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lecture 18 Flashcards

Malaria - background to malaria: clinical features and treatment - immunity: targets and mediators - pathogenesis of disease - immunity and immune evasion - malaria in pregnancy as an example

1
Q

What are the main causes of malaria globally?

A
  • P. vivax

- P. falciparum

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2
Q

Is malaria a modern pandemic?

A
  • no
  • malaria is an ancient disease
  • in 400 BC, Hippocrates described the symptoms of malaria
  • presence of Plasmodium DNA in the remains of King Tut (1324 BC)
  • has evolved with us
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3
Q

Who is at greatest risk of malaria? What is the burden of malaria?

A
  • young children and pregnant women
  • up to 1 millions deaths per year
  • 300 - 500 million cases per year
  • a leading cause of childhood deaths globally
  • malaria in pregnancy:
    • low birth weight
    • miscarriages and stillbirths
  • impedes economic development
  • impacts on learning and education
  • compounds poverty
  • malaria most affects resource-poor communities
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4
Q

What are obstacles to combating malaria ?

A
  • no highly effective control measures available: partially effective measures, poorly applied
  • no vaccine available (yet)
  • drug resistance widespread and increasing
  • insecticide resistance
  • economic, political, and social factors
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5
Q

What are the Plasmodium species and the differences in disease they cause?

A

P. falciparum

  • causes majority of severe malaria disease and death
  • population at risk: 2.2 billion

P. vivax

  • increasingly recognised as a cause of severe illness
  • population at risk: 2.6 billion
  • dormant liver stage

P. ovale and P. malariae

  • limited distribution, mild disease
  • proposed that P. ovale is actually two species

P. knowlesi

  • zoonotic infection, can be severe
  • present in macaques throughout SE asia
  • human to human transmission for the first four
  • if he had malaria and they filled the room with mosquitoes, no one would get it
  • there’s an incubation period before they become infective
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6
Q

What causes the bulk of Malaria disease?

A

P. falciparum

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7
Q

What is P. falciparum transmitted by?

A

female Anopheles mosquitoes

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8
Q

Is there an animal reservoir for P. falciparum?

A

no

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9
Q

At what stage do we see malaria?

A

disease only during blood stage

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10
Q

What are the immune responses primarily against?

A
  • blood stage parasites

- involve both humoral and cellular responses

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11
Q

What are the clinical features of malaria?

A

Uncomplicated (mild) malaria:

  • ‘flu-like’ illness
  • fever, headaches, malaise
  • 90-95% of cases

severe malaria:

  • severe anaemia
  • cerebral complications (cerebral malaria)
    • coma, convulsions
    • long-term neurological deficits
  • respiratory distress and metabolic acidosis
    • reduced tissue perfusion
    • lung damage
  • other: hypoglycemia, kidney failure, blood clotting problems
  • deathrate of 15-20%
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12
Q

What is the treatment of malaria?

A

mild malaria

  • short course of effective anti-malarial tablets
  • aremisinin combination therapy (ACT):
    • e.g. artemether-lumefantrine (AL) (older drugs - chloroquine, sulfadoxine-pyrimethamine)
  • clearance of P. vivax liver stage - primaquine

severe malaria

  • anti-malarials: intavenous artemisinin or quinine (7-10 days)
  • IV fluids, blood transfusion if required
  • supportive treatment (intensive care)
  • anticonvulsant, anticoagulant, anti-inflammatory drugs?
  • little improvement in mortality rate for decades
  • urgent need for new treatments
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13
Q

What is the epidemiology and immunity of malaria?

A
  • immunity eventually develops after many episodes
    three main types of immunity
    1. immunity that prevents severe malaria
    2. immunity that prevents any malaria
    3. immunity to malaria in pregnancy
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14
Q

What are reasons for slow development of immunity?

A

parasite factors:

  • multiple antigenic targets (~5000 genes)
  • antigenic diversity: major targets show substantial polymorphism
  • antigenic variation: gene families allow switching to evade responses

host factors:

  • inadequate response (especially young children)
  • non-functional/irrelevant responses
  • poor development of memory responses?
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15
Q

How does the malaria illness develop?

A

Unrestricted replication in the blood stream

  1. malaria parasites accumulate in vital organs
  2. inflammatory responses
  3. destruction of red blood cells

severe illness: multi-system involvement

  • coma (cerebral malaria)
  • severe anaemia
  • acidosis and respiratory distress
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16
Q

What antigens are on the surface of infected red blood cells?

A
  • produced by P. falciparum developing inside RBC - they are transported (‘trafficked’) to the RBC
  • enable infected red blood cells to adhere in the blood vessels and avoid clearance by spleen
  • infected cells accumulate in large numbers in vascular beds and can cause severe disease (e.g. brain, placenta)
  • antigens are highly variant to evade immune recognition
  • important in virulence and immune evasion
  • adhesion to endothelial cell
  • forming clumps with platelets
17
Q

What does the antigenic variation and diversity of Plasmodium enable?

