Malaria

1. Malaria By: Rebekah Rollston

2. Quick Facts • Malaria is spread by the bite of the Anopheles mosquito. • 350 to 500 million cases of malaria occur annually. • More than one million people die annually from malaria. • Malaria is very prevalent in certain countries of Africa, Asia, the Middle East, and Central and South America. • Malaria has been eradicated from the United States since the 1950’s.

3. Cause • Malaria is caused by the invasion of human erythrocytes (red blood cells) by a protozoan parasite. • The most virulent and severe form of malaria is caused by Plasmodium falciparum. • The merozoites of the protozoan are the actual invaders of the erythrocytes. • Merozoites are the daughter cells of the protozoan parasite.

4. Invasion Pathway • There are four main steps in the invasion pathway of the erythrocytes by Plasmodium falciparum: • 1st Step: Attachment of the merozoite to the erythrocyte • 2nd Step: Merozoite reorients to its apical pole • 3rd Step: Formation of a tight junction between the merozoite and the erythrocyte • A tight junction occurs when the membranes of the erythrocyte and merozoite join together, creating a junction that is impermeable to fluid or debris. • 4th Step:Entry of the parasite into the cell through a parasitophorous vacuole

6. Ligands • Two ligand families are use as receptors for Plasmodium falciparum: • Erythrocyte-binding antigens • Reticulocyte-binding homolog (PfRh) proteins

7. Plasmodium Vivax • Plasmodium vivax is less severe and not considered life-threatening, whereas Plasmodium falciparum is. • Plasmodium vivax invasion utilizes a Duffy antigen and a Duffy binding protein. • The Duffy antigen is present on the surface of the reticulocytes. • The Duffy binding protein is present on the surface of the Plasmodium vivax protozoa. Targets reticulocytes, which are immature erythrocytes. Reticulocytes comprise 1% of the erythrocyte concentration in the human body.

8. Enzymes neuraminidase, trypsin, and chymotrypsin are used to strip the outer erythrocyte surface of particular receptor sites; this determines which receptors are needed for different invasion pathways. The pathway that the Plasmodium falciparum merozoites use to invade the erythrocytes depends upon their sensitivity or resistance to neuraminidase, trypsin, and chymotrypsin. Neuraminidase removes sialic acids. Trypsin eliminates glycoproteins from the outer surface of erythrocytes, including glycophorin A and glycophorin C. Chymotrypsin removes glycophorin B and Band 3. Invasion Pathways

9. Immune System’s Role • The primary reason that a vaccine has not been developed for malaria immunity is because of the utilization of multiple receptor ligands, which leads to several different invasion pathways. • Interleukin-4 is a cytokine that is produced by the activated T cells of the adaptive immune system, thereby increasing the immune response. • The IL4-524 allele was found with parallel levels of “elevated antibody levels against malaria antigens, which raises the possibility that this might be a factor in increased resistance to malaria” (Kwiatkowski). • Interleukins are released when the immune system detects a foreign invader, which then increases the adaptive immune response. • Therefore, the release of interleukin-4 upon detection of merozoites will help to increase the immune response and therefore, offer an increase in malaria resistance.

10. Cause of Severe Malaria • P. falciparum-infected erythrocytes sequester in blood vessels, creating blockages. • Infected erythrocytes also “stick to endothelium, platelets, and other erythrocytes” (Kwiatkowski). • Rosetting -- cohesion of erythrocytes • Leads to immune evasion because of lack of circulation through the spleen. • Aids in the progression of the severity of malaria

11. Falstatin • Falstatin is a cysteine protease inhibitor of Plasmodium falciparum. • Proteases are extremely active in the merozoite invasion of erythrocytes and actually work to restrict the severity of the infection by obstructing the merozoites from performing the desired reaction with the erythrocytes. • The functions of proteases in the erythrocyte invasion pathway include the “breakdown of red cell hemoglobin, the release of parasites from red cells, and the invasion of red cells by free parasites” (Pandey et al.). • “Incubation of malaria parasites with an antibody that prevents the effects of falstatin markedly inhibited red cell invasion” (Pandey et al.). • Red cell invasion is inhibited when falstatin is inhibited; this is true because cysteine proteases are able to work to restrict erythrocyte invasion when falstatin is inhibited. • “Both drugs directed against falstatin or vaccines that elicit antibodies that block its action might offer new means ideally in concert with other approaches, of controlling malaria” (Pandey et al.).

12. Sickle Cell Disease • Substitution from glutamic acid to valine at the sixth codon on the beta globin chain • Homozygotes often experience fatal effects • Heterozygotes have an increased resistance to malaria • Sickle-cell allele is believed to develop in areas of low oxygen concentration • Two proposed mechanisms for how the sickle-cell trait guards against malaria • 1st proposal: “suppression of parasite growth in red cells” (Pasvol et al. quoted in Kwiatkowski). • 2nd proposal: “enhanced splenic clearance of parasitized erythrocytes” (Shear et al. quoted in Kwiatkowski). • “Enhanced splenic clearance” contributes to anemia, particularly in homozygotes, because red blood cells are being discarded as waste more quickly than they are being generated

14. Hemoglobin C Mutation • Substitution from glutamine to lysine at the sixth codon of the beta globin chain • Homozygotes experience “relatively mild hemolytic anemia” (Kwiatkowski). • Increased resistance to malaria; greater resistance in homozygotes • Increases “immune clearance of infected erythrocytes” (Kwiatkowski) • Immune system reduces the level of parasitemia in the bloodstream, ultimately lessening the severity of the malaria infection

15. Hemoglobin E Mutation • Substitution from glutamicacid to lysine at the twenty-sixth codon on the beta globin chain • Causes “symptomless anemia” in homozygotes (Kwiatkowski). • Homozygotes show some resistance to malaria, but it has not been “epidemiologically proven” (Kwiatkowski). • Heterozygotes are “relatively resistant to invasion by P. falciparum” (Kwiatkowski).

16. Questions?