Malaria and the physiology of parasitic infections

Malaria is a disease caused by a unicellular parasite known as Plasmodium. Although more than 100 different species of Plasmodium exist, only four types are known to infect humans including, Plasmodium falciparum, vivax, malariae, and ovale. While each type has a distinct appearance under the microscope , they each can cause a different pattern of symptoms. Plasmodium falciparum is the major cause of death in Africa, while Plasmodium vivax is the most geographically widespread of the species and the cause of most malaria cases diagnosed in the United States. Plasmodium malariae infections produce typical malaria symptoms that persist in the blood for very long periods, sometimes without ever producing symptoms. Plasmodium ovale is rare, and is isolated to West Africa. Obtaining the complete sequence of the Plasmodium genome is currently under way.

The life cycle of Plasmodium relies on the insect host (for example, the Anopheles mosquito) and the carrier host (humans) for its propagation. In the insect host, the Plasmodium parasite undergoes sexual reproduction by uniting two sex cells producing what are called sporozoites. When an infected mosquito feeds on human blood, the sporozoites enter into the bloodstream. During a mosquito bite, the saliva containing the infectious sporozoite from the insect is injected into the bloodstream of the human host and the blood that the insect removes provides nourishment for her eggs. The parasite immediately is targeted for a human liver cell, where it can escape from being destroyed by the immune system . Unlike in the insect host, when the sporozoite infects a single liver cell from the human host, it can undergo asexual reproduction (multiple rounds consisting of replication of the nucleus followed by budding to form copies of itself).

During the next 72 hours, a sporozoite develops into a schizont, a structure containing thousands of tiny rounded merozoites. Schizont comes from the Greek word schizo, meaning to tear apart. One infectious sporozoite can develop into 20,000 merozoites. Once the schizont matures, it ruptures the liver cells and leaks the merozoites into the bloodstream where they attack neighboring erythrocytes (red blood cells, RBC). It is in this stage of the parasite life cycle that disease and death can be caused if not treated. Once inside the cytoplasm of an erythrocyte, the parasite can break down hemoglobin (the primary oxygen transporter in the body) into amino acids (the building blocks that makeup protein). A byproduct of the degraded hemoglobin is hemozoin, or a pigment produced by the breakdown of hemoglobin. Golden-brown to black granules are produced from hemozoin and are considered to be a distinctive feature of a blood-stage parasitic infection. The blood-stage parasites produce schizonts, which rupture the infected erythrocytes, releasing many waste products, explaining the intermittent fever attacks that are associated with malaria.

The propagation of the parasite is ensured by a certain type of merozoite, that invades erythrocytes but does not asexually reproduce into schizonts. Instead, they develop into gametocytes (two different forms or sex cells that require the union of each other in order to reproduce itself). These gametocytes circulate in the human's blood stream and remain quiescent (dormant) until another mosquito bite, where the gametocytes are fertilized in the mosquito's stomach to become sporozoites. Gametocytes are not responsible for causing disease in the human host and will disappear from the circulation if not taken up by a mosquito. Likewise, the salivary sporozoites are not capable of re-infecting the salivary gland of another mosquito. The cycle is renewed upon the next feeding of human blood. In some types of Plasmodium, the sporozoites turn into hypnozoites, a stage in the life cycle that allows the parasite to survive but in a dormant phase. A relapse occurs when the hypnozoites are reverted back into sporozoites.

An infected erythrocyte has knobs on the surface of the cells that are formed by proteins that the parasite is producing during the schizont stage. These knobs are only found in the schizont stage of Plasmodium falciparum and are thought to be contacted points between the infected RBC and the lining of the blood vessels. The parasite also modifies the erythrocyte membrane itself with these knob-like structures protruding at the cell surface. These parasitic-derived proteins that provide contact points thereby avoid clearance from the blood stream by the spleen. Sequestration of schizont-infected erythrocytes to blood vessels that line vital organ such as the brain, lung, heart, and gut can cause many health-related problems.

A malaria-infected erythrocyte results in physiological alterations that involve the function and structure of the erythrocyte membrane. Novel parasite-induced permeation pathways (NPP) are produced along with an increase, in some cases, in the activity of specific transporters within the RBC. The NPP are thought to have evolved to provide the parasite with the appropriate nutrients, explaining the increased permeability of many solutes. However, the true nature of the NPP remains an enigma. Possible causes for the NPP include 1) the parasite activates native transporters, 2) proteins produced by the parasite cause structural defects, 3) plasmodium inserts itself into the channel thus affecting it's function, and 4) the parasite makes the membrane more 'leaky'. The properties of the transporters and channels on a normal RBC differ dramatically from that of a malaria-infected RBC. Additionally, the lipid composition in terms of its fatty acid pattern is significantly altered, possibly due to the nature in which the parasite interacts with the membrane of the RBC. The dynamics of the membranes, including how the fats that makeup the membrane are deposited, are also altered. The increase in transport of solutes is bidirectional and is a function of the developmental stage of the parasite. In other words, the alterations in erythrocyte membrane are proportional to the maturation of the parasite.

See also Parasites