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HCM 124 lecture 8 Malaria.pptx

  1. HCM 124: MEDICAL PARASITOLOGY AND ENTOMOLOGY JACKSON C. KORIR (PhD) 0721- 413 606 Masinde Muliro University of Science and Technology (MMUST) University of Choice
  3. Phylum Apicomplexa: Malaria Taxonomy Phylum: Apicomplexa Class: Coccidia Order: Haemosporida Genus: Plasmodium
  4. Background  Malaria burden: -  3 billion people at risk in 109 malaria prone countries  250 million cases annually  approximately 1 million deaths  5 species of Plasmodium cause human malaria:  P.falciparum,  P.vivax,  P.ovale  P.malariae  P. Knowlesi?  Vector:- ♀ Anopheles mosquitoes (Anopheles gambie complex)  Life cycle is complex, involving developmental stages in both human and mosquito hosts
  5. Life Cycle Overview • The life cycle of Plasmodium that infect humans includes 2 hosts: •1) the human host and 2) the insect vector, a female mosquito belonging to the genus Anopheles •Like other apicomlexa, a significant feature of the life cycle is the alternation of sexual and asexual phases in the 2 hosts • The asexual cycles, termed merogony, occur in the human • The sexual cycle, termed gamogony occurs mainly in the mosquito • Subsequent to the sexual stage, another asexual phase of reproduction occurs in the mosquito, termed sporogony • The infective form in humans is the slender, elongated sporozoite Anopheles sp. Plasmodium sp. sporozoites
  6. Life cycle of Plasmodium Sp Figure 1
  7. Life Cycle (Detail) • During feeding, the mosquito secretes sporozoite-bearing saliva beneath the epidermis of the human victim, thus inoculating the sporozoites into the blood stream • About 24-48 hr later, sporozoites appear in the parenchymal cells in the liver, initiating the exoerythrocytic shizogonic cycle or pre-erthrythrocytic cycle
  8. Exoerythrocytic Shizogonic Cycle • Inside the liver cell, the sporozoite develops into a trophozoite, feeding on host cytoplasm with its functional micropore • After 1-2 weeks, the nucleus of the trophozoite undergoes multiple fission, producing thousands of merozoites • These rupture from the host cell, enter the blood circulation, and invade RBCs, initiating the erythrocytic shizogonic cycle • Some sporozoites become dormant hypnozoites
  9. Note: • Studies of P. vivax show that the membrane receptor site for the engulfment phenomenon is determined by the type of antigen present on the surface of the RBC - e.g., merozoite penetration requires the presence of at least one of two Duffy antigens (Fya+ or Fy b+ ) • People that lack the Duffy antigens (almost all West Africans and about 70% of American blacks) are resistent to vivax malaria • However, P. ovale and P. falciparum malarias are not influenced by Duffy antigens, thus accounting for their prevalence in West Africa
  10. Erythrocytic Shizogonic Cycle • Electron microscopy has confirmed that merozoites interact with the RBC plasma membrane and actively invade the cell • During this process, rhoptries and micronemes are believed to secrete surface active molecules that cause the host RBC membrane to expand and invaginate to form a parasitophorous vacuole which envelops the parasite Erythrocyctic trophozoite Merozoite entering erythrocyte
  11. Erythrocytic Shizogonic Cycle cont. • Once in the RBC, the merozoite assumes an early trophozoite shape consisting of a ring of cytoplasm and a dot-like nucleus - the signet ring stage • These early trophozoites feed on host hemoglobin, grow to the mature trophozoite stage, and then undergo multiple fission as schizonts, producing a characterisitc number of merozoites in each infected RBC
  12. Erythrocytic Shizogonic Cycle cont. • Merozoites eventually rupture RBCs and each merozoite is capable of infecting a new RBC Scanning electron micrograph of Plasmodium-infected red blood cells
  13. Erythrocytic Shizogonic Cycle cont. One of 2 fates await these merozoites: 1. Become signet ring trophozoites and begin shizogony anew 2. Differentiate into sexual stages, becoming male microgametocytes or female macrogametocytes
  14. • Once the surrounding RBC material is lysed, the gametocytes are released into the lumen of the stomach • The microgametocytes undergo a maturation process known as exflagellation Life Cycle cont. • The sexual phase occurs in the female Anopheles mosquito and begins when the mosquito takes a blood meal that contains microgametocytes and macrogametocytes
  15. Exflagellation • The nucleus undergoes 3 mitotic divisions, producing 6-8 nuclei that migrate to the periphery of the gametocyte • Accompanying the nuclear divisions are centriolar divisions, following which one portion joins each nuclear segment to become a basal body, providing the center from which the axoneme subsequently arises
  16. • During this period the macrogametocytes have developed into macrogametes which become penetrated by the microgamete • The fusion of male and female pronuclei (syngamy) produces a diploid zygote that elongates into a motile wormlike ookinete Life Cycle cont. • The nucleus with the axoneme and a small amount of cytoplasm form a microgamete, which detaches from the mass and swims to the macrogametocyte Dr. JC korir 2015
