Malaria and Plasmodium Parasites

• Malaria is a life-threatening disease and has been a major disease for thousands of years.
• Malaria is typically transmitted through the bite of an infected female Anopheles mosquito.
• Infected mosquitoes carry the Plasmodium parasite.
• Malaria is caused by protozoa of the genus Plasmodium.
• When an infected mosquito bites a person, the parasite is released into their bloodstream.

Five Species of Plasmodium Parasite

• Five species of Plasmodium (single-celled parasites) can infect humans and cause illness.
• These Plasmodium species are:
  • Plasmodium falciparum (P. falciparum)
  • Plasmodium malariae (P. malariae)
  • Plasmodium vivax (P. vivax)
  • Plasmodium ovale (P. ovale)
  • Plasmodium knowlesi (P. knowlesi)

Life Cycle Facts

• An infected female Anopheles mosquito injects sporozoites into the skin to start the cycle.
• Sporozoites enter the bloodstream and infect liver cells.
• Parasites develop into schizonts within liver cells.
• Schizonts rupture, releasing merozoites into the bloodstream
• Merozoites infect red blood cells.
• Some parasites become male/female gametocytes.
• Gametocytes are ingested by a mosquito when it feeds.
• Gametocytes emerge from blood cells and become gametes.
• Male gamete fuses with a female gamete, producing a zygote.
• Zygotes elongate into ookinetes, which move through the stomach wall.
• Ookinetes develop into oocysts.
• Oocysts grow and rupture, releasing sporozoites.
• Sporozoites migrate to the salivary glands, ready to be injected and renew the cycle.
• Clinical illness is a result of the erythrocytic stage of the parasite.
• There is no disease associated with sporozoites, the developing liver stage of the parasite, the merozoites released from the liver, or gametocytes.
• First symptoms and signs of malaria are associated with rupture of erythrocytes when erythrocytic-stage schizonts mature.
• The release of parasite material presumably triggers a host immune response.
• Cytokines, reactive oxygen intermediates, and other cellular products released during the immune response cause malaria symptoms.

Symptoms of Malaria

• General symptoms include fever, chills, general discomfort, and headache.
• Other symptoms include nausea, vomiting, diarrhea, abdominal pain, and muscle or joint pain.
• The malaria paroxysm has three successive stages:
  • A cold stage (15-60 minutes) with shivering and feeling of cold.
  • A hot stage (2-6 hours) with fever up to 41°C, flushed, dry skin, often headache, nausea, vomiting.
  • A sweating stage (2-4 hours) where the fever drops rapidly and the patient sweats
• The fever in falciparum malaria may occur every 48 hours, but is usually irregular.
• Classic fever patterns are not usually seen early in the course of malaria

Defense and Immunity

• Susceptibility to malaria infection and disease is regulated by hereditary and acquired factors.
• The sickle cell trait (cause of sickle-cell anemia) developed as a balanced polymorphism to protect against serious P falciparum disease.
• Individuals with sickle cell anemia/trait are as easily infected, but rarely exhibit malaria disease because P falciparum develops poorly in erythrocytes.
• Acquired immunity can protect against malaria infection and development of malaria disease.
• The prevalence and severity of malaria infections decrease with age in malarious areas.
• Multiple infections with malaria do not confer long-lasting, sterile protective immunity like viral infections do.
• People repeatedly exposed to malaria develop antibodies against many sporozoite, liver-stage, blood-stage, and sexual-stage malaria antigens.
• Antibodies against sporozoites, liver-stage and blood-stage organisms are responsible for the decreased susceptibility to malaria infection and disease seen in adults in malarious regions
• Antibodies against the sexual stages of plasmodia reduce malaria transmission
• Acquired antibody-mediated immunity appears to be transferred from mother to fetus across the placenta.
• This passively transferred immunity is lost within 6 to 9 months
• The immunity in adults will dissipate if they leave a malarious area and are no longer exposed to plasmodia.
• A fever is a temporary rise in body temperature and part of an overall response from the body's immune system.
• The average temperature is 37°C; 37.8°C or higher is generally considered to be a fever
• Fever results from immune cells at infected sites sending chemical signals to the brain to raise the body’s temperature.
• Higher temperatures makes it harder for bacteria and viruses to survive.
• When the immune system responds to disease, the hypothalamus can set body temperature higher.
• Shivering increases heat, chills are what is felt when the hypothalamus raises the body temp.
• Higher temperatures put heat-induced stress on pathogens, killing them or at least inhibiting their growth
• Slight heat makes immune cells work better.
• Inflammation is a local defensive response to infection; it involves heat, pain, redness and swelling in the areas where the immune system is most active
• Heat is from the immune cells.
• Reactive oxygen species are generated to kill pathogens, in a process know as the respiratory burst, substantial heat is also produced.
• Immune cells impede pathogens with stressors, including reactive oxygen species, toxic peptides, digestive enzymes, high acidity and nutrient deprivation
• Chemical reactions are sped up by increased temperatures, so heat enhances these defenses.

Diagnosis

• Many deaths from malaria are the result of delayed diagnosis and treatment
• Definitive diagnosis requires direct observation of malaria parasites in Giemsa-stained thick and thin blood smears
• In falciparum malaria, most organisms are not present in the peripheral blood because they are sequestered in the microvascular tissue of internal organs.

Medications

• Parasites may be present in the blood and the liver; different drugs are required to eradicate each.
• Drugs which kill malaria parasites in the blood are called blood-stage schizonticides.
• Drugs which kill malaria parasites in the liver are called tissue schizonticides.
• A clinical cure is the elimination of parasites from the blood.
• A radical cure is the eradication of all parasites from the body, both blood and liver.
• In P falciparum and P malariae (no latent liver forms/hypnozoites), effective dose of a blood schizonticide leads to radical cure.
• In P vivax and P ovale malaria (form hypnozoites), radical cure requires therapy with both a blood schizonticide and a tissue schizonticide.
• Recurrence of malaria infections after treatment is due either to recrudescence or to relapse.
• Recrudescence is when the blood schizonticide doesn’t eliminate all parasites from the blood stream.
• Relapse is in is in P vivax and P ovale infections from the delayed development of liver-stage parasites
• Resistance of malaria parasites to antimalarials may be complete or relative.
• Relative resistance can be overcome by raising the dose of the antimalarial.
• In the body, artemether is metabolized into the active metabolite dihydroartemisinin.
• Artemether works against the erythrocytic stages of P. falciparum by inhibiting nucleic acid and protein synthesis
• Used in combination with lumefantrine for improved efficacy.
• Has a rapid onset of action and is rapidly cleared from the body offering rapid symptomatic relief

Medications Classified

• Blood stage medications include:
  • Artemisinins
  • Antifolates
  • Antimicrobials
  • Quinolones
    • (chloroquine, quinine, quinidine, mefloquine, lumefantrine)
  • Primaquine (P vivax only)
• Liver stage:
  • Primaquine