The impact of malaria parasitism: from corpuscles to communities

Abstract

Malaria continues to exert a tremendous health burden on human populations, reflecting astonishingly successful adaptations of the causative Plasmodium parasites. We discuss here how this burden has driven the natural selection of numerous polymorphisms in the genes encoding hemoglobin and other erythrocyte proteins and some effectors of immunity. Plasmodium falciparum, the most deadly parasite species in humans, displays a vigorous system of antigen variation to counter host defenses and families of functionally redundant ligands to invade human cells. Advances in genetics and genomics are providing fresh insights into the nature of these evolutionary adaptations, processes of parasite transmission and infection, and the difficult challenges of malaria control.

Figure 1. Life cycle of P. falciparum.

Sporozoites injected by anopheline mosquitoes travel through the dermis and enter the bloodstream to invade hepatocytes. Each infected hepatocyte generates tens of thousands of merozoites, which then break out and reenter the bloodstream to invade erythrocytes. Numerous rounds of asexual reproduction follow, with repeated invasion of erythrocytes every 48 hours. Some parasites in the erythrocytes develop into sexual stage gametocytes, which circulate in the bloodstream and are taken up by female mosquitoes during a blood meal. In the mosquito midgut, gametes emerge from the gametocytes and cross-fertilize (118). The resulting zygote develops into an ookinete that crosses the midgut wall and grows into an oocyst. Mitotic division within the oocyst produces thousands of sporozoites that break out and travel through the hemolymph to the mosquito salivary glands, from which they are injected into a human host.

Figure 2. Apicomplexans and their ancestors.

Apicomplexans are obligate intracellular protozoa from ancestors that also gave rise hundreds of millions of years ago (mya) to ciliates, dinoflagellates, and the recently discovered Chromera velia (4). Symbiotic relationships of C. velia and dinoflagellate species with invertebrates suggest that parasitism developed early in the origin of animals. Depicted is an evolutionary tree of the alveolate protozoans, including C. velia, a photosynthetic symbiont of corals (4). The phylogeny of Apicomplexa is not fully resolved, and confirmation of the date of the radiation and branch order awaits further studies. Modified with permission from Trends in Parasitology (ref. , using information available in refs. and 120).

Figure 3. An. gambiae entomological inoculation rates and infection outcomes in Africa.

(A) The clinical outcome of P. falciparum sporozoite inoculation by an An. gambiae mosquito depends on many factors and can range from no infection to severe malaria and death. Greenwood et al. (121) estimated that in areas of high transmission, for every 400 infectious bites, 200 result in a parasite infection, half of which will develop uncomplicated malaria, with two cases of severe malaria and one death. (B) Relationship between the mosquito entomological inoculation rate (EIR) and the proportion of individuals infected with P. falciparum (14). Analysis of combined data from over 90 African communities indicated that 20% of people received 80% of infections and that enormous reductions of existing EIRs would be required to achieve even a modest decrease in parasite prevalence. For example, a two-fold reduction in the EIR, from 200 to 100 infectious bites per year, would reduce parasite prevalence by only 4%, whereas a 100-fold reduction in the EIR, from 100 infectious bites to 1 infectious bite, would reduce parasite prevalence from about 70% to 30%. Part B was generated based on data from ref. .

Figure 4. Malaria death rates in Africa fell after the introduction of chloroquine and rose again in the wake of chloroquine-resistant malaria.

(A) Malaria death rates in the 20th century. Dramatic reductions in mortality occurred outside sub-Saharan Africa. In Africa, mortality rates declined after the introduction of chloroquine but then rose again with the spread of chloroquine-resistant parasites. (B) Rise in mortality associated with the entry of chloroquine-resistant P. falciparum in the village of Mlomp, Senegal. Deaths were primarily among children less than 5 years old, the most susceptible age group in highly malaria-endemic areas. CQ, chloroquine. Part A was generated based on data from ref. . Part B was reproduced with permission from Elsevier (107).

Figure 5. Chloroquine-resistant P. falciparum spread from at least six known origins.

Chloroquine resistance entered Africa in the late 1970s, having originated in Southeast Asia. PfCRT molecules from the individual foci all contain a key K76T amino-acid replacement but are distinguished by different patterns of accompanying codon polymorphisms and chromosome haplotype polymorphisms. In addition to five foci previously depicted (109), the map indicates recently described parasites in India and Iran that probably spread from an additional focus of chloroquine resistance (122, 123). Figure reproduced with permission from ASM Press (109).