Malaria… …thy cunning seeds, Oh, million-murdering Death



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Malaria…


Malaria

  • From the Italian “mal aria” - Bad Air

    • Also known as ague, marsh disease
    • Descriptions of malaria go as far back as 3550 B.C.
  • Caused by species of the genus Plasmodium.

  • There are nine sub-genera.

    • Three occur in mammals
    • Four occur in birds
    • Two occur in lizards


Taxonomy

  • Kingdom: Animalia

  • Phylum: Apicomplexa

  • Class: Coccidia

  • Order: Haemosporidia

  • Genus: Plasmodium

  • Species: vivax, falciparum, ovale & malariae





Parasitic Human Malarias

  • Of the nine sub-genera, there are four that are typically parasitic to humans

    • P. falciparum
    • P. vivax
    • P. malariae
    • P. ovale
      • Each is more closely related to other Plasmodium lineages than each other


Hosts of Plasmodium

  • Plasmodium requires two types of host

    • Vertebrate and Invertebrate
      • Definitive host is the invertebrate (Anopheles spp.)
        • Sexual reproduction occurs
      • Intermediate host is the vertebrate (Humans)
        • Asexual reproduction occurs


Reproduction and maturation in definitive host

  • Anopheles spp. ingest erythrocytes containing Plasmodium gametocytes

    • If an unsuitable species of mosquito ingests Plasmodium gametocytes, they are digested
  • Macrogametocytes and Microgametocytes are released from erythrocytes

    • Macrogametocyte matures into macrogamete (Nucleus shift)
    • Microgametocyte matures into microgamete (exflagellation)
  • Microgametes fertilize macrogametes

    • Diploid zygote becomes a motile ookinete


Reproduction and maturation in definitive host, cont’d

  • The motile ookinete penetrates the stomach lining of the mosquito

    • Once there, the ookinete begins to form an oocyst
  • Sporoblasts begin to form within the oocyst

    • Sporoblasts divide repeatedly to form sporozoites
  • Sporozoites break out of the oocyst and migrate throughout the body of the mosquito

    • This entire process (from ookinete to sporozite) can take from 10-21 days
  • Some sporozoites end up in the salivary gland of Anopheles, where they are transmitted when the mosquito takes a blood meal



Life cycle illustration



Reproduction and maturation in the intermediate host

  • Sporozoites injected by Anopheles migrate to liver from the bloodstream

    • Covered in a protein that aids in access to hepatocytes
  • Entry into hepatocytes is the beginning of the pre-erythrocytic cycle

    • Upon entry into hepatocytes, sporozoites become feeding trophozoites
      • Some sporozoites go dormant indefinitely (depending on Plasmodium spp)
    • After a week, trophozoites are mature
      • At this point, trophozoites undergo schizogony


Reproduction and maturation in the intermediate host, cont’d

  • Merozoites re-enter the blood from the liver and penetrate red blood cells

    • Upon entry, merozoites become trophozoites again
      • At this stage, trophozoites display distinctive “signet-ring” appearance, feed on hemoglobin
    • After maturing in the RBC, trophozoites again form a schizont, creating more merozoites
    • RBC ruptures, releasing merozoites, and parasite metabolic wastes, which causes many of the symptoms of malaria
      • One of these, hemozoin, a byproduct of parasitic consumption of hemoglobin, is toxic, and causes inhibition of macrophages
    • After a number of generations, some merozoites become macro and microgametocytes
      • Ingestion of gametes causes infection in Anopheles
        • If not ingested, gametes are phagocytized


Human cycle



P. falciparum

  • Is the most dangerous of the malaria parasites

    • Accounts for 50 % of all malaria cases
    • Causes malignant tertian malaria
    • Symptoms appear 9 to 14 days after initial infection
    • Parasitemia levels are extremely high
      • Up to 65% of erythrocytes infected
    • Schizonts grow in liver cells
      • Schizont ruptures in 5 1/2 days, releasing 30,000 merozoites
      • Schizonts are more asymmetrical than other Plasmodium spp.
    • Infected RBCs can attach to uninfected RBCs, forming rosettes
      • Rosettes can clog venules
    • Falciparum trophozoites secrete proteins that cause deformations of erythrocytes
    • Falciparum trophozoites extend pseudopodia, but are not as active as P.vivax trophozoites
    • Falciparum gametocytes are crescent shaped


P.vivax

  • Trophozoites of P.vivax are much more motile than other plasmodium spp.

