Malaria: Growth and Selection

Letters Iron Acquisition by Plasmodium spp The acquisition of iron by parasitic protozoa has recently been reviewed1 and commented2. I would like to try to correct some misconceptions concerning iron acquisition by Plasmodium spp that might have emerged from these publications. There is no doubt that the intraerythrocytic parasite acquires iron from intracellular sources. However, it has been assumed that the digestion of host cell hemoglobin cannot be a source for iron because the resulting ferriprotoporphyrin IX (FP) is rapidly polymerized to hemozoin (HZ). This appears not to be the case. For years, it has been known that only around 50% of FP derived from digestion of hemoglobin is found in HZ in P. bergheiinfected mice3 and, recently, this has also been shown in P. falciparum4,5. Non-polymerized FP must leave the food vacuole as otherwise it will further

inhibit the local activity of proteases6. Although P. berghei has a demonstrable heme oxygenase activity that can provide a defense mechanism against the toxicity of FP7, P. falciparum does not display such activity. By contrast, FP has been shown to be degraded by glutathione8; hence, it is tempting to suggest that the major source of iron for the parasite is the degradation of FP that escapes polymerization. However, this process exposes the parasite to the threat of iron that, through redox-cycling, can produce toxic oxidative radicals. As the total amount of iron in erythrocytes remains unchanged during parasite development9, the next intriguing question that must be placed on the agenda of iron metabolism research, is the identification of the mechanism of iron sequestration, similar to that accomplished by ferritin in other cell types.

Malaria: Growth and Selection The article by Molyneux et al.1, ‘Transmission control and drug resistance in malaria: a crucial interaction’ illustrates well the importance of maximizing the value of different intervention approaches – as opposed to the perennially hopeful search for new tools and magic bullets endorsed by many. The main point of the article was to consider the cost implications of reducing the rate of selection for drugresistant malaria parasites through the use of vector-control methods. But the basis of the argument is a specific case of the general relationship between genetic variability and population growth rate. In any population, variability is favoured by an increasing reproductive rate, simply because this increases the likelihood that rarer genotypes could reach reproductive age. This applies equally to clonal and sexual organisms, and even the simplest mendelian model can show that the likelihood of survival of a rare gene will approximate to half the net reproductive rate (R0) (see also Ref. 2). For this reason, selection for different population attributes (such as drug or insecticide resistance) is most readily apparent in organisms that reproduce quickly (eg. the r-strategists of medical parasitology, such as mosquitoes and malaria) rather than in the slower reproducing organisms (K-strategists such as tsetse, triatomine bugs, snails and schistosomes). This does not mean that resistance selection cannot occur among K-strategists but merely that it is less favoured because of the inevitable loss of population diversity in slowly reproducing populations adapted to stable habitats. This is illustrated by domestic Triatominae vectors of Trypanosoma cruzi in Latin America. The primary habitats of important vector 466

species such as Triatoma infestans are rural houses, which represent some of the most stable and predictable habitats available. Here, evolutionary change is driven less by natural selection (there is almost none) and more by founder effects, genetic drift, and inter-sibling competition favouring the most energetically efficient genotypes3,4. The net reproductive rate of each domestic population tends to unity and, in genetic terms, the population tends to monomorphy – behaving almost as a pseudo-clone5. Under such circumstances, the potential to select for a particular genotype becomes extremely limited – the genetic repertoire of the population is too restricted. A similarly extreme case is shown by Rhodnius prolixus, another domestic vector of T. cruzi, where the current populations in Central America seem to have gone through several genetic bottlenecks and now seem both genetically restricted and relatively homogenous, representing highly amenable targets for control interventions (see also Refs 6,7). The situation is different in populations that go through periods of rapid increase, however, when rare mutations or unusual genetic rearrangements become more likely to survive. At this point, in the case of mosquitoes for example, emergency control measures can be employed, enhancing the likelihood of selecting for particular attributes. In such cases, there is an inevitable argument favouring continuous control rather than sporadic emergency interventions, even if only to inhibit periods of intense population growth when genetic variability might increase. The same arguments are valid for the same reasons in drug resistance in parasites.

References 1 Wilson, M.E. and Britigan, B.E. (1998) Parasitol. Today 14, 348–353 2 Tachezy, J. (1999) Parasitol. Today 15, 207 3 Wood, P.A. and Eaton, J.W. (1993) Am. J. Trop. Med. Hyg. 48, 465–472 4 Ginsburg, H., Famin, O., Zhang, J.M. and Krugliak, M. (1998) Biochem. Pharmacol. 56, 1305–1313 5 Zhang, J., Krugliak, M. and Ginsburg, H. (1999) Mol. Biochem. Parasitol. 99, 129–141 6 Vander Jagt, D.L., Hunsaker, L.A. and Campos, N.M. (1986) Mol. Biochem. Parasitol. 18, 389–400 7 Srivastava, P., Puri, S.K., Dutta, G.P. and Pandey, V.C. (1992) Med. Sci. Res. 20, 321–322 8 Atamna, H. and Ginsburg, H. (1995) J. Biol. Chem. 270, 24876–24883 9 Loria, P., Miller, S., Foley, M. and Tilley, L. (1999) Biochem. J. 339, 363–370 Hagai Ginsburg Department of Biological Chemistry Institute of Life Sciences Hebrew University Jerusalem 91904, Israel

Each new infection – whether of a vector or a host – represents a new phase of local but rapid population expansion, when genetic variants could survive. The result is heterogeneity (even if only transient) from which new attributes such as drug resistance can be selected. In parasites, the transmission rate is a generalized surrogate for the population growth rate, so that any reduction in transmission will help reduce the population variability from which new variants could be selected. Molyneux et al.1 are quite correct in their postulates, but the importance of reducing transmission as a means to reduce the selection of resistance is a general concept that is not restricted to malaria. References 1 Molyneux, D.H. et al. (1999) Parasitol. Today 15, 238–240 2 Schofield, C.J. (1996) in Proceedings of the International Workshop on Population Biology and Control of Triatominae, Santo Domingo de los Colorados, Ecuador (Schofield, C.J., Dujardin, J.P. and Jurberg, J., eds), pp 45–50, INDRE Mexico City 3 Dujardin, J.P., Panzera, P. and Schofield, C.J. Mem. Inst. Oswaldo Cruz (Special Volume) (in press) 4 Schofield, C.J., Diotaiuti, L. and Dujardin, J.P. Mem. Inst. Oswaldo Cruz (Special Volume) (in press) 5 Dujardin, J.P., Schofield C.J. and Tibayrenc, M. (1998) Med. Vet. Entomol. 12, 20–29 6 Schofield, C.J. and Dujardin, J.P. (1997) Parasitol. Today 13, 141–144 7 Dujardin, J.P. et al. (1998) Med. Vet. Entomol. 12, 113–115 C.J. Schofield London School of Hygiene and Tropical Medicine London, UK WC1 E7HT J-P. Dujardin IRD/IBBA CP9214, La Paz, Bolivia

Parasitology Today, vol. 15, no. 11, 1999