Plasmodium 1- Most important parasitic disease affecting human. Introduction 1- Most important parasitic disease affecting human. 2- Most common in Tropic –Subtropics mostly Africa, Asia & S. America 3- It is estimated that more than 300 million people suffer annually. 4- Number of Deaths more than 2 million per year mostly among children 5- Transmission of the disease is mainly by bite of female Anopheles. 6- Transmission in an area depends upon: infected cases “Gametocytes carriers” – Anopheles mosquito Vector (which require an optimum condition of humidity & temperature 20-30 ºC) –rainfall provides breeding places. 7- Inhabitants in hyperendemic areas are repeatedly inoculated by Sporozoites through mosquito’s bite 8- Children are more susceptible in areas of high transmission than Adults 9- “Premunition” a form of immunity sufficient to control but not to prevent infection develops which control infection in elders. 10- P. falciparum malaria infection is severe in immune & non-immune pregnant females. DR. RAAFAT T. MOHAMED

Plasmodium DR. RAAFAT T. MOHAMED

Plasmodium Causes Human Malaria Mal: bad aria: air P.vivax: vivax or benign tertian malaria Most predominant P.ovale: ovale or ovale tertian malaria Tropics P.malariae: malariae or quartan malaria Temperate zones P.falciparum: falciparum or subtertian or malignant malaria Tropics Geographical Distribution Presence of Malaria = Presence of Anopheline mosquito DR. RAAFAT T. MOHAMED

Malaria Distribution all over the world Areas where malaria has disappeared or never existed Ø Areas with limited risk + Areas where malaria transmission occurs ++ DR. RAAFAT T. MOHAMED

Life Cycle of Plasmodium I- Development in Man Infective female Anopheles I- Liver phase sporozoites 40 min Liver merozoites P.vivax P.ovale hypnozoite Trophozoite Schizont Rupture II- Blood phase ♂ Blood merozoites P.v. 3rd d P.o. 3rd d ♀ haemozoin P.m. 4th d Ring Trophozoite Schizont Rupture P.f. irreg. gametocyte DR. RAAFAT T. MOHAMED

II- Development in Anopheles Mosquito gut Sporozoites in salivary gland ♂ and ♀ gametocytes Reduction division ♂ and ♀ gametes Sporogony Sporocyst Oocyst exflagellation Ookinete fusion Zygote DR. RAAFAT T. MOHAMED

Plasmodium life cycle Mode of infection: Man (Intermediate Host) – Asexual cycle (Schizogony) ♀Anopheles (Definitive Host) Sexual Cycle (Sporogony) Mode of infection: 1- Bite of ♀Anopheles (common) 2- Blood transfusion – common syringes. 3- Congenital transmission. DR. RAAFAT T. MOHAMED

Plasmodium life cycle DR. RAAFAT T. MOHAMED

Plasmodium life cycle 2 1 DR. RAAFAT T. MOHAMED

Some Stages of Malaria in Anopheles Feeding female Anopheles Exflagellation showing microgametes Sporozoites from salivary gland Oocysts on outside of mosquito stomach DR. RAAFAT T. MOHAMED

Exoerythrocytic Cycle Schizonts take 5-7 days to develop formation of >10,000 merozoites upon rupture of hepatocyte, released merozoites will invade R.B.Cs. The final step involves the release of merozoites (green) into the bloodstream. The signal(s) that trigger the release remain unknown. Plasmodium merozoites are released by the formation of merozoite-filled vesicles (merosomes), which bud off from the infected hepatocytes into the sinusoidal lumen. Nature Reviews Microbiology (2006): 4-849 DR. RAAFAT T. MOHAMED

Plasmodium (Ring form) Accolè form P. falciparum Early Trophozoite (Ring stage): Thin loop of cytoplasm & a small chromatin dot enclosing a pale central vacuole (signet form). In P falciparum it appears like a pair of stereo-head phones. Also more than one ring in the Same RBCs (multiple infection). Accolè form (marginal ring). ovale falciparum vivax P malariae DR. RAAFAT T. MOHAMED

Plasmodium (Late Trophozoite) falciparum vivax ovale malariae Mature Trophozoite (late trophozoite): The parasite develops by increasing the amount of cytoplasm. Digested haemoglobin gives rise to malaria pigments (haemozoin). Parasitised cells become osmotically fragile. DR. RAAFAT T. MOHAMED

