What is malaria? |

Causes and Symptoms

Malaria



in humans is caused by transfer into the bloodstream, through the saliva of the Anopheles mosquito, of the protozoan (single-cell) Plasmodium parasite. There are several different strains of the malaria parasite, all belonging to the phylum Sporozoa, a classification connected with the importance of spores in the organism’s reproductive cycle. Serious and potentially lethal malarial infections in humans are primarily associated with P. falciparum. Other Plasmodium parasites that can produce infection are P. vivax (formerly present in temperate climate zones but now found only in the subtropics), P. malariae (also only subtropical), and P. ovale (quite rare, and mainly limited to West Africa). Other Plasmodium parasites infect only nonhuman primates (P. knowlesi and P. cynomolgi, for example),
only rodents (four different species), or only birds (P. cathemerium and P. gallinaceum). The latter two species have been used widely in experimental testing of antimalarial vaccines.

It is important to note that only one mosquito genus, Anopheles, and only the female Anopheles mosquito, serves the vector function in transmitting malaria. The explanation of the female’s role is surprisingly simple: Only the female Anopheles nourishes itself (usually in the night hours) by piercing the skin of its victim and sucking small quantities of blood. The male of the species feeds mainly on fruit juices.

In the most common scenario, the mosquito ingests the Plasmodium parasite when it sucks the blood of an already infected human. This phase is followed by several others—all connected with the reproductive processes of the same organism (both sexual and asexual)—until subsequent generations of the parasite are passed on by the mosquito to another human host, who then becomes infected. The protozoan’s first, sexual stage of reproduction occurs when male gametes emit flagella that seek out and join their female counterpart, producing a fertilized zygote. Once lodged in the gut tissue of the mosquito in the form of an oocyst, a further, asexual stage of reproduction occurs through what is called sporogony: the release from the oocyst of myriad spores. They spread rapidly throughout the body of the mosquito. Many enter the insect host’s salivary glands, from which they are transferred into the blood of the next human bitten by the mosquito. It is the further development of the spores in the human organism that produces the disease symptoms associated with malaria.

Once transmitted into the human host through the mosquito saliva, the parasite spores flow quickly through the blood, entering the liver. Their next transformation occurs once they lodge themselves in the cells of the liver, becoming what are called hepatic trophozoites. As they feed off of the liver cells, the trophozoites grow and burst open. This process of asexual multiplication in the liver is referred to as hepatic schozogony. At that stage, the parasite has multiplied many hundreds of times, producing the actual agent of malarial disease, merozoites. If the parasite is P. vivax, then this phase may not occur immediately, as a result of a state of dormancy in the parasitic trophozoites. In this case, months or even years can pass before the merozoites are released. Even then, the delayed release is still not final. This explains why some malaria-infected individuals experience a cyclical disappearance of symptoms, followed some time later by a resurgence of the latent disease.

When released from the trophozoites, the merozoites quickly invade the red blood cells of the host. The damage that they inflict leads to anemic reactions as the number of healthy blood cells in the organism decreases. It is not only the liver that is affected; the disease can also spread to the spleen.

Once the effects of malaria begin to take hold in the blood and various organs of the body, certain symptoms will appear. There is an onset of fever, probably caused by the release of a pyrogen (a fever-inducing agent) by the white blood cells reacting to the diseased situation of red blood cells that have been attacked by the malaria parasite. Since this release of pyrogens may follow an irregular pattern, fever can come and go, seemingly sporadically. Meanwhile, as the number of parasitized red blood cells increases, infected red blood cells begin to attach themselves to the inside tissue of capillaries of the internal organs. The effect is blockage of the necessary free flow of blood. If pressure builds because of this blockage, then blood vessels themselves may burst. Such internal hemorrhages allow the directionless dispersion of infected blood within the body, increasing the anemic symptoms that are characteristic of malaria. Perhaps the most dramatic sign of blocked blood vessels occurs if and when the parasitized
cells affect the blood flow to the brain. In such cases, convulsions occur, eventually leading to coma.

