Erythrocyte Invasion by Plasmodium Merozoite
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Erythrocyte Invasion by Plasmodium Merozoite
Human Malaria is caused by infection with four species of the intracellular parasitic protozoan genus Plasmodium that are transmitted by Anopheles mosquitoes. Of these four species, Plasmodium falciparum is the most lethal. At present, at least 300 million people are affected by Malaria globally and accounts for 0.7-2.7 million annual deaths. The life cycle of the Malarial parasite requires specialized protein expression for life in mammals and insects, intracellular and extracellular environments, and evasion of host immune response. Life cycle of Plasmodium inside human body can be broadly classified into 2 phases: Pre/ Exo-erythrocytic phase, and Erythrocytic phase. The Asexual Erythrocytic phase in the life cycle of Malarial parasites produces the clinical symptoms and pathology associated with infection. The Erythrocytic phase starts when the Plasmodium Merozoites infect RBCs (Red Blood Cells). Merozoites are generated either by Sporozoites in the liver, or Trophozoite division in RBCs. Malaria Merozoite invasion process is complex and involved in the multi-step sequence which can be divided into four phases: Initial Recognition and Reversible Attachment of the Merozoite to the Erythrocyte membrane; Reorientation and Junction formation between the Apical end of the Merozoite (Irreversible Attachment) and the release of Rhoptry-Microneme substances with Parasitophorous Vacuole formation; movement of the Junction and Invagination of the Erythrocyte membrane around the Merozoite accompanied by removal of the Merozoite’s surface coat, and finally resealing of the PVM (Parasitophorous Vacuole Membrane) and Erythrocyte membrane after completion of Merozoite invasion (Ref.1).

The initial interaction between the Merozoite and the Erythrocyte is probably a random collision, which is highly dependent on specific molecular interactions between parasite ligands on the Merozoite and host receptors on the Erythrocyte membrane. However, these molecular interactions are not completely defined. Proteins on the surface and in the apical organelles of the Merozoites mediate cell recognition and invasion into the RBCs. This invasive process is conducted by an Actin-Myosin motor process, which involves four components, the MCP1 (Merozoite Cap Protein-1), Actin, MyosinA and MTIP (MyosinA Tail Interacting Protein). MSP1 (Merozoite Surface Protein-1), with GPI (Glycosyl Phosphatidyl Inositol) anchor; also called MSA1, gp195 or PMMSA could be involved in the initial recognition of the Erythrocyte in a Sialic Acid-dependent way. Three other P. falciparum-Merozoite Surface Proteins, named MSP2, MSP3 and MSP4, have been identified. Sialic Acid on Glycophorins are involved in receptor recognition for Merozoite invasion after initial attachment. The microneme derived 175-kD EBA175 (Erythrocyte-Binding Antigen-175) of P. falciparum also binds to Sialic Acids on Glycophorin. The gene structure of EBA175 has striking similarities with the Duffy-Binding Proteins of P. vivax and P. knowlesi. EBA175 seems to be the most important ligand for binding of Merozoites to GlycophorinA on the Erythrocytes; however, some P. falciparum Merozoites can utilize alternative pathways for invasion. GlycophorinB can also act as an Erythrocyte receptor. Furthermore malaria Merozoites can utilize independent pathways for invasion without Sialic Acid. Other vacuolar proteins, such as the ABRA (Acidic Basic Repeat Antigen) and SERA (Serine Repeat Antigen) are also found in Merozoite.  Many apical organellar proteins in the Micronemes and Rhoptries, which include, AMA1 (Apical Membrane Antigen-1) and MAEBL (in Rodent Malaria) are also present in Merozoite. Components of the low molecular mass Rhoptry Complex, the RAP1 (Rhoptry-Associated Protein-1), RAP2 and RAP3, also occur in Merozoites. The high molecular mass Rhoptry protein Complex (RhopH), together with RESA (Ring-infected Erythrocyte Surface Antigen), which is a component of dense granules, is transferred intact to new Erythrocytes at or after Invasion and may contribute to the host cell remodeling process. RhopH1 (High Molecular Weight Rhoptry Protein-1), RhopH2 (High Molecular Weight Rhoptry Protein-2) and RhopH3 (High Molecular Weight Rhoptry Protein-3) are found in the Merozoite proteome. The Merozoite develops within the Erythrocyte through ring, Trophozoite and Schizont stages (Erythrocytic Schizogony) (Ref.2).