A
  • antigenically distinct waves of parasitemia enable
  • chronic and recrudescent infections
  • repeat infections
18
Q

How do we get antigenic diversity and variation?

A

antigenic diversity and polymorphisms

  • most infectious organisms have evolved polymorphisms in targets of immune responses
    • enables reinfection with different ‘strains’
  • each infection is caused by genetically different parasites that have different polymorphisms in key antigens

antigenic variation

  • an ability to switch the expression of different variant antigens
  • a feature of Plasmodium and trypanosomes
19
Q

What is PfEMP1?

A
  • the major antigen on the surface of parasitised red blood cells
  • serum samples from kenyan adults have antibodies that recognise malaria antigens
  • PfEMP1 is both polymorphic and encoded by a large gene family
  • encoded by var genes – multigene family
  • each genome has around 60 different var genes – can express around 60 different PfEMP1 variants
  • between genomes, PfEMP1 variants differ
  • extensive polymorphism, and clonal variation in expression of different PfEMP1 types mediates immune evasion
    • thousands of different var genes exist in nature
  • actual antigenic diversity is not as extensive as suggested by sequence analysis
20
Q

What happens when we grow a parasite in the lab?

A
  • single parasite grown in the lab
  • spontaneous variation
  • different phenotypes
  • if you look at the different phenotypes at a molecular level they are expressing different variants of PfEMP1
  • this gives different adhesive properties
21
Q

What does the expression of different PfEMP1 variants enable?

A
  • enables infected cells to adhere in different organs
  • each variant is antigenically different: not recognised by the same antibodies
  • expression of new variant form of PfEMP1 allows escape from the developing immune response - waves of parasitemia
22
Q

What are immune responses to malaria?

A

blood stage:
- passive transfer of antibodies is protective

antibodies to merozoites

  • inhibit RBC invasion and growth
    • direct inhibition by antibodies
    • antibody-dependent cell mediated inhibition of parasite growth

antibodies to infected RBCs

  • parasite antigens expressed on the surface of RBCs
  • opsonization for phagocytosis

not very good at targeting the liver stage

23
Q

What is antibody-mediated killing of malaria blood-stage parasites?

A
  • e.g. opsonise merozoites and parasitised RBCs for killing by immune cells (monocytes, macrophages, neutrophils)
24
Q

What are pregnant women at a high risk of malaria infection?

A
  • more frequent infections, higher density of parasitemia
  • occurs despite immunity that may have developed prior to pregnancy
  • risk of malaria decreasing with each pregnancy:
    • women develop immunity to malaria in pregnancy
  • serious consequences for mother and baby
  • pregnancy studies in Blantyre, Malawi
25
Q

How do we identify key properties of malaria infections?

A
  • parasites from the placenta mostly adhere to carbohydrate receptors (esp. CSA)
  • from children mostly adhere to other receptors e.g. CD36, ICAM-1
  • can use this to determine key receptors and malaria proteins for infection and disease
26
Q

What specific variant of PfEMP1 is important for placental infection?

A
  • var2csa
  • mediates adhesion of parasitised RBCs to receptors in the placenta: Primary receptor is a carbohydrate (CSA, chondroitin sulfate A)
  • poorly recognised by children and adults who have not been pregnant: little immunity to it is acquired before pregnancy
  • enables parasitised RBCs to accumulate in large numbers in the placenta
  • evades existing immunity
27
Q

Is it possible to have a vaccine against PfEMP1?

A
  • PfEMP1 is a highly diverse antigen - a major challenge to vaccine development
  • effective vaccines would require the inclusion of many different variants
  • may be possible for malaria in pregnancy:
    • one major PfEMP1 variant?
    • this would not protect children and non-pregnant adults
    • use in combination with other antigens?
    • clinical trial planned
28
Q

What are the economic and health benefits of vaccines?

A
  • immunising children is one of public health’s “best buys”
  • vaccines boost development through:
    • direct medical savings
    • indirect economic benefits such as cognitive development, educational attainment, labour productivity, income, savings and investment
  • vaccines boost economic growth in the poorest countries
  • expanding childhood immunisation rates in the world’s 72 poorest countries over the next decade would result in an estimated $151 billion in treatment and productivity savings
29
Q

What are the research objectives at Burnet?

A

Malaria in early childhood

  • development of immunity
  • specific targets of protective antibodies

malaria in pregnancy

  • mechanisms of placental infection
  • immunity to malaria in pregnancy

vaccines and interventions

  • identification and prioritisation of vaccine candidates
  • clinical trials: vaccines and preventive approaches
  • new therapeutics
30
Q

What is a challenge faced by people researching malaria?

A
  • access and resources in rural and remote communities

BIOM30002 (36 decks)

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