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BIOM30002 - M2M > Lecture 18 - Malaria 3 > Flashcards

Lecture 18 - Malaria 3 Flashcards

1
Q

Compare global burden of P. falciparum and P. vivax

Which communities are most affected?

A

P. falciparum: Sub-Saharan Africa

P. vivax: North of South america

• Resource-poor communities (rural, remote) are the most affected

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2
Q

Is Malaria ancient or novel?

A

Ancient

It has evolved with us

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3
Q

Which people are at greatest risk of Malaria?

A
  • Pregnant women

* Young children

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4
Q

How many deaths per year due to Malaria?

A

1 million

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5
Q

What can malaria cause in pregnancy?

A
  • Low birth weight

* Miscarriages & stillbirths

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6
Q

What is the impact of malaria on economy & education?

A

Malaria compounds poverty

It is predicted that if malaria was controlled in many of the world’s poorest countries, we would see dramatic economic, educational, employment improvements.

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7
Q

Describe the facilities available to pregnant women in these resource poor communities

A

Extremely basic
• Traditional birthing houses
• No running water or electricity
• Traditional birth attendant
• Has very little training, normally just experience with child birth
• Only a handful of drugs available to treat everything

This is why a vaccine would be so beneficial

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8
Q

What are some obstacles to combatting malaria?

A
  • No highly effective control measures
  • No vaccine yet
  • Drug resistance is widespread and increasing
  • Insecticide resistance
  • Economical, political, and social factors
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9
Q

What are some control measures available at the moment?

A
  • Bed nets

* Insecticides; resistance emerging

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10
Q

How many species of Plasmodium infect humans?
List them.
Which are transmitted human to human?

A

5

Human to human w/ mosquito vector:

  • P. falciparum
  • P. vivax
  • P. ovale & P. malaria

Macaques to humans:
• P. knowlesi

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11
Q

When do symptoms of malaria develop?

A

2 weeks after, during the blood stage

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12
Q

What are the clinical features of malaria?
• Uncomplicated
• Severe

A 
1. Uncomplicated, mild malaria: 95% of cases
 • 'Flu like' illness
 • Fever
 • Headaches
 • Malaise
2. Severe malaria: small proportion
 • Severe anaemia
 • Cerebral complications
- coma
- long term neurological deficits
 • Respiratory distress w/ metabolic acidosis
 • Hypoglycaemia
 • Kidney failure
 • Blood clotting problems
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13
Q

Describe the treatment of malaria
• Uncomplicated
• Severe

A
  1. Uncomplicated
    Very easy and effective
    All you need is tablets
  • Short course of anti-malarial tablets
  • ACT: Artemisinin combination therapy

P. vivax:
• Primaquine
• Need this to clear the parasites from the liver

2. Severe malaria
Much tougher
Need intravenous injections
 • Artemisinin
 • Quinine
 • IV fluids, blood transfusion
 • Supportive treatment
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14
Q

What is the death rate for severe malaria?

How has this changed over the recent years?

A

15-20%
This death rate has not changed very much over recent years.
We need a new treatment for severe malaria

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15
Q

Can people get multiple malaria infections?

A

Yes
Immunity only develops after many episodes

Even if women have had malaria when they are younger, when they become pregnant, they return to a highly susceptible state.

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16
Q

Describe the three main types of immunity to malaria

A
  1. Immunity that prevents severe malaria
  2. Immunity that prevents any malaria
  3. Immunity that prevents malaria in pregnancy
17
Q 
At what ages do the following types of malaria most frequently occur:
 • Symptomatic malaria
 • Severe malaria
 • Malaria in pregnancy
?
A

Symptomatic malaria:
• Most in young children, then decline

Severe malaria:
• 0-5 years of age

Malaria in pregnancy:
• 17-30 years of age

18
Q

What are the various reasons for slow development of immunity

A
  1. Parasite factors
    • Multiple antigenic targets
    • Antigenic diversity, i.e. polymorphism
    • Antigenic variation, i.e. antigenic switching
  2. Host factors
    • Inadequate response (esp. young children)
    • Poor development of memory responses
19
Q

Describe the pathogenesis of malaria

A
  1. Unrestricted replication of parasites in blood
  2. Accumulation in vital organs
    • Brain; vasculature gets clogged with RBCs
    • Placenta:
    - parasitised RBCs accumulating in the placenta
    - Impedence of nutrient & oxygen transfer
    - Inflammatory responses
  3. Inflammatory responses
    • Accumulation of the parasitised RBCs triggers inflammation
  4. Destruction of red blood cells
    • through parasitism
Leading to:
5. Multisystem involvement
 • Coma
 • Severe anaemia
 • Acidosis & respiratory distress
20
Q

Why do parasites accumulate in blood vessels?

