Malaria

• Malaria


  Infectious disease caused by a protozoan parasite of the genus Plasmodium
• Characteristic periodic fevers of malaria have been recorded by every civilised society from China

  2700 BC
• Italy was only declared malaria free on November 17th 1970
• Marshlands of Kent and Essex had exceptionally high levels of mortality from the malaria from the sixteenth to the nineteenth century
• Five indigenous species of Anopheles mosquito are capable of transmitting malaria in England
• Nearly half world's population at risk of malaria (91 countries)
• In 2015, estimated 211 million cases of malaria - 429,000 deaths
• Between 2010-15, new malaria cases fell by 21% (mortality rates fell ~29%) – but significant increase in cases in 2016 (216 million)
• Burden is heaviest in WHO African Region; estimated ~90% of all malaria deaths occur in this region
• Children <5 particularly susceptible to malaria – in 2015 malaria killed ~303,000 under-fives of these 292,000 were in Africa (1 child every 2 minutes)
• Plasmodium species that infect humans

  • P. falciparum
  • P. vivax
  • P. malariae
  • P. ovale
  • P. knowlesi
• Quotidian


  Malaria with a 24 hour fever cycle
• Tertian


  Malaria with a 48 hour fever cycle
• Quartan


  Malaria with a 72 hour fever cycle
• Malaria transmission


  • Transmitted by the bite of a female Anopheles mosquito
  • Transmission limited to areas where Anopheles mosquitoes can survive and multiply (between latitudes 60°N and 40°S and below 2000 metres)
• Life cycle of Plasmodium parasite in humans

  1. Sporozoite invasion of liver cells

  2. Merozoite invasion of red blood cells

  3. Trophozoite growth in red blood cells

  4. Schizont formation and merozoite release
• Life cycle of Plasmodium parasite in mosquitoes

  1. Gametocyte ingestion by mosquito

  2. Zygote formation

  3. Ookinete invasion of mosquito gut

  4. Oocyst formation

  5. Sporozoite release and migration to mosquito salivary glands
• Plasmodium species (e.g. P. vivax and P. ovale) can form hypnozoites which are less sensitive to antimalarial drugs and can reactivate many years after initial infection
• Merozoites must invade red blood cells to continue the infection and cause disease
• Trophozoites ingest haemoglobin and break it down to form haemozoin pigment which accumulates in the food vacuole
• Schizogony occurs in the schizont stage where the trophozoite divides to give 8-16 merozoites which are released when the red blood cell ruptures
• The zygote is the only diploid stage in the Plasmodium life cycle, all other stages are haploid
• Trophozoite divides


  1. Gives 8-16 merozoites

  2. Merozoites released when red blood cell ruptures
• Red blood cell surface

  • Irregular appearance
  • Presence of 'knobs'
• Schizont


  Developing merozoites with individual nuclei
• Life cycle of Malaria in Mosquitoes

  1. Gametocyte to ookinete to oocyst to sporozoite

  2. Zygote
• Erythrocytic cycles


  1. Some trophozoites develop into sexual forms called gametocytes

  2. Gametocytes take approximately 4 days to mature, but stay viable in the blood for prolonged periods
• Nothing further will happen to gametocytes unless they are taken up by a mosquito in a blood meal
• For Plasmodium the mosquito is the definitive host
• Exflagellation


  1. Within minutes of ingestion by a mosquito the male and female gametocytes burst out of the red blood cells

  2. The male gametocyte produces 8 microgametes - these consist of a flagellum with an attached nuclear mass

  3. The micro and female macrogamete fuse to form a zygote
• The zygote is the only stage in the Plasmodium life cycle that is diploid - all the other stages are haploid
• Zygote


  Formed when a male and female gamete fuse
• Ookinete


  • Oo (egg) + kinetos (motile)
  • Invasive, motile and actively penetrates the intestinal wall of the mosquito
• Oocyst


  • Oo (egg) + kystis (bladder)
  • Attaches to the external side of the midgut wall of the mosquito
• Oocyst to sporozoites


  1. Each oocyst produces up to 1000 sporozoites

  2. When the oocyst bursts, sporozoites are released into the body cavity of the mosquito

  3. The sporozoites migrate to the salivary glands and accumulate in the salivary ducts

  4. The cycle is completed when the mosquito bites a susceptible host and injects saliva along with the sporozoites
• Pathogenesis


  • Toxins released when schizonts burst stimulate T-cells to produce cytokines such as TNF-a, which mediate fever, bone marrow depression and erythrophagocytosis
  • Loss of rbc due to parasite growth, depression of erythropoiesis, and erythrophagocytosis lead to anaemia
  • Hypoglycaemia in severe malaria
  • Clotting defects may develop
  • Immunodepression may lead to enhanced susceptibility to septicaemia
• Clinical features and complications of malaria

  • Periodic fevers - every 24, 48 or 72 hours (depending on species)
  • Anaemia - deficiency of red cells or haemoglobin in the blood
  • Acute respiratory distress syndrome - body deprived of oxygen
  • Hypoglycaemia - abnormally low blood sugar
  • Hepatomegaly and splenomegaly - enlargement of liver and spleen
  • Haemoglobinaemia - haemoglobin in blood plasma
  • Haemoglobinuria - haemoglobin in the urine (Blackwater fever)
  • Capillary blockages - leading to haemorrhage and anoxia (O2 deficiency) esp P. falciparum
• Sequestration


  • Infected RBCs (iRBC) stick (cytoadhere) to endothelial cells lining post-capillary venules in brain, heart, liver, kidney, muscles and placenta
  • Parasite proteins transported to surface of iRBC - concentrated in knob-like structures
  • Parasite proteins bind to host receptors on endothelial cells - iRBCs in capillaries are removed from the peripheral circulation
  • P. falciparum and cerebral malaria
• Diagnosis


  • Blood smears - stained with Giemsa to detect and identify Plasmodium species
  • Rapid diagnostic tests (RDTs) detect Plasmodium proteins - >200 RDT products on the market - some detect single species, others multiple species or distinguish between P. falciparum and non-P. falciparum infection. Finger-prick sample - results ~15-30 minutes.
  • Nucleic acid amplification-based diagnostics - sensitive detection of low density malaria infections (approx. limit of detection <1 parasite/µl)
• Quinine


  • Originally extracted from the bark of the cinchona tree – found in rain forest on the eastern slopes of the Andes
  • For 300 years quinine was the only effective treatment for malaria
  • After World War II quinine was replaced by synthetic drugs such as chloroquine - Safer, More effective (against all Plasmodium species), Easier to make, Few side effects - low cost