Malaria pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Malaria in humans develops via two phases: an exoerythrocytic (hepatic) and an erythrocytic phase. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and 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. However, P. falciparumis the most important cause of disease, and responsible for about 15% of infections and 90% of deaths.

Life Cycle

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

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

The bite of Anopheles mosquito allows it to 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 that become ookinetes, which are motile and elongated forms of the parasites. Later, they develop into oocysts within the mosquito midgut wall. As oocysts continue to grow, they divide and form active haploid forms, the sporozoites. Thousands of sporozoites are produced in each oocyst. The latter bursts after 1-2 weeks and sporozoites travel to the mosquito salivary glands to re-infect humans when the mosquito bites humans and inject the sporozoite into the bloodstream, allowing the cycle of 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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