Facts and Figures¹
• malaria is caused by a parasite of the Plasmodium genus, which is transmitted by the female Anopholes mosquito. Once injected into a human host, it invades the liver and then spreads to the red blood cells.
• countries in Africa account for 90% of malaria cases worldwide, with another 6% of cases coming from South America and southern Asia.
• malaria accounts for up to 500 million acute clinical cases and up to 3 million deaths annually.
• malaria causes more deaths annually than AIDS has in 15 years.
• malaria kills 20 times more people each day than died in the 1995 Ebola outbreak.
• Despite these horid figures, funding to spot this global killer remains at a minimum: World wide contributions to malaria research totaled (US) $84 millin in 1994. Funding from the US accounted for $35 million alone, with much of that coming from the NIAID (around $22.8 million).
compare to world wide funding for:
cancer (US) $2.3 billion
AIDS (US) $1.5 billion
Alzheinmers (US) $300 million

Brief History

It is believed that the malaria parasite has been with us since the dawn of time. Most assume that it originated in AFrica, although there is some speculation that it may have orginated in Asia^2-7. In addition, this inveterate relationship is assumed becuase of the persistence of sickly cell disease alleles in the AFrican population, since those infected with SCD also have a reduced level of acute malaria infection⁸.

The disease appeared as early as 2700BC, when the Chinese cannon of medicine described the classic symptoms of the disease: high fever and enlarged spleen⁹.

Hippocrates was the first to look beyond the supernatural as the source of malaria⁹. Pointing to pools of stagnant water (ideal breading grounds for the Anapholes mosquito), he inspired the Romans to begin drainage programs, the first anti-malaria intervention.

It wasn't until the early 1600's, however that treatment was first available to the developed world. Native Peruvian Indians gave Jesuit missinaries bark of the cinchona tree, which contained quinine⁹. Shortly thereafter, this "Jesuit powder" was avialable in the UK to those suffering from the "auges."

In 1889, Laveran discovered the protozoal cause of malaria, and in 1897, the Anapholes mosquito was demonstrated to be the only known vector of the disease⁹.

Interestingly, malaria was the most common reason for hospitalization during the Civil War⁸.

In the 1940's, the discovery of DDT insecticide gave hope for global eradication, as huts and houses world wide were sprayed⁹. This program saw initial success, as malaria was eliminated or reduced in 77 countries¹. However, soon the number of reported cases met and then quickly exceeded previous levels⁸. There is no singly expanation for the inability to eliminate the disease, but many point to political and social barriers which stunted this eradication program⁹. Unfortunately, the incomplete nature of these measures only increased selection pressures for insecticide resistant mosquitoes.

Recognizing the almost insurmountable nature of the disease, in 1970, the WHO downgraded the eradication program to a global malaria control program⁸. The change did little to stop the spread of the disease, as by the mid 70's there was a 2-3 fold increase in cases globally⁹.

The battle against the Plasmodium parasite and its vector, the Anapholes mosquito has seen little improvement in recent years. As shall be discussed later, drug resistance is now reported in every malaria endemic country; a sobering thought in light of the fact that a widely available vaccine is still not avialable.

Life Cycle of the Plasmodium Parasite⁹

The four malaria causing species of the Plasmodium parasite (P. falciparum, P. vivax, P. ovale, and P. malariae) have similar life cycles, which can be divided into three stages: I, II, and III.

In Stage I, the secretion of anticoagulant into the human host by the female Anapholes mosquito while taking a blood meal also releases the parasitic sporozoites, which are found in the mosquito's salivary gland. Upon entrance to the blood stream, the sporozoites immediately penetrate into the liver cells, where they multiply. After 9-16 days, the life cycle enters Stage II, where the parasitic merozoites rupture from the liver and invade the red blood cells. While inside the RBC's the parasite undergoes erythrocytic schizogony after which the RBC ruptures, releasing either merozoites (which reinvade the liver) or micro- and macrogametocytes (which circulate in the blood stream). In Stage III, the completion of the life cycle, the gametocytes are taken up by a mosquito, where they undergo sexual reproduction. The subsequent fertilization takes place in the mosquito but wall, where an oocyst then develops. Finally, the oocyst ruptures, releasing the sporozoites, which then migrate to the salivary gland, where they await transfer to another host.

Immune Response

Symptoms of malaria can develop anywhere from 10 to 16 days after infection; in some cases, they may never develop¹⁰. Typical symptoms include headache, fever, chills, and/or body aches. Also the spleen and liver are often palpable upon clinical examination.

Recent years have seen a signifcant increasse in the still limited understanding of the specifics of the immune respnose to malaria. Both cell mediated and humoral responses are involved in the initial response and natural immunity¹¹, althugh it seems that the immune system never is able to completely kill all the parasites¹¹.

