Why do we need to know more about mixed Plasmodium species infections in humans?

Abstract

Four Plasmodium species cause malaria in humans. Most malaria-endemic regions feature mixed infections involving two or more of these species. Factors contributing to heterogeneous parasite species and disease distribution include differences in genetic polymorphisms underlying parasite drug resistance and host susceptibility, mosquito vector ecology and transmission seasonality. It is suggested that unknown factors limit mixed Plasmodium species infections, and that mixed-species infections protect against severe Plasmodium falciparum malaria. Careful examination of methods used to detect these parasites and interpretation of individual- and population-based data are necessary to understand the influence of mixed Plasmodium species infections on malarial disease. This should ensure that deployment of future antimalarial vaccines and drugs will be conducted in a safe and timely manner.

Figure 1

Adaptation of clinical summaries originally presented by Boyd and Kitchen from two patients receiving Plasmodium falciparum and Plasmodium vivax simultaneously. Each record shows the natural history of the patient’s temperature (green line) and blood-smear parasitemia (no. of parasitized erythrocytes per μl) monitored daily. (a) The data obtained from Ref. [13] exhibits a fairly regular pattern of P. falciparum (blue line) and P. vivax (red line) parasitemia where numerous consecutive blood smears detected only one species; P. falciparum gametocytes are represented by light blue dots. (b) Data obtained from Ref. [14] exhibits a similar (above) mixed infection pattern until Day 83. Following this time-point, both species were equally prominent in the blood smears and could represent chronic infections observed in individuals from malarious regions. Reproduced, with permission, from Refs [13,14].

Figure 2

The characteristics of pre-erythrocytic and erythrocytic phases of parasitemia for different malaria species of humans. The blood smear kinetics shown here assume that a single sporozoite from different malaria species were used to infect humans, as indicated: Plasmodium falciparum (blue bar and circle), Plasmodium vivax (red bar and circle); Plasmodium ovale resembles P. vivax; and Plasmodium malariae (yellow bar and square). The minimum duration of liver-stage infection is represented by blue (P. falciparum), red (P. vivaxand P. ovale), and yellow (P. malariae) bars. Key: E, elimination; M, parasitemia when malaria infection will be observed by conventional blood-smear analysis (2×10⁸ total number of parasites in the body); PCR, parasitemia when malaria infection will be observed byPCR-based diagnosis (1infected erythrocyte per 5×10⁶ erythrocytes μl⁻¹).

Figure 3

Further consideration that a species-transcending density-dependent force regulates mixed Plasmodium species infections. A summary of the proportion of each Plasmodium species is given in (ai) and (bi), observed by blood smear corresponding to simulated data for each of 12 three-day sample collection time points [indicated in (aii,bii)] Hypothetical data predicted to occur by asexual replication characteristics of the human Plasmodium species parasites and principles proposed in the species-transcending density-dependent (STDD) model. Orange shading represents parasite density above a threshold of ~1000 parasitized erythrocytes per μl (T). Gray shading identifies the limits of detection by microscopy (M). The black broken line represents the limits of detection by PCR. Acquired immunity is indicated by arrows. Asexual replication of the different Plasmodium species is shown as colored solid lines and parasite killing as colored broken lines. Key: purple, Plasmodium falciparum strain A; gray bars, no parasites; light blue, P. falciparum strain B; red, Plasmodium vivax; yellow; Plasmodium malariae.