Malaria: progress, perils, and prospects for eradication

Abstract

There are still approximately 500 million cases of malaria and 1 million deaths from malaria each year. Yet recently, malaria incidence has been dramatically reduced in some parts of Africa by increasing deployment of anti-mosquito measures and new artemisinin-containing treatments, prompting renewed calls for global eradication. However, treatment and mosquito control currently depend on too few compounds and thus are vulnerable to the emergence of compound-resistant parasites and mosquitoes. As discussed in this Review, new drugs, vaccines, and insecticides, as well as improved surveillance methods, are research priorities. Insights into parasite biology, human immunity, and vector behavior will guide efforts to translate parasite and mosquito genome sequences into novel interventions.

Figure 1. The life cycle of malaria-causing Plasmodium parasites.

The Plasmodium life cycle comprises numerous transitions and stages, and any of these can be targeted by host immune responses. Upon inoculation by an Anopheles mosquito into the human dermis, elongated motile sporozoites must evade antibodies to (i) access blood vessels in the skin and then (ii) transit through liver macrophages and hepatocytes to initiate liver stage infection. Intrahepatocytic parasites (iii) are susceptible to CTLs. After approximately one week, infected hepatocytes rupture and release merozoites as aggregates called merosomes that might allow merozoites to (iv) evade antibodies and invade erythrocytes. Intraerythrocytic parasites (v) are susceptible to opsonizing antibodies and macrophages, and cytokine responses have been related to both protection and disease during this stage of infection. Antibodies that block (vi) binding of P. falciparum–infected erythrocytes to endothelium might prevent disease and control parasitemia. Human antibodies specific for (vii) sexual stage parasites are taken up by mosquitoes during the blood meal and can block transmission to mosquitoes, although these might require complement for parasite killing. Anopheles mosquito innate immune responses can also kill parasites during early (vii) or late (viii) sporogonic stages and lead to refractoriness to infection.

Figure 2. Antimalarial drugs mediate their effects by disrupting processes or metabolic pathways in different subcellular organelles.

The 4-aminoquinolines, including chloroquine and amodiaquine, and the quinolinemethanols, including quinine and mefloquine, concentrate inside the acidic digestive vacuole, where they are believed to bind β-hematin and interfere with heme detoxification. The falcipain inhibitors that are under development target cysteine proteases that participate in hemoglobin degradation in this digestive vacuole. Antibiotics such as azithromycin, doxycycline, and clindamycin act inside the chloroplast-like plastid organelle, where they inhibit protein translation, resulting in the death of the progeny of drug-treated parasites (the “delayed-death” phenotype). Atovaquone and select other compounds inhibit electron transport in the mitochondrion, whereas antifolates disrupt de novo biosynthesis of folate in the cytosol. Only drugs for which the site of action is known with confidence are assigned to a subcellular location. Indeed, the targets and sites of action of other antimalarials, including artemisinin and artemisin derivatives, remain an area of active investigation. Reproduced with permission from Nature Publishing Group (44).