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The Plasmodium species that infect humans have a complex life cycle that involves both asexual and sexual reproductive stages (Figure 3.10). They are all transmitted by Anopheline mosquitoes and multiplication takes place in both humans and the mosquito vector. Only female mosquitoes feed on blood, as they require nutrients contained within it to produce their eggs. Male mosquitoes feed on nectar and other sugary solutions, and therefore, only female mosquitoes transmit malaria.

Figure 3.10 Life cycle of Plasmodium falciparum. 1: An infected mosquito injects sporozoites into the blood stream and these travel to the liver. The sporozoites invade the hepatocytes and undergo exoerythrocytic schizogony to produce numerous merozoites. 2: Merozoites leave the liver cells, enter the circulation, and infect red blood cells. They transform into ring‐shaped trophozoites that develop into schizonts (erythrocytic schizogony), which then form numerous merozoites. The parasites export proteins that re‐model the cell membrane of infected red blood cells so that ‘knobs’ are formed. When an infected cell dies, it releases merozoites that reinfect other red blood cells. 3: At some point, merozoites develop into male and female gametocytes. Those of P. falciparum have a characteristic banana shape that deforms the host red blood cell. 4: After ingestion by a mosquito, the male and female gametocytes are released from the red blood cells and fuse to form a zygote. 5: The zygote differentiates into an ookinete that invades a mosquito gut cell within which it forms an oocyst. The oocyst undergoes sporogony to form numerous sporozoites that are released into the haemolymph. 6: The sporozoites penetrate the mosquito salivary glands and are transmitted within mosquito’s saliva when it feeds. Drawings not to scale.

We contract malaria when a female mosquito harbouring the sporozoite stage of the parasite bites us. The sporozoites enter our body with her saliva and the blood stream transports them to the liver where they penetrate the hepatocytes (liver cells). Within the hepatocytes, the sporozoites change their morphology and multiply asexually by ‘exoerythrocytic schizogony’ to form thousands of merozoites. The term exoerythrocytic indicates that the reproduction takes place in cells other than the red blood cells. Schizogony is a form of asexual reproduction in which first, the nucleus divides several times and then the parent cell divides to form as many individual merozoites as there are nuclei. Schizogony also occurs in many other apicomplexan parasites. In P. vivax and P. ovale, not all the parasites immediately undergo schizogony but instead some remain in a quiescent state known as the hypnozoite form. These hypnozoites can remain in the liver for weeks or even years before undergoing further development. They are therefore responsible for the onset of illness/relapses long after the initial infection.

The formation of merozoites destroys their host liver cells, thereby releasing them into the blood stream. The merozoites proceed to invade red blood cells in which they transform into the trophozoite stage – these also reproduce asexually by shizogony. Because these divisions take place in red blood cells, it is referred to as erythrocytic schizogony. The ingestion of host cytoplasm by a trophozoite causes the formation of a large food vacuole. This gives the parasite the appearance of a ring of cytoplasm with the nucleus conspicuously displayed at one edge – hence, the moniker of the ‘signet ring stage’. As the trophozoite grows, its food vacuole becomes less noticeable by light microscopy, but pigment granules of hemozoin in the vacuoles become apparent. Hemozoin is an insoluble polymer of haem and is the end product of the parasite’s digestion of the host’s haemoglobin. The growth of the parasites within an infected red blood cell eventually destroys it and it ruptures. This releases the merozoites, hemozoin and other parasite waste products, and dead cell material. These merozoites then infect other red blood cells and the process of infection, replication, and destruction repeats many times. At some point in this cycle, certain merozoites transform into sexual stages referred to as macrogametocytes (female) and microgametocytes (male). These gametocytes do not develop any further and remain within their host red blood cells until a suitable female anopheline mosquito ingests them.

Shortly after ingestion by a mosquito, the male and female gametocytes swell, leave their host red blood cells, locate one another, and fuse to form a zygote. This is the only diploid stage in the whole Plasmodium life cycle. The zygote then differentiates into an ookinete. The ookinete is capable of movement and it bores through the mosquito’s gut until it comes to rest at the outer wall of the midgut epithelium where it transforms into an oocyst. Inside the oocyst further rounds of asexual multiplication take place called sporogony that result in the formation of numerous sporozoites. Once it is mature, the oocyst bursts and the sporozoites migrate through the mosquito’s haemolymph (blood) to the salivary glands. The next time the mosquito feeds, it injects the sporozoites along with its saliva. Depending upon the species of Plasmodium and mosquito, the oocyst stage lasts between 8 and 35 days, thereby making it the longest part of the life cycle. It also means that successful transmission depends heavily on the lifespan of the mosquito. This is because the mosquito must survive long enough after its initial infected blood meal for the sporozoites to form and then reach its salivary glands. Infection stimulates mosquitoes to feed more frequently, thus increasing the chances of transmission. Once infected, a mosquito remains infective for the rest of her life.