The malaria parasite has a complex, multistage life cycle occurring within two living beings, the vector mosquitoes and the vertebrate hosts. The survival and development of the parasite within the invertebrate and vertebrate hosts, in intracellular and extracellular environments, is made possible by a toolkit of more than 5,000 genes and their specialized proteins that help the parasite to invade and grow within multiple cell types and to evade host immune responses.[1,2] The parasite passes through several stages of development such as the sporozoites (Gr. Sporos = seeds; the infectious form injected by the mosquito), merozoites (Gr. Meros = piece; the stage invading the erythrocytes), trophozoites (Gr. Trophes = nourishment; the form multiplying in erythrocytes), and gametocytes (sexual stages) and all these stages have their own unique shapes and structures and protein complements. The surface proteins and metabolic pathways keep changing during these different stages, that help the parasite to evade the immune clearance, while also creating problems for the development of drugs and vaccines.
Video Depicting the Life Cycle of Malaria parasite
Sporogony Within the Mosquitoes:
Mosquitoes are the definitive hosts for the malaria parasites, wherein the sexual phase of the parasite’s life cycle occurs. The sexual phase is called sporogony and results in the development of innumerable infecting forms of the parasite within the mosquito that induce disease in the human host following their injection with the mosquito bite.
When the female Anopheles draws a blood meal from an individual infected with malaria, the male and female gametocytes of the parasite find their way into the gut of the mosquito. The molecular and cellular changes in the gametocytes help the parasite to quickly adjust to the insect host from the warm-blooded human host and then to initiate the sporogonic cycle. The male and female gametes fuse in the mosquito gut to form zygotes, which subsequently develop into actively moving ookinetes that burrow into the mosquito midgut wall to develop into oocysts. Growth and division of each oocyst produces thousands of active haploid forms called sporozoites. After the sporogonic phase of 8–15 days, the oocyst bursts and releases sporozoites into the body cavity of the mosquito, from where they travel to and invade the mosquito salivary glands. When the mosquito thus loaded with sporozoites takes another blood meal, the sporozoites get injected from its salivary glands into the human bloodstream, causing malaria infection in the human host. It has been found that the infected mosquito and the parasite mutually benefit each other and thereby promote transmission of the infection. The Plasmodium-infected mosquitoes have a better survival and show an increased rate of blood-feeding, particularly from an infected host.[3-5]
Schizogony in the Human Host:
Man is the intermediate host for malaria, wherein the asexual phase of the life cycle occurs. The sporozoites inoculated by the infested mosquito initiate this phase of the cycle from the liver, and the latter part continues within the red blood cells, which results in the various clinical manifestations of the disease.
Pre-erythrocytic Phase – Schizogony in the Liver:
With the mosquito bite, tens to a few hundred invasive sporozoites are introduced into the skin. Following the intradermal deposition, some sporozoites are destroyed by the local macrophages, some enter the lymphatics, and some others find a blood vessel.[6–8] The sporozoites that enter a lymphatic vessel reach the draining lymph node wherein some of the sporozoites partially develop into exoerythrocytic stages and may also prime the T cells to mount a protective immune response.
The sporozoites that find a blood vessel reach the liver within a few hours. It has recently been shown that the sporozoites travel by a continuous sequence of stick-and-slip motility, using the thrombospondin-related anonymous protein (TRAP) family and an actin–myosin motor.[7,10,11][See video from ref.10] The sporozoites then negotiate through the liver sinusoids, and migrate into a few hepatocytes, and then multiply and grow within parasitophorous vacuoles. Each sporozoite develop into a schizont containing 10,000–30,000 merozoites (or more in case of P. falciparum).[12–14] The growth and development of the parasite in the liver cells is facilitated by a a favorable environment created by the The circumsporozoite protein of the parasite.[15,16] The entire pre-eryhrocytic phase lasts about 5–16 days depending on the parasite species: on an average 5-6 days for P. falciparum, 8 days for P. vivax, 9 days for P. ovale, 13 days for P. malariae and 8-9 days for P. knowlesi.[Also See] The pre-erythrocytic phase remains a “silent” phase, with little pathology and no symptoms, as only a few hepatocytes are affected. This phase is also a single cycle, unlike the next, erythrocytic stage, which occurs repeatedly.
The merozoites that develop within the hepatocyte are contained inside host cell-derived vesicles called merosomes that exit the liver intact, thereby protecting the merozoites from phagocytosis by Kupffer cells. These merozoites are eventually released into the blood stream at the lung capillaries and initiate the blood stage of infection thereon.
In P. vivax and P. ovale malaria, some of the sporozoites may remain dormant for months within the liver. Termed as hypnozoites, these forms develop into schizonts after some latent period, usually of a few weeks to months. It has been suggested that these late developing hypnozoites are genotypically different from the sporozoites that cause acute infection soon after the inoculation by a mosquito bite,[18,19] and in many patients cause relapses of the clinical infection after weeks to months.
