Malaria

Exo-erythrocytic (hepatic) cycle

Sporozoites

Mosquito Salivary Gland

Malaria Life CycleLife Cycle

Gametocytes

Oocyst

ErythrocytiErythrocytic c CycleCycle

Zygote

Schizogony

Sporogony

Hypnozoites(for P. vivax and P. ovale)

Plasmodium spp.1.Plasmodium vivax : Benign

Tertian, Tertian Malaria2.Plasmodium ovale : Ovale tertian Malaria3.Plasmodium malariae : Quartan malaria4.Plasmodium falciparum : Malignant

Tertian malaria.

Affinity of Parasite to ErythrocytesP.vivaxP.malariae Infectes only

young or P.ovale Old

Erythocytes

P.falciparum Infects all age groups

AAlteration of lteration of HHost ost CCells ells A variety of structural changes, which alter

its function, appearance or antigenicity. These alterations are a consequence of

parasite growthAdvantage to the parasite (e.g. increased

membrane permeability, increased selective intake of nutrients, or escape from immunity by sequestration).

The nature of the alterations induced are variable from one species to another.

1. A visible change of shape and reduced deformability

2. The presence of electron-dense protrusions or 'knobs‘

3. The presence of small depressions, or "caveolae", at the surface of the red cell, connected by a network of small vesicles and clefts in P. vivax and P. ovale

The alterations identified The alterations identified include :include :

4.4. TThe cytoadherence to he cytoadherence to endothelial cellsendothelial cells

5.5. TThe adherence to normal he adherence to normal erythrocytes ("rosetting") or to erythrocytes ("rosetting") or to other infectedother infected erythrocyteserythrocytes ("auto-agglutination“("auto-agglutination“ or or clumpingclumping))

6.6. TThe presence of new metabolic he presence of new metabolic channels; evidence of new channels; evidence of new parasite-specific antigens parasite-specific antigens associated with the red cell associated with the red cell membranemembrane

The alterations identified The alterations identified include :include :

PathogenesisRelated to erythrocytic infection by the asexual stages, Gametocytes not involve in pathogenesis

Pathology is associated with: Haemolysis

- Direct invasion & rupture of RBC during erythrocytic cycle- Increased osmotic fragility of RBC

Increased adhesiveness of infected RBC- Increases with the maturity of the parasite (schizont > trophozoite)- Knob theory

Release of pyrogens, toxin and cytokines Immunological responses Capillary permeability Tissue hypoxia

Rosetting

Sludging

Sequestration

PathoPathogenesisgenesis

Pathogenesis

Cytokines can induce (mimic) many of symptoms Cytokines can induce (mimic) many of symptoms and signs of malaria (shivering, headache, chills, and signs of malaria (shivering, headache, chills, spiking fever,sweating, vasodilation, hypoglycemia)spiking fever,sweating, vasodilation, hypoglycemia)

Adherence and inflammation reinforce each other Adherence and inflammation reinforce each other in an unholy circle causing pathologyin an unholy circle causing pathology

Cytoadherence seems to be the mainCytoadherence seems to be the main culprit culprit for for pathogenesispathogenesis Infected RBCs will adhere to the endothelium Infected RBCs will adhere to the endothelium as as well as to each other well as to each other HHigh cytokine levels igh cytokine levels induce induce expression of endothelialexpression of endothelial adhesins -- inflammation adhesins -- inflammation makes the endothelia makes the endothelia ‘‘stickier’ stickier’

ImmunityInfluenced by

GeneticsAgeHealth conditionPregnancy statusIntensity of transmission in regionLength of exposureMaintenance of exposure

ImmunityInnate

Red cell polymorphisms associated with some protectionHemoglobin S sickle cell trait or diseaseHemoglobin C and hemoglobin EThalessemia – α and β Glucose – 6 – phosphate dehydrogenase deficiency

(G6PD)Red cell membrane changes

Absence of certain Duffy coat antigens improves resistance to P.v.

ImmunityAcquired

Transferred from mother to child3-6 months protectionThen children have increased susceptibility

Increased susceptibility during early childhoodHyper- and holoendemic areas

By age 5 attacks usually < frequent and severeCan have > parasite densities with fewer

symptomsMeso- or hypoendemic areas

Less transmission and repeated attacksMay acquire partial immunity and be at higher

risk for symptomatic disease as adults

ImmunityAcquired

No complete immunityCan be parasitemic without clinical disease

Need long period of exposure for inductionMay need continued exposure for maintenance Immunity can be unstable

Can wane as one spends time outside endemic areaCan change with movement to area with different

endemicityDecreases during pregnancy, risk improves with

increasing gravidity

Immune Mechanisms

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Stage specific : Anti sporozoite antibodies in adults in

endemic areas- blocks liver invasionAnti sporozoite/merozoite antibodies -

block rbc invasionCytokines : TNF blocks merozoite

development; IL1 ; IL10Erythrocyte clearance - liver and spleenBlock cyto-adherenceEnhance clearance through opsonisationADCC likely NK activity

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