lecture 16

Question 1

What are pandemics?

Answer 1

• global outbreaks of infectious diseases
• major historical pandemics include: typhoid, plague, smallpox, cholera, 1918 ‘Spanish’ flu, tuberculosis, malaria
• major current pandemics: HIV/AIDS, tuberculosis, malaria
• infectious diseases that have shaped our history
• we tend to think of them as something of our past
• don’t tend to be as scared of them in our western society
• threat to us in australia is flu
• major current pandemics really keep countries poor

Question 2

What are the top causes of mortality around the world?

Answer 2

• e.g. HIV/AIDS = 4
• Malaria = 8
• single cause infections
• pneumonia and diarrhoea have multiple causes
  (report from 2003)

Question 3

Who suffer the primary burden of infectious diseases?

Answer 3

• children under 5

Question 4

What is the major infectious killer of children under five?

Answer 4

• one malaria species: malaria falciparum

Question 5

What is some history of malaria?

Answer 5

• ancient problem
• most lethal infectious organism in history
• still a major problem
• discovery in the blood ~1880 by Charles Laveran (Nobel Prize in 1907)
• discovery of transmission by mosquitoes in 1897 by Ronald Ross (Nobel Prize in 1902)

Question 6

What is the taxonomic classification of malaria?

Answer 6

• phylum: Apicocomplexa (a lot of pathogenic plasmodiums belong to this phylum, single celled and polar, apical-complex important for invading host cells) e
• genus: Plasmodium
• 4 species infect humans: P. falciparum, P. vivax, P. ovale, P. malariae (recently a 5th, P. knowlesi)
• many other species infect animals

Question 7

Where are people most affected by malaria?

Answer 7

• Africa: particularly equatorial countries
• other countries located around the equator
• e.g. myanmar, papua new guinea
• a lot of disease but not death is caused by non-falciparum malaria so you get a more widespread burden of disease across the globe (as opposed to death which is concentrated in africa)
• p. vivax causes disease without death and is predominant in south america

Question 8

How important is malaria now?

Answer 8

• est. 300-500 million cases/year (110 million reported)
• 1 million deaths/year (mostly children)
• malaria seriously hinders social and economic development
• • est. $12 billion in direct costs
• • 10% of yearly household spending in Africa
• • work and school absenteeism as high as 28% in some areas)
• how does it compare to other diseases?
• still very significant?

Question 9

What is the life cycle of the malaria plasmodium?

Answer 9

• begins in the mosquito and ends in the blood
• parasite in a blood cell that is maturing
  three stages:
  1. mosquito state: sexual reproduction

2. liver stage - asexual reproduction
3. blood stage: asexual reproduction, major mplification stage

Question 10

What is a diagnostic feature of malaria?

Answer 10

• characteristic is gold particulate matter - as it matures inside the red blood cell, it invades and matures for 48 hours before it is replicated and comes back out again
• red blood cells are packed full of haemoglobin –> eats this, but the haem compound is toxic to the parasite, so it crystallises the haem compound into a material haemazoan
• this gold particle is diagnostic of malaria

Question 11

What is the mosquito stage of malaria?

Answer 11

• this is where the malaria starts
• the parasite inside a mosquito has a sophisticated life cycle
• the mosquito doesn’t just carry the parasite
• in parasitology we’d call the mosquito the definitive host –> this is where sex happens
• parasite becomes diploid
• meiosis occurs to form sporozoites (haploid)

Question 12

What happens in the liver stage?

Answer 12

• sporozoite enters the liver
• very few parasites get to the liver and infect a few hepatocytes (1, 2, 10… maybe 100 but not many)
• and it replicates inside those hepatocytes
• no disease
• still a mystery why it has a liver stage
• released as a merozoite

Question 13

What is the blood stage of the p. falciparum?

Answer 13

• infect blood cells very quickly
• go from one parasite to 16 or 30 within a 48 hour period
• amplify up from the 10^3 blood cells initially infected to 10^11 red blood cells
• (we have about 10^13)
• huge biomass of infection
• this is where disease happens
• this is also the stage most drugs target

Question 14

What are the ‘egg and sperm’ of the malaria parasite?

Answer 14

• gametocytes
• the liver/blood stage is haploid
• something happens in the blood where they become male and female gametocytes
• end up back in the insect - become gametes
• fertilise inside the mosquito
• if the mosquito has bitten two different people it can cross fertilise

Question 15

What are important aspects of lifecycle and spread?

Answer 15

• sexual stage in the female Anopheles mosquito (1-2 weeks)
• injected sporozoites enter hepatocytes via the skin (~30 mins)
• asexual liver stage (1-2 weeks)
• asexual blood stage cycle is relatively synchronous and takes 2-3 days
• disease occurs a week to a month after infection
• gametocytes form in the blood and are taken up by a feeding mosquito

Question 16

How does disease present in malaria?

Answer 16

• disease occurs only in the blood-stage
• fever, chills, anaemia
• most deaths (95%) are caused by P. falciparum
• • cerebral malaria, coma
• • severe anaemia
• • placental malaria
• P. vivax also results in significant morbidity but low mortality
• • relapsing malaria (hypnozoites in liver)
• • this becomes a crucial issue in clearing malaria
• • in half a billion people in the world

Question 17

What happens to all red blood cells?

Answer 17

• pass through the spleen periodically
• every cell gets checked by the spleen
• squeezes through fenestrations
• can tell when a RBC is not right, or too old etc
• reticuloendothelial mechanisms kick in and get rid of that cell
• cling on to the walls of the blood vessels: a process that avoids splenic clearance

Question 18

What is most death by malaria caused by?

Answer 18

• adherence of blood vessels to the walls of the brain blood vessels
• cerebral malaria - infected brain capillary
• it’s not straight ischemic damage
• if they get treated they don’t have the oxygen depletion type damage typical of ischaemia

Question 19

How does cytoadherence occur?

Answer 19

• can stick to blood vessels that permeate adipose tissue, skeletal muscle, kidney, brain
• different p. falciparum parasites adhere to different tissues
• they adhere due to protein PfEMP1 (erythrocyte membrane protein 1)
• parasite modifies the wall of the infected red blood cell
• parasite protein sticks out of wall of infected RBC
• PfEMP1 is an adherence ligand
• binds to receptors on endothelial cells e.g. CD36
• maybe ICAM-1 in the brain?
• placental malaria associated with binding to chondroitin sulfate A?
• not just one protein: there are 60 different copies in the one parasite
• only presenting one at one time

Question 20

What is antigenic variation?

Answer 20

• peaks and troughs of parasitaemia
• almost clears parasite but then returns as a form that the antibodies don’t recognise
• the reason is PfEMP1
• switches in the whole population of parasites
• great way for the parasites to persist over a long period of time
• it’s like a roulette wheel - very virulent or not ? severe consequences in the brain, less so in the skeletal muscle

Question 21

What are the var genes?

Answer 21

• encode PfEMPs
• ~60 copies per genome
• only one is expressed at any one time - key to antigenic variation
• lots are found in the sub telomeric regions
• in a population expressing the same var gene, one will occasionally randomly switch and avoid the immune response to form the next generation