Treatment and Therapy

Long before researchers were able to explain the causes of malaria, treatment of its symptoms, primarily manifested in spells of fever, involved giving the patient doses of quinine. As knowledge of the disease increased, different forms of treatment evolved. Such developments occurred not only as new discoveries emerged; they also became necessary as the malaria parasite itself evolved genetically, in effect developing its own immunity to quinine-based treatment.

Several compounds were developed in the later decades of the twentieth century to complement or, more recently, to replace complete dependence on quinine.

Depending on the Plasmodium species coming into contact with it, the alkaloid quinine could kill the parasitical organism at key stages in its reproductive activity. Sometimes, however, toxic side effects accompanied the use of quinine in malaria cases. These negative effects eventually sparked research aimed at producing synthetic drugs that could be as effective as quinine in preventing malaria, even though they might not be as effective in treating the disease once contracted. The earliest synthetic antimalarials, introduced between 1926 and the early 1950s, included pamaquine, the first synthetic; mepacrine; and chloroquine and primaquine, two well-known drugs from the mid-1940s through the 1950s. These synthetic agents intervened to stop reproduction of the malaria parasite at different points in its life span. Depending on which preventive drug was taken, treatment might have to begin well before expected exposure, during the period of exposure, or for a certain period after being present in a malaria-infected area. Several generations of antimalarial drugs are on the market, but such progress in pharmaceutical options has not effectively resolved the problem of endemic malaria in regions of the world where those most in need lack either public health information programs or the financial means to obtain necessary drugs.

Research involving vaccination to protect against malarial infection has tended to follow one of two main approaches: vaccines to combat the diffusion of spores directly, and vaccines to block one or several stages of the parasite’s life cycle. Some vaccines have been developed by extracting spores from the blood of infected patients and using methods such as radiation to reduce their potency. Injection of these weakened agents into the blood can induce formation of antibodies that are able to fight invasive spores coming from an outside source (mosquito saliva) into a potential host organism. Commercial production of such vaccines, however, would require finding an economically viable way of obtaining and treating large quantities of Plasmodium spores, not only from P. falciparum but also from other malaria parasites that are less deadly but an important threat to large numbers of people around the world. For this reason, researchers have tended to concentrate more on isolating antigens that the body produces naturally to fight invasive spores and merozoites, analyzing them, and attempting to use biotechnology to produce effective synthetic antigens.

Observation over a long period of time has provided statistical evidence that, in a number of subtropical areas where malaria is endemic, fatalities from the disease are more frequent among children than among adults. The reason for this is linked to the adult population’s prior exposure to one or more nonlethal malarial infections. In essence, the adult body’s production of natural antigens seems to neutralize the effects of blood cells that have become carriers. If they remain in the bloodstream, these antigens reduce the susceptibility to what, in children, takes the form of a sudden invasion of infected and (for the body’s immune system) unrecognizable blood cells transmitted through Anopheles mosquito bites.

There is, therefore, an entire field of malaria research dealing with the body’s own immune responses. Where malaria is concerned, researchers pay particular attention not only to the challenge of understanding how immunity can build in populations living in endemic zones but also to the possibility of increasing the efficiency of certain body organs that naturally affect the bloodstream in ways that can impede the spread of the parasite’s damage. Attention has focused, for example, on the internal functions of the spleen. The spleen can prevent the progress of intravascular pathogens in general by reducing the flow of infected red blood cells to other organs and isolating them in a chemical state that renders them less directly dangerous to the body. This capacity is called splenic filtration. Although research has not yet identified an effective way to use externally applied medications to enhance this facet of the spleen’s natural defense system, it is agreed that here there is a serious prospect for another area of treatment to complement, if not replace, preventive drugs and synthetic antigens.