Erythrocytic Schizogony – Centre Stage in Red Cells
Red blood cells are the ‘centre stage’ for the asexual development of the malaria parasite. Within the red cells, repeated cycles of parasitic development occur with precise periodicity, and at the end of each cycle, hundreds of fresh daughter parasites are released that invade more number of red cells.
The merozoites released from the liver recognize, attach, and enter the red blood cells (RBCs) by multiple receptor–ligand interactions in as little as 60 seconds. This quick disappearance from the circulation into the red cells minimises the exposure of the antigens on the surface of the parasite, thereby protecting these parasite forms from the host immune response.[1,8,20] The invasion of the merozoites into the red cells is facilitated by molecular interactions between distinct ligands on the merozoite and host receptors on the erythrocyte membrane. P. vivax invades only Duffy blood group-positive red cells, using the Duffy-binding protein and the reticulocyte homology protein, found mostly on the reticulocytes. the more virulent P. falciparum uses several different receptor families and alternate invasion pathways that are highly redundant. Varieties of Duffy binding-like (DBL) homologous proteins and the reticulocyte binding-likehomologous proteins of P. falciparum recognize different RBC receptors other than the Duffy blood group or the reticulocyte receptors. Such redundancy is helped by the fact that P. falciparum has four Duffy binding-like erythrocyte-binding protein genes, in comparison to only one gene in the DBL-EBP family as in the case of P. vivax, allowing P. falciparum to invade any red cell.[21,22]
The process of attachment, invasion, and establishment of the merozoite into the red cell is made possible by the specialized apical secretory organelles of the merozoite, called the micronemes, rhoptries, and dense granules. The initial interaction between the parasite and the red cell stimulates a rapid “wave” of deformation across the red cell membrane, leading to the formation of a stable parasite–host cell junction. Following this, the parasite pushes its way through the erythrocyte bilayer with the help of the actin–myosin motor, proteins of the thrombospondin-related anonymous protein family (TRAP) and aldolase, and creates a parasitophorous vacuole to seal itself from the host-cell cytoplasm, thus creating a hospitable environment for its development within the red cell. At this stage, the parasite appears as an intracellular “ring”.[20,23,24]
Within the red cells, the parasite numbers expand rapidly with a sustained cycling of the parasite population. Even though the red cells provide some immunological advantage to the growing parasite, the lack of standard biosynthetic pathways and intracellular organelles in the red cells tend to create obstacles for the fast-growing intracellular parasites. These impediments are overcome by the growing ring stages by several mechanisms: by restriction of the nutrient to the abundant hemoglobin, by dramatic expansion of the surface area through the formation of a tubovesicular network, and by export of a range of remodeling and virulence factors into the red cell. Hemoglobin from the red cell, the principal nutrient for the growing parasite, is ingested into a food vacuole and degraded. The amino acids thus made available are utilized for protein biosynthesis and the remaining toxic heme is detoxified by heme polymerase and sequestrated as hemozoin (malaria pigment). The parasite depends on anaerobic glycolysis for energy, utilizing enzymes such as pLDH, plasmodium aldolase etc. As the parasite grows and multiplies within the red cell, the membrane permeability and cytosolic composition of the host cell is modified.[25,26] These new permeation pathways induced by the parasite in the host cell membrane help not only in the uptake of solutes from the extracellular medium but also in the disposal of metabolic wastes, and in the origin and maintenance of electrochemical ion gradients. At the same time, the premature hemolysis of the highly permeabilized infected red cell is prevented by the excessive ingestion, digestion, and detoxification of the host cell hemoglobin and its discharge out of the infected RBCs through the new permeation pathways, thereby preserving the osmotic stability of the infected red cells.[25,26]
The erythrocytic cycle occurs every 24 hours in case of P. knowlesi, 48 h in cases of P. falciparum, P. vivax and P. ovale and 72 h in case of P. malariae. During each cycle, each merozoite grows and divides within the vacuole into 8–32 (average 10) fresh merozoites, through the stages of ring, trophozoite, and schizont. At the end of the cycle, the infected red cells rupture, releasing the new merozoites that in turn infect more RBCs. With sunbridled growth, the parasite numbers can rise rapidly to levels as high as 1013 per host.
A small proportion of asexual parasites do not undergo schizogony but differentiate into the sexual stage gametocytes. These male or female gametocytes are extracellular and nonpathogenic and help in transmission of the infection to others through the female anopheline mosquitoes, wherein they continue the sexual phase of the parasite’s life cycle. Gametocytes of P. vivax develop soon after the release of merozoites from the liver, whereas in case of P. falciparum, the gametocytes develop much later with peak densities of the sexual stages typically occurring 1 week after peak asexual stage densities.[27,28]
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