The Digestive Apparatus of P falciparum

P falciparum undergoes cycles of erythrocytic schizogony, which produce the main clinical features of the disease. During an erythrocytic cycle approximately 80 of the host-cell haemoglobin is ingested and is degraded by the developing trophozoite. As the parasite develops, host cell cytoplasm is taken up through the endolysosomal system. A mouth-like structure termed the cytostome is formed from a localized invagination of the para-sitophorous vacuolar membrane (PVM) and the parasite plasma...

Outstanding Questions in Ookinete Biology of Fundamental Biological Interest

There are a number of questions about ookinete biology that remain to be answered. Such investigations are not only of fundamental biological interest but are also relevant to understanding the fundamental biology of other development stages of the malaria parasite, may be applicable to other apicom-plexan parasites, and will be useful in studying the mechanisms of mosquito responses to parasite invasion. What are the molecular bases for ookinete recognition of mosquito midgut epithelial cells...

Barriers Presented by the Mosquito Midgut to Plasmodium Invasion

Within the mosquito midgut there are two main physical barriers to parasite invasion the chitin- and protein-containing peritrophic matrix and the epithelial surface itself. Morphologically mature ookinetes and their invasion of midgut epithelial cells begins approximately 24 h post bloodmeal ingestion (Sieber et al. 1991 Torii et al. 1992), atleast for P. falciparum and P.gallinaceum, with maximal invasion at approximately 30-35 h. Timing of invasion is substantially earlier with P.yoelii...

FA Synthesis

A set of enzymes that form a complete biosynthetic pathway for FAs from acetyl-CoA are encoded in the nuclear genome of P. falciparum. Acetyl-CoA carboxylase (ACC) that catalyses carboxylation of acetyl-CoA to produce malonyl-CoA is the first enzyme in this pathway (see Like other eukaryotes, apicomplexan ACC has both acetyl-CoA carboxyltransferase and biotin carboxylase activities and contains a biotin-carboxyl-carrier protein domain (Zuther et al. 1999). Two genes specifying different ACCs...

Mosquito Transcriptome and Proteome

Transcriptome The initial route taken to describe the molecular immune system of mosquitoes was the identification of individual transcription-ally responsive genes (Dimopoulos et al. 1998 Richman et al. 1997). The first transcriptome-based projects described immune ESTs from a mosquito hemocyte-like cell line (Dimopoulos et al. 2000) and from whole-mosquito subtractive hybridization (Oduol et al. 2000). These and other projects have recently yielded the resources for larger scale...

Genomics

Falcilysin is an M16 family metalloprotease identified in a search for a food vacuole activity that could cleave hemoglobin fragments at polar residues 66 . It is a single copy gene on falciparum chromosome 14. There are a number of other metalloproteases in the falciparum genome, all quite distantly related 67 . There are several other M16 family members one is an apicoplast enzyme 68 and several others appear to have mitochondrial targeting sequences. Falcilysin may be the only food vacuole...

The Role of the Spleen in Limiting the Progression of Disease

Although still poorly understood in its full complexity, it is evident that the spleen plays an essential role in limiting the acute expansion of the infection not only by removing parasitized erythrocytes but also by modulating parasite antigen expression on the surface of infected erythrocytes, as well as by enhancing cellular and humoral immune responses of the host (Garnham 1970 David et al. 1983 Chotivanich et al. 2002). The important role of the spleen becomes dramatically evident in...

The Mitochondrial Electron Transport Chain

In most eukaryotes, the electron transport chain is a key part of the cell's energy transduction machinery, transferring the reducing equivalents from catabolic metabolism to oxygen in a series of energy-conserving steps that establish a transmembrane proton gradient across the mitochondrial inner membrane. The proton gradient is used to power the production of the majority of ATP in metabolically active cells, as well as to assist mitochon- drial transport and other processes. In metazoans,...

Band

The naturally occurring mutations in human genes encoding erythrocyte membrane proteins have been valuable in understanding host receptor requirements for malaria parasite invasion. For example, the successful invasion of human En (a-) and MkMk erythrocytes that are completely deficient in either GPA or both GPA and GPB, by a SAD P. falciparum strain (Camp) argues that GPA alone is not sufficient as the host receptor for parasite invasion into erythrocytes (Miller et al. 1977 Hadley et al....

Merozoite Invasion

The landmark video recording (Dvorak et al. 1975) and two ultrastructural studies (Bannister et al. 1975 Aikawa et al. 1978) of simian malarial parasite P.knowlesi invading erythrocytes have shown that invasion is a stepwise process requiring an attachment of the apical end of the merozoite to the erythrocyte followed by a deformation of the erythrocyte (Fig. 1). The actual penetration of the merozoite into the erythrocyte only takes about 30-60 s to complete. The internalized merozoites are...

