Answer:
The malaria parasite is transmitted to the human host when an infected female Anopheles mosquito takes a blood meal and simultaneously injects a small number of sporozoites into the skin. After reaching the liver, the sporozoites invade hepatocytes in which they develop into a liver schizont and replicate asexually. After about seven days of liver stage development, each infected hepatocyte releases up to 40,000 merozoites that enter the peripheral blood stream. Once in the blood stream, merozoites quickly invade circulating red blood cells (RBCs), thereby initiating the repeated asexual replication cycle. Over the course of 48 hours, the parasite progresses through the ring and the trophozoite stages before finally replicating into 8–32 daughter merozoites at the schizont stage (schizogony). At this point, the parasitized RBC (pRBC) ruptures and releases merozoites into circulation, commencing another round of asexual replication. Mature asexual stages that display increased stiffness, trophozoites and schizonts, adhere to the vasculature in various organs, which allows them to avoid splenic clearance. During each cycle, a small subset of parasites divert from asexual replication and instead produce sexual progeny that differentiate the following cycle into male and female sexual forms, known as gametocytes. A subset of parasites (see possible scenarios in Fig 4) leave the peripheral circulation and enter the extravascular space of the bone marrow, where gametocytes mature and progress through stages I–V over the course of eight to ten days (gametocytogenesis). Although evidence suggests that the bone marrow is the primary location of gametocyte maturation, some immature gametocytes have been observed elsewhere in the human body, such as in the spleen. By stage V, male and female gametocytes re-enter peripheral circulation, in which they become competent for infection to mosquitoes. Once ingested by a mosquito, male and female gametocytes rapidly mature into gametes (gametogenesis). Within the midgut, the male gametocyte divides into up to eight flagellated microgametes (exflagellation), whereas the female gametocyte develops into a single macrogamete. Fertilization of a macrogamete by a microgamete results in the formation of a zygote, which undergoes meiosis and develops into an invasive ookinete that penetrates the mosquito gut wall. The ookinete forms an oocyst within which the parasite asexually replicates, forming several thousand sporozoites (sporogony). Upon oocyst rupture, these sporozoites migrate to the salivary glands, where they can be transmitted back to the human host during a blood meal. Asexual parasites (in RBCs) are represented in pale yellow, sexual parasites in green.
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