Malaria pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alison Leibowitz [2]

Overview

Malaria in humans develops in two phases: an exo-erythrocytic (hepatic) and an erythrocytic phase. When an infected mosquito pierces an individual's skin for blood, sporozoites in the mosquito's saliva enter the bloodstream and subsequently migrate to the liver.

Pathophysiology

Malaria is caused by protozoan parasites of the genus Plasmodium (phylum Apicomplexa). In humans, malaria is caused by P. falciparum, P. malariae, P. ovale, and P. vivax. P. vivax is the most common cause of infection, responsible for about 80% of all malaria cases. P. falciparum, the most significant cause of disease, is responsible for about 15% of infections and 90% of deaths.

Life Cycle

The life cycle of Plasmodium parasites begin when the sporozoite, a haploid form of the parasite, is injected into the human bloodstream by the female Anopheles mosquito. The sporozoites travel in the bloodstream to the liver and invade human hepatocytes. Over 1-2 weeks later, in the exo-erythrocytic phase, the sporozoites grow into schizonts and produce thousands of merozoites in each hepatocyte. The merozoite is a haploid form of the parasite. While some hepatocytes rupture and release the merozoites, other parasites remain dormant within the liver. The release of merozoites, by the hepatocytes, into the bloodsteam results in the manifestation of the malarial symptoms. The latency of cell rupture between various hepatocytes and the consequent merozoite release into the bloodstream, is responsible for the characteristic periodic fever associated with malarial infections.

As merozoites are released into the bloodstream, they infect erythrocytes and undergo asexual multiplication (mitosis). Some merozoites continue the cycle of asexual replication into mature trophozoites and schizonts, which rupture to re-release merozoites. Others develop into sexual forms, the gametocytes, which involve male (microgametocyte) and female (macrogametocyte) parasites.

Though biting, Anopheles mosquitos ingest the gametocytes within the red blood cells, initiating the sporogonic cycle inside the mosquito. In the mosquito's gut, the cells burst and the gametocytes are then released, allowing their development into mature gametes. The fusion of male and female gametes forms diploid zygotes, which become ookinetes, motile and elongated forms of the parasites. Within the mosquito midgut wall, they develop into oocysts. As oocysts continue to grow, they divide into active haploid forms, the sporozoites. Thousands of sporozoites are produced in each oocyst. When oocysts burst following 1-2 weeks, sporozoites travel to the mosquito's salivary glands, so that when the mosquito bites other humans they inject the sporozoites into their bloodstream, leading the cycle to restart.

While parasites generally shift from a sporozoite into a morozoite as they invade red blood cells, some species, such as P. vivax and P. ovale are characterized by their ability to produce hypnozoites, an intermediate stage where the parasite remains dormant for a few months/years before reactivation into merozoites. The hypnozoite stage gives these species the capacity to demonstrate late relapses and long incubation periods.

The life cycle of malaria parasites in the human body. The various stages in this process are discussed in the text.

Human Factors

Some human factors may play an advantageous role in the protection against malarial infection. Most importantly, individuals with sickle cell trait, defined as the heterozygous for the abnormal globin gene, HbS, are protected against P. falciparum. It seems that red blood cells invaded by P. falciparum in sickle cell trait patients tend to sickle more readily than other red blood cells, forcing them to be eliminated from the bloodstream by macrophages. Of note, the advantage seen in heterozygous sickle cell patients is not observed in patients who have sickle cell anemia and carry a homozygous sickle gene. On the contrary, these patients are more susceptible to lethal complications of severe anemia. Other similar hematological diseases that provide a protective effect against malaria are thalassemia, hemoglobin C, and G6PD deficiency.

Similarly, individuals who have a negative Duffy blood group are resistant to infection by P. vivax. Nonetheless, they are still susceptible against other species of malaria, namely P. ovale, which often infects patients with negative Duffy blood group.

References

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