Antimalarial Drugs Are Losing the Battle Against Resistance
Annually, malaria kills more than one million individuals—mostly children and pregnant women. Many antimalarial drugs have been developed, but they are almost universally subject to increasing resistance from the parasite. This means that many antimalarial drugs that were effective for more than 40 years are no longer useful. Furthermore, it is thought that the useful life a drug is becoming shorter, which may be due to the development of broad-spectrum mechanisms of resistance, such as the production of pumps to decrease the intraparasitic accumulation of a drug. That is the case for chloroquine and related drugs. Furthermore, by using transporters that have become adapted to pump chloroquine and quinine, the parasite is now apparently able to pump out other drugs. There are also mechanisms of resistance specific to the protein targeted by the drug, such as point mutations in the active sites of target enzymes—mutations that decrease the binding affinity of the drug.

As long as drugs target the parasite, it will continue to develop mechanisms to outwit pharmacologists. Because malaria is a constant companion to hundreds of millions of individuals and these people live in environments where appropriate administration of drugs is impossible, new mutations and mechanisms will continue to arise. The parasite also undergoes meiosis, allowing reassortment of new mutations that results in a gradual increase in complementary, genetically nonlinked mutations; selection and this genetic reassortment cause a gradual accumulation in resistance. Given that these novel antichemotherapeutic mutations can also co-segregate with novel antigens, the parasite has a powerful strategy for avoiding antiparasite therapies.

The Malarial Parasite Relies on the Host for Metabolites and Enzymes
The malarial parasite is an obligate intracellular organism. The merozoite phase is short and appears largely to be a means of transit from one erythrocyte to the next. Therefore, the malarial parasite spends most of its metabolic life in a red blood cell. Malarial parasites have lived in red blood cells for almost the entire history of vertebrate evolution and therefore have adapted to that environment. They scavenge nutrients, metabolites, and enzymes from the cytoplasm of the red blood cell. Such is their dependence on their host cell that they have lost some genes that encode vital enzymes in metabolic pathways.

Conversely, malaria has placed enormous selective pressure on the human genome; this pressure is reflected in the large number of red blood cell diseases overlapping geographically with malarial endemicity. Mutations in the genes encoding red blood cell proteins have given rise to the thalassemias, sickle cell anemia, Melanesian ovalocytosis, glucose-6-phosphate dehydrogenase deficiency, and so forth. These mutations can be seen as genetic antimalarials, as they undoubtedly raise the host's resistance to malarial infection or its sequelae. The mutations are also more enduring than the chemical antimalarials to which we have been subjecting the parasite. These protective genetic events probably endure because they are not under the control of the parasite genome, and thus the parasite cannot evade them by mutating a drug target. The effects of the genetic mutation are seen outside the parasite, by either rendering the red blood cell hostile to parasitic growth and survival, such as limiting important growth factors, or by rendering the infected cell more easily recognizable by the reticuloendothelial system that removes the cell from circulation.

Directing Therapy Against the Host May Overcome the “Resistance Problem”
Both host and parasite factors support the hypothesis that directing antimalarial therapy to the host rather than to the parasite would avoid the issue of parasitic antimalarial chemotherapeutic resistance. We are working on the assumption that directing chemotherapy at the host, by knocking out a function of the host vital to the survival of the parasite, would deprive the parasite of the chance of mutating genes, pumping the drug out of the cell, or blocking its entry. The place of action of the drug would be outside the parasite and would interfere with a molecule whose gene was in the human genome rather than in that of the parasite.

We are developing such a strategy using N-ethyl-N-nitrosourea mutagenesis to identify mutations that would render an otherwise susceptible mouse resistant to Plasmodiumchabaudi malaria. The protein products of genes carrying such suppressor mutations will be targets for antimalarial therapy. The screen is straightforward. We are in the process of generating 10,000 G1 animals and a smaller number of G3 pedigrees, looking for mutations that protect the animals from death from malaria.

We are also using bioinformatic tools to uncover host enzymes for metabolic components that are scavenged by the parasite. We are developing inhibitors of these components and are assaying, in cultured Plasmodium falciparum, their utility as potential antimalarial compounds.

Platelets Are an Important Part of the Innate Immune Response to Malarial Infection
In addition, we have identified platelets as an important component of the innate immune response to malarial infection and are documenting their role in both human and mouse infections. We are using knockout models with low levels of platelets as well as adding purified platelets to cultured malarial parasites. Initial observations implicate platelets in the direct killing of intracellular parasites. Mpl is the receptor for thrombopoietin, and mice deficient in the gene encoding the receptor have 10 percent of the normal number of circulating platelets. We tested mice with the Mpl knockout on a background resistant to death by P.chabaudi parasites, and these mice are more susceptible to malaria than their wild-type counterparts. Parasites with bound platelets stain TUNEL-positive, indicating that the parasites are dead, and there are fewer TUNEL-positive cells in Mpl−/− mice than in controls. Administering aspirin to normal mice also increases their susceptibility to parasites. We have begun to purify platelets from human blood and have good evidence that they are able to inhibit the growth of P. falciparum, the human malarial parasite,in culture.

Last updated April 2007