Malaria Plasmodium Species Infects 600 Million People Worldwide

Malaria is one of the most devastating diseases in the world today, infecting nearly 10% of the world population and causing 1-2 million deaths every year. Malaria is caused by various species of the genus Plasmodium, of which P. falci-parum is the most virulent and prevalent. The alarming development of multiple-drug resistance in Plasmodium and the increased resistance of its vector, the Anopheles mosquito, to DDT underscore the importance of developing new strategies to hinder the spread of malaria.

PLASMODIUM LIFE CYCLE AND PATHOGENESIS OF MALARIA

Plasmodium progresses through a remarkable series of developmental and maturational stages in its extremely complex life cycle. Female Anopheles mosquitoes, which feed on blood meals, serve as the vector for Plasmodium, and part of the parasite's life cycle takes place within the mosquito. (Because male Anopheles mosquitoes feed on plant juices, they do not transmit Plasmodium.)

Human infection begins when sporozoites, one of the Plasmodium stages, are introduced into an individual's bloodstream as an infected mosquito takes a blood meal (Figure 17-11). Within 30 min, the sporozoites disappear from the

Gametocytes

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Gametocytes

FIGURE 17-11

The life cycle of Plasmodium. Sporozoites enter the bloodstream when an infected mosquito takes a blood meal. The sporozoites migrate to the liver, where they multiply, transforming liver hepatocytes into giant multinucleate schizonts, which release thousands of merozoites into the bloodstream. The merozoites infect red blood cells, which eventually rupture, releasing more merozoites. Eventually some of the merozoites differentiate into male and female gametocytes, which are ingested by a mosquito and differentiate into gametes. The gametes fuse to form a zygote that differentiates to the sporozoite stage within the salivary gland of the mosquito.

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Gametocytes

FIGURE 17-11

The life cycle of Plasmodium. Sporozoites enter the bloodstream when an infected mosquito takes a blood meal. The sporozoites migrate to the liver, where they multiply, transforming liver hepatocytes into giant multinucleate schizonts, which release thousands of merozoites into the bloodstream. The merozoites infect red blood cells, which eventually rupture, releasing more merozoites. Eventually some of the merozoites differentiate into male and female gametocytes, which are ingested by a mosquito and differentiate into gametes. The gametes fuse to form a zygote that differentiates to the sporozoite stage within the salivary gland of the mosquito.

blood as they migrate to the liver, where they infect hepato-cytes. Sporozoites are long, slender cells that are covered by a 45-kDa protein called circumsporozoite (CS) antigen, which appears to mediate their adhesion to hepatocytes. The binding site on the CS antigen is a conserved region in the carboxyl-terminal end (called region II) that has a high degree of sequence homology with known cell-adhesion molecules.

Within the liver, the sporozoites multiply extensively and undergo a complex series of transformations that culminate in the formation and release of merozoites in about a week. It has been estimated that a liver hepatocyte infected with a single sporozoite can release 5,000-10,000 merozoites. The released merozoites infect red blood cells, initiating the symptoms and pathology of malaria. Within a red blood cell, merozoites replicate and undergo successive differentiations; eventually the cell ruptures and releases new merozoites, which go on to infect more red blood cells. Eventually some of the merozoites differentiate into male and female gameto-cytes, which may be ingested by a female Anopheles mosquito during a blood meal. Within the mosquito's gut, the male and female gametocytes differentiate into gametes that fuse to form a zygote, which multiplies and differentiates into sporo-zoites within the salivary gland. The infected mosquito is now set to initiate the cycle once again.

The symptoms of malaria are recurrent chills, fever, and sweating. The symptoms peak roughly every 48 h, when successive generations of merozoites are released from infected red blood cells. An infected individual eventually becomes weak and anemic and shows splenomegaly. The large numbers of merozoites formed can block capillaries, causing intense headaches, renal failure, heart failure, or cerebral damage—often with fatal consequences. There is speculation that some of the symptoms of malaria may be caused not by Plasmodium itself but instead by excessive production of cytokines. This hypothesis stemmed from the observation that cancer patients treated in clinical trials with recombinant tumor necrosis factor (TNF) developed symptoms that mimicked malaria. The relation between TNF and malaria symptoms was studied by infecting mice with a mouse-specific strain of Plasmodium, which causes rapid death by cerebral malaria. Injection of these mice with antibodies to TNF was shown to prevent the rapid death.

HOST RESPONSE TO PLASMODIUM INFECTION

In regions where malaria is endemic, the immune response to Plasmodium infection is poor. Children less than 14 years old mount the lowest immune response and consequently are most likely to develop malaria. In some regions, the childhood mortality rate for malaria reaches 50%, and worldwide the disease kills about a million children a year. The low immune response to Plasmodium among children can be demonstrated by measuring serum antibody levels to the sporozoite stage. Only 22% of the children living in endemic areas have detectable antibodies to the sporozoite stage, whereas 84% of the adults have such antibodies. Even in adults, the degree of immunity is far from complete, however, and most people living in endemic regions have lifelong low-level Plasmodium infections.

A number of factors may contribute to the low levels of immune responsiveness to Plasmodium. The maturational changes from sporozoite to merozoite to gametocyte allow the organism to keep changing its surface molecules, resulting in continual changes in the antigens seen by the immune system. The intracellular phases of the life cycle in liver cells and erythrocytes also reduce the degree of immune activation generated by the pathogen and allow the organism to multiply while it is shielded from attack. Furthermore, the most accessible stage, the sporozoite, circulates in the blood for only about 30 min before it infects liver hepatocytes; it is unlikely that much immune activation can occur in such a short period of time. And even when an antibody response does develop to sporozoites, Plasmodium has evolved a way of overcoming that response by sloughing off the surface CS-antigen coat, thus rendering the antibodies ineffective.

DESIGN OF MALARIA VACCINES

An effective vaccine for malaria should maximize the most effective immune defense mechanisms. Unfortunately, little is known of the roles that humoral and cell-mediated responses play in the development of protective immunity to this disease. Current approaches to design of malaria vaccines focus largely on the sporozoite stage. One experimental vaccine, for example, consists of Plasmodium sporozoites attenuated by x-irradiation. In one study, nine volunteers were repeatedly immunized by the bite of P. falciparum-infected, irradiated mosquitoes. Later challenge by the bites of mosquitoes infected with virulent P. falciparum revealed that six of the nine recipients were completely protected. These results are encouraging, but translating these findings into mass immunization remains problematic. Sporozoites do not grow well in cultured cells, so an enormous insectory would be required to breed mosquitoes in which to prepare enough irradiated sporozoites to vaccinate just one small village.

Current vaccine strategies are aimed at producing synthetic subunit vaccines consisting of epitopes that can be recognized by T cells and B cells. While no effective vaccine has been developed, this is an active area of investigation.

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Responses

  • sayid
    Where gamets fuse malaria plasmodium?
    3 years ago

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