  17. Life Cycle cont. •The ookinete penetrates the gut wall of the mosquito to the area between the epithelium and the basal lamina, where it develops into a rounded oocyst • Growth of the oocyst is, in part, due to the proliferation of haploid cells called sporoblasts, within the oocyst
  18. Life Cycle cont. • Sporoblast nuclei undergo numerous divisions, producing thousands of sporozoites enclosed within the sporoblast membranes • As membranes rupture, sporozoites enter the cavity of the oocyst • The sporozoite- filled oocysts themselves rupture, releasing the sporozites in the hemocoel • The sporozoites are carried to the salivary gland ducts of the insect and are ready to be injected into the next victim when another blood meal is taken
  19. Longitudinal section of mosquito intestine showing numerous oocysts Sporozoites isolated from the salivary glands of a mosquito
  20. Dr. JC korir 2015
  21. Plasmodium vivax (benign tertian malaria) • Less than 1% of the total RBC population is parasitized • Predilection for immature RBCs (reticulocytes) • Schuffner’s dots usually stains pink to red when subjected to stains • Hemozoin granules, by-products of hemoglobin degradation by the parasite, are prominent •The cytoplasm of the trophozoite stages is very irregular and displays an active ameboid movement Dr. JC korir 2015
  22. P. ovale (mild tertian malaria) •Less than 1% of the total RBC population is parasitized • Predilection for immature RBCs (reticulocytes) • Schuffner’s dots usually stains pink to red when subjected to stains • Hemozoin granules, by-products of hemoglobin degradation by the parasite, are prominent •The cytoplasm of the trophozoite stages is very irregular and displays an active ameboid movement Dr. JC korir 2015
  23. Plasmodium malariae (quartan malaria) • Parasitizes about 0.2% of older RBCs • Trophozoites accumulate pink staining Ziemann’s dots • Hemozoin granules appear in the center or periphery of the shizont • Trophozoite often appear as a band across the cell • Mature trophozoites resemble macrogametocytes • Recrudescensces as long as 52 years after initial infection Dr. JC korir 2015
  24. • Only ring trophozoites and gametocytes seen in peripheral circulation; later stages trapped in capillaries of muscle and visceral organs • Plasma membranes of infected RBCs undergo alteration causing them to adhere to the walls of capillaries • Infects RBCs of any age; about 10% of the total RBCs • Multiple infections of single RBCs are common • Gametocytes are crescent shaped cells • Hemozoin as well as Maurer’s dots (precipitates in the cytoplasm of RBCs infected to P. falciparum), tend to aggregate around the nuclear region of gametocytes Plasmodium falciparum (Malignant tertian malaria) Dr. JC korir 2015
  25. Diagnosis Asexual stages seen in Both thin and thick blood smears stained with: Giemsa (preferred) Field's Wright's Leishman's stain
  26. RDTs • Rapid, simple, sensitive, and specific antibody-based diagnostic stick or card tests that detect P. falciparum– specific, in finger-prick blood samples are now being used widely in control programs • RDTs are replacing microscopy in many areas because of their simplicity and speed, but they are relatively expensive and do not quantify parasitemia.
  27. PCR PCR tests is increasingly used for genotyping and speciation in mixed infections
  28. Pathogenesis of malaria  Pathology and clinical manifestations almost exclusively due to the asexual erythrocytic stage parasites.  Plasmodium infection causes an acute febrile illness  Notable for its periodic fever paroxysms at either 48 or 72 hour intervals depending on the species  Severe disease forms associated with P.falciparum: • Cerebral malaria • metabolic acidosis • Hypoglycemia • Severe anemia
  29. Cerebral malaria - Characterized by impaired consciousness. - In malaria endemic areas affects older children >5yrs - May be due to:  microvascular obstruction by parasites and platelets  Rosettes  Microparticles  Effects of pro-inflammatory cytokines
  30. Metabolic acidosis - Predominantly but not exclusively a lactic acidosis - Commonly manifested as organic acidosis - increased production and impaired metabolism of lactate and ketoacids Hypoglycaemia - Glucose levels are lower than normal(<40 mg/dL) -Usually associated with severe anemia, jaundice, hyperparasitemia and there may be lactic acidosis - In children it is independently associated with poor outcome and an increased mortality
  31. Severe malarial anemia  SMA commonly occurs predominantly in children who are <3 years  Primagravidae and secundagravidae women also at risk in holoendemic areas  defined as having hemoglobin (Hb) concentration of 5 g/dL and a P. f parasitemia of 10,000 parasites/mL or more  Development of SMA is multifactorial, involving both the destruction of RBC’s and their decreased production.
