Lecture 18 - Malaria 3 Flashcards by Eleanor Nicklason

Compare global burden of P. falciparum and P. vivax

Which communities are most affected?

P. falciparum: Sub-Saharan Africa

P. vivax: North of South america

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

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Is Malaria ancient or novel?

Ancient

It has evolved with us

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Which people are at greatest risk of Malaria?

Pregnant women

* Young children

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How many deaths per year due to Malaria?

1 million

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What can malaria cause in pregnancy?

Low birth weight

* Miscarriages & stillbirths

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What is the impact of malaria on economy & education?

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

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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What are some obstacles to combatting malaria?

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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What are some control measures available at the moment?

Bed nets

* Insecticides; resistance emerging

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

Human to human w/ mosquito vector:

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

Macaques to humans:
• P. knowlesi

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When do symptoms of malaria develop?

2 weeks after, during the blood stage

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

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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Describe the treatment of malaria
• Uncomplicated
• Severe

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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What is the death rate for severe malaria?

How has this changed over the recent years?

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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Can people get multiple malaria infections?

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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Describe the three main types of immunity to malaria

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Immunity that prevents severe malaria
Immunity that prevents any malaria
Immunity that prevents malaria in pregnancy

At what ages do the following types of malaria most frequently occur:
 • Symptomatic malaria
 • Severe malaria
 • Malaria in pregnancy
?

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Symptomatic malaria:
• Most in young children, then decline

Severe malaria:
• 0-5 years of age

Malaria in pregnancy:
• 17-30 years of age

What are the various reasons for slow development of immunity

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

Describe the pathogenesis of malaria

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Unrestricted replication of parasites in blood
Accumulation in vital organs
• Brain; vasculature gets clogged with RBCs
• Placenta:
- parasitised RBCs accumulating in the placenta
- Impedence of nutrient & oxygen transfer
- Inflammatory responses
Inflammatory responses
• Accumulation of the parasitised RBCs triggers inflammation
Destruction of red blood cells
• through parasitism

Leading to:
5. Multisystem involvement
 • Coma
 • Severe anaemia
 • Acidosis & respiratory distress

Why do parasites accumulate in blood vessels?

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

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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

How do parasitised RBCs avoid the immune system?

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

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

What is the role of PfEMP1?

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• 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

Describe parasitaemia in malaria

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

What are the var genes?

Describe diversity / variation

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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

What is the major antigen on the surface of parasitised RBCs? How do we know this?

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

Describe the antigenic diversity of the var genes in the population

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)

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

``` 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

Describe the effector function of the immune system against malaria

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

Describe some features of malaria in pregnancy

* Infection despite immunity prior to pregnancy * More frequent infections * Risk of malaria decreases with each pregnancy

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

Placenta • More adhesive to carbohydrates: • CSA • HA Children: • CD36 • ICAM-1

Describe PfEMP1 in malaria in pregnancy

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

Describe the adhesive properties of var2csa

* 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

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

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

What are the challenges of a vaccine against PfEMP1? What about in malaria in pregnancy?

* 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

What are the economic and health benefits of vaccines?

* Immunising is one of public health's 'best buys' * Direct medical savings * Indirect economic benefits

What are some logistical challenges to malaria treatment?

* 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

Lecture 18 - Malaria 3 Flashcards

(36 cards)