Most important to the immune response seems the production of IgG antibodies. In a 1996 study exploring the role of these cytophilic antibodies and avidity, Ferreira et al. fournd that 1) clinical immune patients displayed a predominance of high-avidity cytophilic antibodies; 2) acutely ill patients showed high levels of cytophilic antibodies as well, but of low avidity; 3) such a response was short lived as antibody levels fell after two months; 4) however, in another study group, affinity maturation was seen in cytophilic antibodies. It has also been shown that IgG antibodies are specific for circumsporozoite proteins on the sporozoites⁹. This protein is part of a complex pellicle which is responsible for motility and interaction with host plasma membranes¹². Once bound to an antigen, IgG1 and IgG2 antibodies bind to Fc RI and Fc RII receptors on monocytes and macrophages¹³. This binding initiates opsnization and phagocytosis, as well as antibody-dependant cellular inhibition of blood-stage malaria parasites¹⁴.

Despite the specificity of the immune system to recognize and kill the Plasmodium parasite, it likewise ahs develped mechanisms intended to counter those of its host. The parasitic gene encoding circumsporozoite protein appears to have high degree of mutation¹². This could explain the inability of the immune system to completely rid the body of the parasite. Additionally, upon entrance to the RBC's, the parasite produces adhesion proteins which are expressed upno the cell surface. These proteins cause the blood cells to stick to vessel walls, theoretically to avoid transport to the spleen where the RBC's would be eliminated. Researchers have found that as expected, this region of the parasite chromosome is also highly variable, so that the parasite might escape antibody recognition¹².

Drug Therapy

Current drug therapies to malaria infection can be divided into three classes, according to the parasitic stage upon which they act: gametocytocidal drugs (e.g. primaquine) which directly destroy the gametocytes, sporontocidal drugs (e.g. pyrimethamine) which inhibit oocyst develpment in the mosquito, and schizontocides (e.g. chloroquine) which destroy asexual forms of the parasite¹⁵.

The mechanisms of the most common antimalarial drugs are mentioned below⁹:

Primaquine: used primarily against gametocytes and hypnozoites, this supposedly works by inhibiting the parasite's electron transport chain, although the specifics are still not understood.

Pyrimethamin, Proguanil (antifols): These drugs inhibit the action of the enzyme dihydrofolate reductase. This enzyme reduces dihydrofolate to tetrahydrofolate, derivatives of which make one-carbon transfers in many biosynthetic pathways¹⁶.

Chloroquine and related derivatives: This classic antimalarial drug attacks the hemoglobin metablism of parasites, possibly by preventing the neutralization f the toxic ferriprotoporphyrin IX. It is proposed that chloroquine is taken up into parasitic food vacuoles and there complees with the mebinder for ferriprotoporphyrin IX, forming a membrane damaging complex, which acts by increasing the parasite's membrane permiability.

Quinine and mefloquine: These drugs cause blebbing of the parasitic membrane.

Sulfonamindes: These drugs inhibit para-aminobenzoic acid (p-ABA) which is needed t synthesize dihydroprerate which is an intermediate compound in the synthesis of tetrahydrofolate. As mentioned above, intermediates of tetrahydrofolate serve as donors of one carbon comounds.

Antibiotics: Many times, antibiotics, such as tetracycline, are used in combination with other therapies when resistant strains of Plasmodium are encountered. It is thought that they affect the parasite's mitochondrial ribosomes, thus disrupting protein sythesis.

Artemisinins: These newest anti-malarials are synthetic versions of traditional Chinese therapies and also seem to affect protein synthesis. They promise to be the next wave of treatment in a never-ending race against drug resistant parasites.

Drug Resistance

Drug resistance has become the major obstacle to malaria control in recent years. The most current definition of drug resistance given by the WHO¹⁷ is "the ability of a parasite strain to survivie and/or multiply despite the administratino and absorption of a drug given in the doses equal to or higher than those usually recommended but within the limits of tolerance of the subject." The primary reason for drug resistance has been the "indiscriminate and incomplete" use of drugs accross the world, especially in the poorer endemic regions, leading to heightened selection pressures upon Plasmodium¹⁸.

Chloroquine resistance in P. falciparum was first observed in 1961 in Columbia¹⁹. Since then, chloroquine reistance has been observed in every part of the world--to such a degree that chloroquine is now considered ineffective against this species unless coupled with antibiotics²⁰. Additionally, resistance to every drug therapy except the new artemisinins has been observed¹⁸. Even more unsettling, it seems that resistance has spread beyond the falciparum species and is now observed in each of the other species²¹.

There is no way to overcome drug resistance, thus for every resistant strain, a new drug therapy must be developed. The most advisable method of treatment in a given region is to use a drug as long as it is viable. Once it loses efficacy, quickly remove it as a treatment, and replace it with a new therapy. Also, it is imperative that drug treatments be taken in completion.

Hopefully once treatments are administered in a more responsible manner, drug resistance will be brought under control, and finally malaria control can become a reality.

References:

For more about malaria, visit these sites:

Please send questions or comments to me at grnoland@davison.edu.

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