Malaria and Apicomplexans Overview

Plasmodium and Malaria

• Malaria is caused by different Plasmodium species
• Malaria pathology is linked to immune evasion via sequestration
• The Plasmodium lifecycle is complex
• Plasmodium infects specific human host cells
• Sickle cell anemia can result in resistance to Plasmodium
• Chloroquine kills parasites, but some have developed resistance

Apicomplexans

• Apicomplexans are a group of single-celled eukaryotes
• Six genera infect humans
  • Plasmodium (causes malaria)
  • Cryptosporidium (causes diarrhea)
  • Isospora (causes diarrhea)
  • Cyclospora (causes diarrhea)
  • Toxoplasma (causes neurological pathology)
  • Babesia (causes rare zoonotic disease)

Apicomplexan Cell Organelles

• Apicoplast: a metabolic organelle (derived from endosymbionts) found in most but not all
• Inner Membrane Complex (IMC): a series of membrane sacs found under the plasma membrane
• Proteins complexes for gliding motility and invasion
• Cytoskeleton (including microtubule corset, alveolin network, and actin)
• Secretory organelles (micronemes, rhoptries, dense granules)

Malaria Epidemiology

• Plasmodium falciparum causes most deaths (99.7% of African cases, 97% worldwide)
• Plasmodium vivax is usually uncomplicated, causing 75% of cases in the Americas and ~50% of SE Asia cases
• Plasmodium ovale is usually uncomplicated (<1% of cases)
• Plasmodium malariae is usually uncomplicated (<1% of cases)
• 94% of malaria cases and deaths occur in Africa
• More than half the global malaria cases happen in 6 African countries
  • Nigeria (25%)
  • Democratic Republic of the Congo (12%)
  • Uganda (5%)
  • Cote d'Ivoire, Mozambique, and Niger (4% each)

Decline in Malaria (Since 2010)

• There were an estimated 228 million cases of malaria worldwide in 2018
• 405,000 people died from malaria in 2018, with 76% of these deaths occurring in children under 5
• Vector control and improved access to medicine has resulted in 93 million fewer cases and 590,000 fewer deaths each year

Malaria Pathology

• Malaria is characterized by bouts of fever, occurring every other day
• The fevers are linked to the synchronized release and invasion of parasites from red blood cells
• Complicated/severe malaria includes severe anemia, cerebral malaria (causing coma and death), caused by P. falciparum

Infected Red Blood Cells

• Infected red blood cells change shape, developing knobs
• Knobs contain the parasite protein PfEMP1
• Only P. falciparum has PfEMP1 and forms knobs

Cytoadhesion, Sequestration, and Occlusion

• Cytoadhesion causes red blood cell changes
• PfEMP1 makes infected red blood cells sticky to endothelium
• This causes red blood cell and vessel occlusion/sequestration which prevents effective immune response

Sequestration and Cerebral Malaria

• Massive sequestration of the parasite in the brain leads to cerebral malaria
• Blocked capillaries in the brain swell, leading to hemorrhage, coma and death
• A direct link exists between the parasite's immune evasion mechanisms and the human pathology

Plasmodium Lifecycle

• The Plasmodium lifecycle involves a mosquito vector and a human host
• Sporozoites are injected into the skin by infected mosquitos
• Sporozoites travel to the liver, invade liver cells
• Merozoites are released, infecting red blood cells
• Merozoites develop into schizonts
• Merozoites replicate, bursting out of the red blood cells, infecting new cells
• Some infected red blood cells become gametocytes, which are transmitted to the mosquito
• Fertilization occurs in the mosquito's gut
• Oocysts develop, releasing sporozoites into the salivary glands, ready to infect a new host

Mosquito Feeding and Injections

• Mosquitoes feed from blood vessels
• Saliva contains anti-clotting chemicals and other compounds to prevent blood clotting from the blood vessel
• Infected mosquitoes' saliva also contains Plasmodium parasites

In Vivo Imaging

• Fluorescent Plasmodium sporozoites can be observed passing through the mosquito proboscis and into the dermis

Liver Stage Invasion and Development

• Sporozoites reach the liver within an hour of infection.
• They invade liver cells, differentiate into schizonts
• Schizonts rupture, releasing merozoites into the blood stream
• This event takes 7 days and causes 20,000-fold parasite growth.

Merozoites Replication (in red blood cells)

• Merozoites enter red blood cells within a parasitophorous vacuole
• They replicate in the ring stage
• They develop into schizonts
• They rupture, releasing new merozoites to infect more red blood cells

Gametocytogenesis

• Merozoites differentiate into gametocytes (male-micro and female-macro)
• These gametocytes are needed to continue the life cycle and infect another host
• The mechanisms for sexual development in parasites are not well understood

Chloroquine

• It is an antimalaria drug
• It's mechanism of action prevents parasite heme breakdown into hemozoin
• Malaria parasites have developed resistance to chloroquine

Malaria Resistance and Sickle Cell Anemia

• Sickle cell anemia is caused by a mutation in beta hemoglobin, causing red blood cells to become sickle shaped under low oxygen tensions.
• These sickle-shaped cells are more likely to be cleared by the immune system
• Malaria resistance in sickle-cell carriers is due to reduced parasite growth in these cells