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Malaria-The Microbe
Jana Jacobs IDM 2001 November 25, 2008
Abstract The causative agents of malaria are mosquito-born eukaryotic parasites of the genus Plasmodium takes different forms during its life cycle, some of which are invasive, and some of which, including P. falciparum , P. vivax , P. ovale and P. malariae. The parasite are motile. The structure is similar to mammalian cells, containing most of the same organelles, but which is highly polarized and contains a plastid-like apical complex. This complex is composed of various secretory vesicles. They also have a specialized actomyosin-based system for movement along a substrate. Due to the plastid-like apicalcomplex and phylogenetic analyses of the apicomplexa, it is thought that they evolved through secondary endosymbiosis of algal organism. The genome of P. falciparum was fully sequenced in 2002. There are 5,269 predicted proteins, 10% of which are thought to belong to the apicoplast and 4% of which are thought to belong to the mitochondria. It was also found that the parasite expresses a different profile of proteins in different stagesof its life cycle. Virulence of P. falciparum is determined by the gene families of var and rif , and possibly stevor.
Malaria is caused by one of four eukaryotic parasites of the genus Plasmodium , including P. falciparum , P.vivax , P. ovale and P. malariae. The most severe disease is caused by P. falciparum and P. vivax , most commonly P. falciparum (1). It is a vector- borne disease, and is transmitted by the Anapholes mosquito. The taxonomic classification is as follows: Kingdom Protista, Subkingdom Protozoa, Phylum Apicomplexa, Class Sporozoasida, Order Eucoccidiorida, Family Plasmodiidae, Genus Plasmodium , and Species f alcipraum , malariae , ovale or vivax (2). There are different morphologies the parasite takes throughout its life cycle (see figures 1 & 2).
invasion. Since they lack pseudopods, cilia or flagella, the zoites have the ability to move on solid substrates by gliding, which is powered by a linear actomyosin motor just underneath the zoite plasma membrane (5). The ‘glideosome’ is considered to be substrate-dependent motility, and consists of adhesive proteins released from the secretory organelles of the apical complex and translocated to the posterior pole of the parasite by the actomyosin motor (See Fig. 3) (6). This has puzzled microbiologists since there are no microfilaments in the cytoplasm, and the actin is restricted to a small space between the plasma membrane and the underlying inner membrane complex, and actin filaments are very small compared to other eukaryotes. Once it was discovered that the myosin is fixed to the inner membrane complex, it began to make sense (6). Their microtubule structure is also very unusual, they are very stable and resistant to most microtubule depolymerizing drugs. They are located below the inner membrane, begin at the apical polar rings (structures of unknown composition and function) and end near the nucleus (7).
Figure 2: Invasive forms of Plasmodium. Top: merozoite. This form is non-motile and invades erythrocytes. Middle: sporozoite. This form is motile and invades mosquito
salivary glands and liver cells. Bottom: ookinete. This form is motile and invades mosquito gut epithelial cells (3)
Figure 3: Small actin polymers are thought to function as the framework upon which movement occurs beneath the plasma membrane of motile Plasmodium parasites. The direction of parasite movement is shown in the top figure. (i) At the apical ends of motile parasites, actin monomers (white) are captured by auxiliary proteins, possibly capping proteins or formins (pink), and begin polymerization. (ii) The short actin polymers, stabilized by additional components (dark green), are attached to transmembrane receptors of the TRAP family (light green) through bridging molecules, possibly aldolase (blue). These complexes are the framework used by the parasite to bridge the myosin causing the movement and the substrate along which the parasite is moving. The directionality of actin filaments is indicated. (iii) The actin–transmembrane-receptor scaffolds interact with the MyoA motor (yellow), which moves towards the plus end of the actin polymers and is tethered to the inner membrane complex (IMC) by accessory
The genome of the P. falciparum laboratory strain 3D7 (the strain used in many experiments) was fully sequenced in 2002. It is composed of 22.8 Mb distributed among 14 chromosomes. The average gene density is 1 gene per 4,338 bp. Excluding introns, the average length of P. falciparum genes is 2.3 kb (10). The chromosomes of the parasite vary considerably in length, which is thought to be due to recombination inside the mosquito vector during meiosis of different strains (10). There are 5,269 predicted proteins, and roughly 60% share little or no similarity to proteins in other organisms and are therefore without functional assignment. It is estimated that about 10% of the total proteins belong to the apicoplast, and about 4% to the mitochondria (10). Different proteins were found to be expressed at different life stages of the parasite. In a study, 2,415 of the total proteins (about 46%) were identified in one of four stages in the life cycle. Only 6% of these were found in all four of the stages. Merozoites contained high levels of cell recognition and invasion proteins, trophozoites contained proteins used for erythrocyte remodeling and hemoglobin digestion, gametocytes contained high amounts of gametocyte-specific transcription factors and cell cycle and DNA processing proteins, and sporozoites contained proteins related to invasion, and members of the virulence families var and rif (11). Virulence is determined mainly by the var , rif and possibly stevor gene families, which encode for the PfEMP1, rifin and stevor proteins. PfEMP1 is P. falciparum erythrocyte membrane protein 1 and is inserted into the infected red blood cell surface. It is considered to be a key adhesive ligand mediating sequestration of red blood cells (12). The rifin (repetitive interspersed family) proteins are also transported to the surface of the infected erythrocyte, but their function is unknown. Both of these protein families
undergo antigenic variation at the red blood cell surface, contributing to the persistent and chronic nature of the disease. Another family of possible virulence factors has also been described, the stevor proteins (subtelomeric variable open reading frame proteins), but their function remains unknown. Therefore, PfEMP1 and rifin proteins are considered the key virulence factors (12).