Plasmodium (E. Schizont) ovale falciparum vivax malariae Erythroytic Schizont: The chromatin & cytoplasm break into fragments merozoites . The pigments remains as a single mass in the center.  The Schizont (mature stage of the parasite) eventually occupies the entire R.B.C Rupture of E. Schizonts merozoites - malaria pigments - toxins into the blood stream: *Merozoites attack new R.B.Cs repeating the cycle. *Pigments (haemozoin) are engulfed by R.E.Cs. *Toxins (immunogenic) induce malarial paroxysm. Merozoites attack clean RBCs repeating the cycle DR. RAAFAT T. MOHAMED

Plasmodium (Gametocytes) vivax falciparum malariae ovale Following repeated cycles Merozoites invade RBCs - develop into: *Microgametocytes (male gametocytes) & * Macrogametocytes ( female gametocyte). Gametocytes are infective to the female Anopheles . DR. RAAFAT T. MOHAMED

Pathogenesis and Clinical Picture 1- Destruction of osmotically fragile infected R.B.C.s intra & extra-vascular haemolysis HAEMOLYTIC ANAEMIA. 2-Toxins activate the macrophage / monocyte series of cells which will stimulate sensitized T -lymphocytes to produce Cytokines FEVER. 3- Merozoites - parasitized R.B.C.s -lysed R.B.C.s - toxins - pigments are cleared from the circulation by stimulation of the R.E.S. SPLENOMEGALY besides HEPATOMEGALY. 4-Destruction of immature Reticulocyte together with suppressed erythropoiesis decreased production of R.B.C.s ANAEMIA. 5- Enlarged spleen early destruction of RBCs (activation of the complement system) ANAEMIA 6- Large number of circulating immune complexes 'C.LC.s' (takes place with P.malariae & P falciparum infections) deposit in the glomerular capillaries acute glomerulopathy NEPHROTIC syndrome. 7- Parasite feeds on haemoglobin depletion of iron stores inappropriate haemoglobin metabolism ANAEMIA. DR. RAAFAT T. MOHAMED

Pathogenesis and Clinical Picture 8- Haemolysis of R.B.C.s JAUNDICE 9- Parasitised erythrocytes of P falciparum Cytoadhere to the endothelial surface of capillaries occludes the microcirculatory blood flow PERNICIOUS syndrome as a result of Tissue Anoxia - Focal Necrosis - Hemorrhage - Oedema of vital organs 'multiorgan involvement‘. 1- Paroxysms are repeated for few weeks or longer with decreasing intensity.   The disease is self-limited (due to cytokine activity & Premunition). In between attacks the patient may be exhausted but generally feels well.   2- Relapse of the infection may occur in both P. vivax & P.ovale after resolution of the primary infection (mainly due to Hypnozoites). 3- Recrudescence of the infection may occur in both P.malariae & P falciparum (due to persistent low grade undetectable parasitaemia) flare up of the infection with recurrence of the clinical attack. DR. RAAFAT T. MOHAMED

Pathogenesis and Clinical Picture All species of Plasmodium will give rise to the following Clinical Picture: 1- FEVER 2- SPLENOMEGALY 3- HEPATOMEGALY 5- JAUNDICE. 4- ANAEMIA 1- FEVER (PAROXYSM) three successive stages: Cold - Hot - Sweat Cold stage : Shivering "chills"(O.5 - 1 hr.) followed by sharp rise in the temperature. Hot stage : High fever- headache - flushed face - rapid pulse (1 - 4 hrs.). Sweat stage : Sweat with drop of temperature (1- 4 hrs.). paroxysms associated with synchrony of merozoites release between paroxysms temperature is normal and patient feels well falciparum may not exhibit classic paroxysms (continuous fever) Subtertian malaria tertian malaria quartan malaria DR. RAAFAT T. MOHAMED

Pathogenesis and Clinical Picture 2- ANAEMIA Haemolytic anaemia - multifactorial due to rupture of R.B.C.s- deficient Hb.metabolism - suppressed erythropoiesis - early R.B.C.s destruction. *Severe in P falciparum (high parasitaemia "young & old RBCs" are infected). *Moderate in P vivax & P.ovale (moderate parasitaemia "young RBCs" are infected). *Mild in Pimalariae (mild parasitaemia "old RBCs" are infected). 3- SPLENOMEGALY The Spleen: is enlarged - soft - tender *Mild to moderate "P vivax & P ovale". *Marked enlargement "P malariae"(prolonged duration of infection "chronic" with repeated attacks that end up by hypersplenism). *Marked enlargement "P falciparum" (cytoadherence phenomenon). 4- JAUNDICE *Mild "P. vivax – P ovale – P malariae" (haemolysis of RBC). *Severe "P .falciparum'' (liver involved by cytoadherence) DR. RAAFAT T. MOHAMED