Bioavailable Iron and Heme Metabolism in Plasmodium falciparum

Sullivan2 (K) department of Environmental Health Sciences, Baltimore, MD 21205, USA 2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, E5628, 615 North Wolfe Street, Baltimore, MD 21205, USA dsulliva jhsph.edu 1 Human Host Iron 2 Perturbations of Human Iron Metabolism by Malaria 296 3 Plasmodium Iron 3.1 Hemozoin Structure and 3.2 Biochemical Formation In Vivo and In Vitro 301...

Relation of Ookinete Cell Biology to Plasmodium Invasion of the Mosquito Midgut

The ookinete has a number of features that are unique among the diverse developmental stages of Plasmodium. The ookinete does not form a para-sitophorous vacuole within its target cell, the midgut epithelial cell, in contrast to invasive merozoites and sporozoites. Rather, the ookinete continues its journey through one or more epithelial cells (Han et al. 2000), exiting on the basement membrane, coming to rest on the lumenal aspect of the basement membrane, and rounding up to form the oocyst....

Perturbations of Human Iron Metabolism by Malaria

Malaria infection and disease impacts iron metabolism in many diverse ways (see the chapter by D. Roberts et al., this volume). Malaria infection geo graphically coincides with iron deficiency anemia. As a chronic infectious disease, malaria further decreases iron uptake from the intestine, contributes to ineffective erythropoeisis and sequesters bioavailable iron in ferritin stores (Spivak 2002). Lysis of infected erythrocytes may increase urinary losses of hemoglobin iron. The increased...

Models and Mechanisms of Plant Disease Resistance

Like insects, plants lack a circulating immune system and rely exclusively on a form of innate immunity to defend themselves from pathogen attack. The best-understood form of plant disease resistance is known as gene-for-gene resistance. It is so named because of early observations that particular loci in plant hosts (called R genes for Resistance) conferred resistance to pathogens carrying particular genes called avirulence genes (Flor 1955). Typically, a single R gene confers resistance to...

Plasmodium Iron Sources and Pathways

The Plasmodium parasite requires iron for DNA synthesis, glycolysis, pyrimi-dine synthesis, heme synthesis and electron transport. Debate continues on the critical source of iron for the intraerythrocytic parasite. An important paradox regarding iron is that millimolar desferrioxamine (DFO), an iron chelator, is cytostatic for mammalian cells and bacteria, while a 60-fold lower concentration of 15 M DFO is cytocidal for P. falciparum despite the availability of 20 mM heme iron in hemoglobin...

Physical Barrier Peritrophic Matrix

Soon after ingesting ablood meal, mosquitoes synthesize a structure known as the peritrophic matrix that surrounds the bloodbolus (Tellamet al. 1999). The peritrophic matrix, whose presumed function is to prevent physical trauma to the delicate microvillar surface of the midgut epithelial cell, is comprised of chitin (ranging from 1 to 15 by weight) cross-linked by chitin-binding proteins known as peritrophins. The structure of the peritrophic matrix varies between mosquito species but has been...

Heme Crystal Inhibition

Much of the interest in heme crystal formation derives from the extensive data showing many antimalarials like the quinolines, phenanthrenes and hy-droxyxanthones inhibit p-hematin formation. Extensive work has been done on the heme binding interaction by the quinoline class of drugs (Egan et al. 1997 Fitch and Kanjananggulpan 1987 Leed et al. 2002 Moreau et al. 1985). Other drugs that bind heme have also been explored as antimalarials (Huy et al. 2002 Kalkanidis et al. 2002 Kristiansen and...

Overview of Ookinete Biology

The Plasmodium ookinete is the stage of the malaria parasite that invades the midgut of its definitive host, the mosquito (Fig. 1). After a mosquito takes an infectious blood meal, gametocytes are stimulated to form male Fig. 1A,B The biology of the malaria parasite within the mosquito midgut. A Development stages of Plasmodium within the mosquito midgut. After ingestion of game-tocytes (1), exflagellation (2), and fertilization to produce a zygote (3), the ookinete (4) develops over 15-24...

Structure and Mechanism

The crystal structure of falcilysin has not yet been solved. The structure of one M16 family member that has 20 identity with falcilysin, mitochondrial processing peptidase MPP , is known but is a dimeric enzyme with its catalytic pocket at the subunit interface 71 . This is unlikely to be the case for falcilysin, which has poor homology with MPP in the dimer interface sequence and is a larger protein with its catalytic residues near the N terminus. The function of the rest of the molecule is...

References

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