    • This motility caused Italian researchers to nickname it “vivace”, Italian for “quick and lively”
  • P.vivax flourishes in temperate zones

    • Most cases of P.vivax malaria now occur in Asia
    • P.vivax is common in North Africa, but not in tropical Africa
      • Africans have a natural resistance to this form of malaria
  • Schizonts are formed in the liver parenchyma and release 10,000 merozoites upon maturation

  • Trophozoites cannot penetrate mature red cells

    • In addition, merozoites can only penetrate RBCs with mediated receptor sites
      • Receptor sites are genetically determined, conferring resistance
  • A defining characteristic of P.vivax is the development of hypnozoites

    • Hypnozoites cause relapse of malarial infection


P.vivax, cont’d

  • P.vivax gametocytes are rounded

    • It appears that P.vivax gametocytes do not require several generations to appear
  • Causes benign tertian malaria

  • Symptoms appear between 12 and 18 days after initial infection



P. Malariae

  • Causes quartan malaria

    • Causes paroxysms every 72 hours
  • Is cosmopolitan, but does not have continuous distribution

    • Is found in many regions of tropical Africa, Asia, South America, and even Europe
  • Is thought to be the only Plasmodium organism that lives in wild animals

  • Parasitemia levels are low

    • One parasite per 20,000 red cells
  • Symptoms appear between 18 and 40 days after initial infection



P. Ovale

  • Rarest of the four malaria parasites

  • Causes tertian malaria

  • Symptoms appear between 12 and 18 days after initial infection

  • Common to western coastal Africa, also found in India, the Philippines, New Guinea, and Vietnam

  • Difficult to diagnose due to its similarity to P.vivax

  • Gametocytes take longer to appear in blood than those of other species



Symptoms

  • Common symptoms

    • Fever
    • Chills
    • Headache
    • Sweats
    • Fatigue
    • Nausea and vomiting
  • P.falciparum

    • Causes Cerebral Malaria, which accounts for 10 % of hospital admitted malaria cases and 80%
    • Mild jaundince
    • Enlarged liver
    • Increased respiratory rate
    • Pulmonary edema
  • P.vivax

  • P.ovale

  • P.malariae



Pathogenesis

  • Clinical signs of malaria can be attributed to two factors

    • Host inflammatory response
      • Produces chills and fever
      • Correlated with maturation of merozoites, rupture of RBCs
      • Toxins released from burst RBCs can stimulate secretion of TNF by macrophages
      • TNF overproduction and toxicity can cause most or all of malaria symptoms
    • Anemia
      • Caused by destruction of RBCs


Control





Diagnosis

  • Diagnosis of malaria can be difficult, because many symptoms are general

  • Demonstration of the parasites in peripheral blood is important to a diagnosis

  • Individuals with very low parasitemias can often be overlooked

  • Several effective methods for diagnosis have been developed

    • Fluorescent dye staining
    • DNA probe specific for P.falciparum
    • PCR diagnostics
    • ELISA detection of P.falciparum antigen


Treatment

  • Treatment of malaria focuses on eradication of the blood parasites

    • Several drugs can be administered, such as
      • Chloroquine
      • Quinine
      • Doxycycline
      • Malarone
      • Lariam
      • Fansidar
  • Treatment is dependent on several factors, including:

    • Type of malaria
    • Drug-resistance
      • Nearly all strains of P.falciparum are now chloroquine resistant, in addition to developing resistance to nearly all other currently available antimalarial drugs
      • P.vivax has also developed resistance to chloroquine and primaquine, though they are not as widespread as P.falciparum


Impact of malaria

  • According to the WHO - World Malaria Report 2005:

    • At the end of 2004, some 3.2 billion people lived in areas at risk of malaria transmission in 107 countries and territories.
    • Between 350 and 500 million clinical episodes of malaria occur every year.
    • At least one million deaths occur every year due to malaria.
    • About 60% of the cases of malaria worldwide and more than 80% of the malaria deaths worldwide occur in Africa south of the Sahara.
      • In 1995, 990,000 deaths reported in some African countries where malaria infection is high (2,700 deaths per day)
      • In 2000, 84% of the blood transfusion given in Kinshasa, Congo were for anemia caused by malaria


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