After binding to the Erythrocyte, the parasite reorients itself so that a junction is formed between the apical end of the Merozoite and Erythrocyte membrane. This Merozoite reorientation also coincides with a transient Erythrocyte deformation. Specialized secretory organelles are located at the Apical end of the invasive stages of the parasite. Three morphologically distinct apical organelles are detected by electron microscopy: Micronemes, Rhoptries, and Dense Granules. The contents of the Apical organelles are expelled as the Parasite invades, thus suggesting that these organelles play some role in invasion. As the invasion progresses, the depression of the Erythrocyte membrane deepens and conforms to the shape of the Merozoite. The junction is no longer observed at the initial attachment point but now appears at the orifice of the Merozoite-induced invagination of the Erythrocyte membrane. An increase in the cytoplasmic concentration of calcium is associated with Microneme discharge, as is typical of regulated secretion in other eukaryotes. The Rhoptries are discharged immediately after the micronemes and the release of their contents correlate with the formation of the Parasitophorous vacuole. Dense granule contents are released after the parasite has completed its entry, and therefore, are usually implicated in the modification of the host cell. During host cell invasion, no surface coat is visible on the portion of the Merozoite within the Erythrocyte invagination, whereas the surface coat on the portion of the Merozoite still outside the Erythrocyte appears similar to that seen on the free Merozoites. When the Merozoite has completed entry, the junction fuses at the posterior end of the Merozoite, closing the orifice in the fashion of an iris diaphragm. The Merozoite still remains in close apposition to the thickened Erythrocyte membrane at the point of final closure (Ref.3).

After completion of host cell entry, the Merozoite is now surrounded by the PVM. As the Incipient Parasitophorous vacuole is being formed, the junction between the parasite and host becomes ring-like and the parasite appears to move through this annulus as it enters the expanding Parasitophorous Vacuole. The Merozoite moves through the ring-shaped tight junction formed by the receptor/ligand complex. The force is generated by Myosin motors associated with the trans-membrane parasite ligands moving along Actin filaments within the parasite. Myosin motors, presumably associated with the cytoplasmic portion of the parasite ligands, could move along Actin filaments within the parasite and drag the transmembrane ligand/receptor complexes through the fluid lipid bilayer toward the parasite posterior. The movement of the ring-like junction between the parasite and host towards the posterior of the Merozoite results in a forward movement of the parasite into the host cell. Once the parasite has completed its entry, the tight junction will disappear and the respective PVM and the host Erythrocyte membrane will fuse and separate, thus completing the entry process (Ref.4).

Then the Merozoite rounds up due to the rapid degradation of the inner membrane complex and sub-pellicular microtubules of the pellicular complex, and becomes a Trophozoite. Dense granules within the Merozoite move to the Merozoite pellicle, and the contents of dense granules are released into the Parasitophorous Vacuole space. Molecules such as nutrients must cross the PVM from the host cell to the parasite and other molecules, such as metabolites and parasite synthesized surface proteins (e.g. knob proteins), must cross the PVM in the opposite direction. The Trophozoite survives intracellularly by ingesting host cell cytoplasm through a circular structure named the Cytostome. The Cytostome possesses a double-membrane, consisting of an outer membrane (parasite plasmalemma) and an inner membrane (PVM). KAHRP (Knob-Associated Histidine-Rich Protein) and EMP2 and 3 (Erythrocyte Membrane Proteins-2 and 3) bind to the Erythrocyte cytoskeleton. Of the proteins of the Parasitophorous Vacuole and the tubovesicular membrane structure extending into the cytoplasm of the RBC, three (the Skeleton-Binding Protein 1, and exported proteins EXP1 and EXP2) were represented by peptides; although a fourth (Sar1 homologue, small GTP-binding protein; PFD0810w) was not (Ref.5).

Malaria parasites use host Hemoglobin as a source of amino acids; however, they cannot degrade the hemoglobin heme byproduct. Free heme is potentially toxic to the parasite. Therefore during Hemoglobin degradation, most of the liberated Heme is polymerized into Hemozoin (Malaria pigment), which is stored within the food vacuoles. The Plasmodium contains members of Plasmapepsin family (Aspartic proteinase), Falcipain family (Cysteine Proteases), and Falcilysin (a metallo peptidase), which have been implicated in the digestion of Haemoglobin.  In the next phase of Schizogony (the final  18 h of the asexual development in the blood cell), nuclear division is followed by Merozoite formation and release. Several proteases expressed in the Merozoite and Trophozoite fractions, and not involved in Haemoglobin digestion, may be important in Parasite release at the end of schizogony, invasion of the new cell, or Merozoite protein processing. Possible candidates for this mechanism include cysteine proteinases of the falcipain and SERA families, or subtilisins such as SUB1 and SUB2, both located in apical organelles. Concomitantly, a small portion of the parasites differentiates from newly invaded Merozoites into sexual forms, which are Macrogametocyte (female) and Microgametocyte (male). They are arrested in the cell cycle until they enter the mosquito where development is induced within minutes to form the male and female gametes. During this Intraerythrocytic period, the parasite modifies the host to make it a more suitable habitat. Another modification of the host cell concerns the cytoadherence of P. falciparum-infected Erythrocytes to endothelial cells and the resulting sequestration of the mature parasites in capillaries and post-capillary venules. This sequestration likely leads to microcirculatory alterations and metabolic dysfunctions, which could be responsible for many of the manifestations of severe Falciparum malaria (Ref.6).