P. falciparum life cycle
1) a, b, c
2) a, b
3) a, b
4)

1) Mosquito stage (in mosquito gut)
a) Gamete
b) Zygote
c) Ookinete

MOSQUITO BITES HUMAN

2) Hepatocyte stage
a) Sporozoites infect hepatocytes
b) Merozoites form, exit hepatocytes

3) Blood stage
a) Merozoites infect erythrocytes, divide rapidly
b) Gametocytes form

4) Mosquito ingests gametocytes from human host, sexual reproduction in mosquito

17

When does malaria cause illness?

During merozoite stage
Hepatocyte stage is asymptomatic

18

Number of infected erythrocytes directly after hepatocyte stage Vs number of infected erythrocytes after merozoite expansion

10^3 infected erythrocytes Vs 10^11 infected erythrocytes

19

What does merozoite release coincide with?

Periodic fever, cytokine storm

20

Basic overview of three stages of malarial infection

Mosquito stage - Sexual reproduction
Hepatocyte stage - Asexual reproduction
Erythrocyte stage - Asexual reproduction, major amplification stage

21

Where does the sexual stage occur, and for how long?

1 - 2 weeks in female Anopheles mosquito

22

How long does it take for injected sporozoites to enter hepatocytes from skin?

~30 minutes

23

How long does the asexual liver stage last for?

~1-2 weeks

24

How long after infection does disease occur?

~1 month

25

How long does the asexual erythrocyte stage last for?

~2-3 days, is quite synchronous

26

Symptoms of malaria

Fever, chills, anaemia, coma

27

Proportion of malaria deaths caused by P. falciparum

95%

28

How does P. vivax cause relapsing malaria?

Hypnozoites in the liver

29

What role does cytoadherence play?

Malaria doesn't want infected blood cells to enter the spleen, as they would be destroyed there.

Instead, cause infected erythrocytes to adhere to vascular wall.

30

What coincides most with malarial death?

Infected erythrocytes adhering to walls of blood vessels in brain.

Exact mechanism of death not known. Not straight ischaemia

31

What adheres infected erythrocytes to the vascular wall?

PfEMP1

32

PfEMP1 role

Binds to molecules on microvascular endothelium

33

Surface protein in the brain microvasculature that PfEMP1 binds to

ICAM1

34

Number of different genomic copies of PfEMP1 in a malarial genome

Over 60

35

Name of genes encoding PfEMP1

var genes

36

How are different var genes expressed?

Epigenetic silencing of all var genes except for 1.
A parasite can change var gene expression

37

What correlates with different waves of parasitaemia?

Expression of different PfEMP1 genes
Express different ones when an effective antibody response is launched against one

38

Where are most var genes located?

Sub-telomeric regions of chromosomes

39

Why do different P. falciparum parasites have a greater variety of var genes than expected?
1)
2)
3)

1) Chromosomes cluster at at nuclear periphery of parasite
2) Recombination between heterologous chromosomes that are clumped together, aligned
3) Results in great variation of var genes and expressed PfEMP1s

40

Number of proteins that P. falciparum exports into erythrocyte cytoplasm

Hundreds

41

KAHRP function

Knob formation.
Knob allows parasite to hang onto microvascular endothelium under flow pressure

42

Evidence for KAHRP function

With KAHRP, infected RBC surface is rough, cell sticks to microvascular endothelium

Without KAHRP, infected RBC surface is smooth, doesn't stay attached to vascular wall

43

Motif allowing P. falciparum to export proteins into RBC cytoplasm

PEXEL motif

44

Amount of P. falciparum proteome estimated to be exported out of parasite

~5%

45

PEXEL motif role

Allow proteins to cross parasitophorous vacuole membrane

46

Two important sites in P. falciparum protein export

1) Endoplasmic reticulum
2) Parasitophorous vacuole membrane

47

What is PEXEL?

A protease cleavage site
Cleaved by Plasmepsin IV

48

What does plasmepsin IV cleave?

PEXEL motif, in the endoplasmic reticulum

49

Where is PEXEL cleaved by plasmepsin IV?

RxLxE/Q/D --> RxL | xE/Q/D

In the ER

50

Where is plasmepsin IV present?

In the ER of P. falciparum

51

PTEX

A putative translocon of PEXEL proteins

52

Criteria for PTEX
1)
2)
3)
4)

1) Plasmodium-specific, in the correct location
2) Essential to blood-stages
3) Energy source, a protein-unfolding mechanism
4) Binds transiting cargo PEXEL proteins

53

PTEX structure
1)
2)
3)

1) 5 proteins
2) HSP101 is an energy source, unfolds proteins so that they can fit through pore
3) EXP2 is a pore protein

54

PTEX location

Parasitiphorous vacuole membrane in RBC

55

How long does it take for a merozoite to enter an erythrocyte?

~30 seconds

56

Possible anti-malarial drug targets
1)
2)

1) Plasmepsin IV
2) PTEX

57

Types of anti-malarial vaccine
1)
2)
3)

1) Pre-erythrocytic
2) Transmission-blocking
3) Blood-stage (anti-merozoite)

58

Example of possible pre-erythrocytic vaccine

RTS, S
In stage III clinical trials

59

Difficulty for anti-merozoite antibodies

Only have about 1.5 minutes when merozoites are susceptible to action.

~1.5 minutes between when merozoites exit former host cell, enter erythrocyte

60

Primary interaction target of possible vaccine

Binding to cell

61

Secondary interaction target of possible vaccines
1)
2)
3)
4)
5)

1) Actin/myosin motor
2) Surface protein shedding
3) Secondary ligand shedding
4) Resealing
5) Recovery from echinocytosis

62

Problems with making an anti-malaria vaccine
1)
2)
3)
4)

1) Empirical vaccine techniques aren't working
2) Very little functional knowledge of individual antigens
3) Many antigens are identified, but which to target?
4) Vaccine must cover three major invasion pathways

63

Target of P. vivax on erythrocytes

Duffy protein

64

Adaptation of West Africans against P. vivax

Don't express Duffy protein on erythrocyte membrane

As a result, no P. vivax in West Africa

65

Families of surface proteins that bind erythrocytes in P. falciparum

1) EBA (erythrocyte-binding antigen) (5 members)
2) PfRh (5 members)

66

What does the W2mef strain of P. falciparum use to bind erythrocytes?

Can use EBA175 to bind sialic acid on GlyA

67

What does W2mef strain do when RBCs have been depleted of sialic acid by neuraminidase?

Expresses a silaic acid-independent invasion phenotype using a different surface ligand (Rh4)

68

Important targets of inhibitory antibodies

EBA, Rh proteins

69

Why does P. falciparum use several invasion pathways?
1)
2)

1) Accommodate RBC polymorphism
2) Immune avoidance

70

Major invasion pathways now identified

Three major invasion pathways