What is the downside (for the parasite) of this?

A
  • Malaria parasite produces proteins that are trafficked to the surface of RBCs
  • This enables the parasite to stick to the walls
  • and avoid continued circulation to the spleen

• These foreign proteins on the RBCs alerts the immune system

21
Q

How do parasitised RBCs avoid the immune system?

A

They are expressing antigens on the surface of the RBC, however they avoid the immune system:

  1. Antigenic diversity / polymorphisms
    • Many versions of the antigens present in the population
    • Different strains expressing different antigens can reinfect
  2. Antigenic variation / Switching
    • Immune system no longer recognises parasite
    • Var genes
22
Q

What is the role of PfEMP1?

A

• A parasite protein that is trafficked to the cell surface
• Responsible for formation of ‘knobby’ surface
• Allows RBC to adhere to:
1. Endothelial cells
2. Platelets of uninfected RBCs

23
Q

Describe parasitaemia in malaria

A

Successive waves
• in each wave, the parasite is expressing different variants of PfEMP1
• Different antibody response required for each antigenic variant

24
Q

What are the var genes?

Describe diversity / variation

A

Genes that encode PfEMP1 and its variants

Polygeny:
60 different copes of PfEMP1 variants within the genome of a parasite

Polymorphism:
Each parasite has a different set of var genes

25
Q

What is the major antigen on the surface of parasitised RBCs?

How do we know this?

A

PfEMP1

They did a study with the serum of many Kenyan adults:

  • The serum was neutralising to normal parasitised RBCs
  • When PfEMP1 was knocked out, the serum was no longer neutralising
26
Q

Describe the antigenic diversity of the var genes in the population

A

Thousands of different var genes exist in nature
However, actual antigenic diversity is not as extensive as suggested by sequence analysis

(components of the various genes are the same)

27
Q

Describe the functional differences of the various var genes / PfEMP1 variants

A 
Different PfEMP1 variants can bind to different adhesion molecules on host cells
e.g.
 • CD36
 • CSA
 • ICAM-1
etc.

Based on the antigens that are expressed, they are sequestered in different organs:
• Brain
• Skin, gut, eyes
• Placenta

All these different variants will be neutralised by different antibodies

28
Q

Describe the effector function of the immune system against malaria

A

Antibodies against merozoites
• Direct neutralisation
• ADCC

Antibodies to infected RBCs
• Opsonisation → phagocytosis by monocytes
(parasite antigens on the surface of the RBC recognised)

29
Q

Describe some features of malaria in pregnancy

A
  • Infection despite immunity prior to pregnancy
  • More frequent infections
  • Risk of malaria decreases with each pregnancy
30
Q

Compare adhesive properties of parasites taken from the placenta and from children

A

Placenta
• More adhesive to carbohydrates:
• CSA
• HA

Children:
• CD36
• ICAM-1

31
Q

Describe PfEMP1 in malaria in pregnancy

A
  • A specific PfEMP1 variant : var2csa
  • var2csa binds to CSA
  • These variants are better able to adhere to the placenta (through CSA)
32
Q

Describe the adhesive properties of var2csa

A
  • Binds CSA (in placental vascular beds)
  • Parasites expressing this PfEMP1 will mainly be able to infect pregnant women
  • Won’t be able to infect children and non-pregnant adults
33
Q

Compare location of expression of:
• CSA
• ICAM-1 & CD36

A

CSA: placenta

ICAM-1 & CD36: vascular beds all over the body

34
Q

What are the challenges of a vaccine against PfEMP1?

What about in malaria in pregnancy?

A
  • It is highly polymorphic
  • The vaccine would need to cover the multiple variants

• Or, we would need the vaccine to be cross reactive

Malaria in pregnancy:
• Only one variant is expressed (var2csa)
• Possibility of vaccine
• Clinical trial planned
• Would not protect children & non-pregnant adults

35
Q

What are the economic and health benefits of vaccines?

A
  • Immunising is one of public health’s ‘best buys’
  • Direct medical savings
  • Indirect economic benefits
36
Q

What are some logistical challenges to malaria treatment?

A
  • The communities most often affected are very remote and resource poor.
  • It is very difficult to access these communities (roads etc.)
  • Everything needs to be brought in

BIOM30002 - M2M (36 decks)

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