  32. Postulated mechanisms of malarial anaemia Parasitology today (Mackintosh et al. 2004) Figure 2 Dr. JC korir 2015
  33. Epidemiology • Endemicity of human malaria is usually determined by the geographic distribution of its anophelene mosquito; areas where the vector is not present are free of the disease • Local environmental factors determine which particular species of mosquito transmits malaria in a given area; local epidemiological surveys can be used to assay the prevalent vectors • Precipitin tests of ingested blood from infected mosquitoes reveal whether the vectors have zoophilic or anthrophilic feeding preferences • Water dependency for breeding varies greatly • The control of malaria depends on a variety of factors, such as availability of antimalarial drugs, use of screens on houses to keep out mosquitoes, proper use of insecticides, elimination of mosquito breeding sites, etc.
  34. Relapse of Infection • Victims of vivax or ovale malaria may suffer a relapse • Originally, the relapse was thought only to be due to populations of cryptozoites (pre-erythrocyte shizont) being maintained in the exoerythrocytic cycle •A more recent view also recognizes the existence of 2 different populations of sporozoites • Short prepatent sporozoites - upon entering the human host, undergo the usual exoerythrocytic and erythrocytic phases of development and cause malaria • Long prepatent sporozoites or hypnozoites - remain dormant in the hepatocytes for an indefinite period • Some kind of physiological fluctuation activates them into exoerythrocytic and erythrocytic cycles and a relapse occurs
  35. Recrudesence • Recurrence of malaria among victims infected by P. malariae many years after apparent cure fostered the idea that this species produced relapses like those produced by P. vivax and P. ovale • But, it has been shown that the periodic increase in numbers of parasites results from a residual population persisting at very low levels in the blood after inadequate or incomplete treatment of the initial infection • The situation may persist for as long as 53 years before something triggers a parasite population explosion with accompanying disease manifestations - •This phenomenon is referred to as recrudesence
  36. Symptomatology and Diagnosis • Pathology in human malaria (P. falciparum) is generally manifested in 2 basic forms: host inflammatory reactions and anemia • Host inflammatory reactions are initiated by the periodic rupture of infected RBCs, which release malarial pigment such as hemozoin and parasite metabolic wastes • These ruptures are accompanied by fever paroxysms that are usually synchronous except during the primary attack (correlated with the merozoites rupturing from RBCs) • During cell rupturing, toxins are released which in turn cause macrophage cells to release tumor necrosis factor (TNF); it’s TNF that actually induces the fever • During the primary attack synchrony may not be evident, since the infection may arise from several populations of liver merozoites at different stages of development
  37. Black Water Fever • A condition known as black water fever often accompanies falciprum malaria infections • It is characterized by massive lysis of RBCs and it produces abnormally high levels of hemoglobin in urine and blood • Fever, vomiting with blood, and jaundice also occur • There is between 20-50% mortality rate, usually due to renal failure; probably due to renal anoxia • The exact cause of this condition is uncertain • It may be a reaction to quinine, or it may result from an autoimmune phenomenon in which hemolytic antibodies are produced in response to chemotherapy
  38. Chemotherapy • Malaria control requires effective treatment of the disease in humans and continuous efforts to control mosquito populations • The first known antimalarial drug was quinine • The drug primarily destroys the schizogonic stages of malaria •Since WWII several synthetic drugs have been used: chloroquine, amodiaquin, and primaquine • Chloroquine is a weak base and it increases the pH of the food vacuole which in turn prevents the digestion of hemoglobin •Pyrimethamine used in combination with sulfadoxine have been effective in inhibiting the folic acid cycle of malarial parasites •Current first line therapy is a combination of Artemesinin and lumefantrin
  39. Immunity • In addition to chemotherapy research, development of a protective vaccine against malaria is being pursued • Interestingly, the surface coat of the sporozoite acts as a renewable “decoy” to the vertebrate host’s immune system, stimulating the production of antibodies • When the sporozoite is attacked and its “decoy” coat sloughs off, a replacement coat is synthesized and its “decoy” effect continues • This system provides ideal protection for the sporozoite which only spends a brief amount of time in the blood before it penetrates a liver cell as is protected from circulating antibodies • In endemic areas, premunition is the basis for protective immunity as long as low-level infection persists; however, with complete cure, the victim regains susceptibility • Also, while nursing infants in endemic areas are protected through antibodies in their mother’s milk, they are at risk at the time of weaning • Also, P. falciparum can cross the placenta and cause infection on the fetus
  40. Genetics and Malaria Infections Several genetic conditions are known to affect the malarial organism: • Susceptibility is conferred by the presence of Duffy antigens e.g., vivax merozoite penetration of RBCs requires 1 of 2 Duffy antigens •Genetic deficiency in G6PDH activity in RBCs (favism) creates and inhospitable environment for the parasites • Humans heterozygous for sickle cell anemia possess a selective advantage over individuals with normal hemoglobin in regions where P. falciparum is endemic