Once it was clear that malaria was transmitted by mosquitoes, the most logical tactic to prevent spread of the disease involved campaigns to eradicate, or at least diminish the life chances of, Anopheles. Thus, drainage of swamp areas (a costly but effective measure where possible), public health measures to guard against insalubrious concentrations of stagnant water, and insecticide spraying have been practiced throughout the world to combat Anopheles. During World War II and until the late 1950s, DDT was the insecticide of choice. When the harmful side effects of DDT for humans and the environment became apparent, legislation in most but not all countries banned the chemical. Research has since aimed at, but not fully succeeded in, developing safer insecticides that can approach DDT’s levels of efficiency.

Perspective and Prospects

Research in the field of malarial disease and its biological origins advanced rather slowly, with most major advances occurring fairly late in the nineteenth century. It was in 1897 that a surgeon in the British Indian army, Sir Ronald Ross, following British tropical disease expert Sir Patrick Manson’s suggestions, announced his discovery that malaria was transmitted to humans by mosquitoes. There had been earlier theories concerning the role of mosquitoes, some going back as far as the early eighteenth century in Italy (where the term “malaria,” meaning “bad air,” had originated). It took the work of a French military doctor in Algeria, Alphonse Laveran, to show, under a microscope, the ongoing activity of parasites in the blood of malaria patients. Laveran also did postmortem studies of malaria victims’ blood and organs and found a dark pigment composed mainly of iron which came from the parasites’ apparent digestion and waste disposal of vital hemoglobin in the red blood cells. He became the first to posit that malaria was a disease of red blood cells and that it was caused by an invasion of parasites.

From there, it was a question of finding how the parasites entered the human bloodstream. This was the result of Ross’s observation in India of a particular variety of mosquito larvae (later identified as the small brown Anopheles, distinct from Culex varieties commonly observed in the daytime) collected from stagnant waters in the region. When Ross followed Manson’s suggestion that mosquitoes hatched from these larvae should be induced to feed from a known malaria patient, he found that only a few insects survived the next few days. When these were dissected, he found oocysts embedded on the wall of the mosquitoes’ gut. Microscopic analysis showed that they contained the same dark pigment that Laveran had found in the blood of malaria victims in Algeria.

Both Ross (in 1902) and Laveran (in 1907) received Nobel Prizes in recognition of their work, Ross in medicine and Laveran in physiology or medicine. Other contributors, notably the Italian Giovanni Batista Grassi, carried on significant work in the same first decade of the twentieth century that paralleled (or, according to Grassi, may have been accomplished before) Ross’s studies. The most important suggestion by Grassi—which was correct but which took much more work to prove in the laboratory—was that there must be significant transformations, in fact multiple stages of reproduction, between the sporozoite phase of dissemination of the parasite via mosquito saliva and the merozoite phase, when the actual attacking parasite can destroy red blood cells in the human host. Later researchers finally provided, in 1934, convincing evidence that there was a sequence of sexual and asexual phases of reproduction (the later labeled “schizogony”) in the life cycle of the Plasmodium parasite.

Over the years, other researchers helped broaden the understanding of malaria, its causes, and treatment. Despite the obvious costs paid during the first half of the twentieth century involving debilitation and loss of human lives in areas where malaria was endemic, truly major breakthroughs occurred only during the extraordinary conditions created by World War II. The fact that large numbers of troops were sent to areas in East, South, and Southeast Asia as well as Africa meant that the danger of widespread malarial infection could hamper strategic operations. Distribution of all forms of preventive equipment, including both mosquito nets and insect repellents, was destined to become standard procedure in tropical zones. Doses of quinine were also part of each soldier’s medical supply packet.

Bibliography

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Farmer, Paul. Infections and Inequalities: The Modern Plagues. Berkeley: University of California Press, 2001.

Honigsbaum, Mark. The Fever Trail: In Search of the Cure for Malaria. New York: Farrar, Straus and Giroux, 2002.

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Rocco, Fiammetta. “Corrections and Clarification: The Global Spread of Malaria in a Future, Warmer World.” Science 289 (September, 2000): 2283–284.

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