Plasmodium Species Infecting Humans

Four distinct Plasmodium species infect humans: P. falciparum, P. vivax, P. malariae, and P. ovale. However, molecular methods have revealed the possible existence of other species or morphological variants (see box). For example, sequencing of the gene for the circumsporozoite surface protein (CSP) revealed that some individuals diagnosed with P. vivax infections were actually infected with a distinct species more closely related to P. simiovale, a simian malaria parasite which is morphologically identical to P. vivax. In addition, molecular analysis indicates that P. ovale consists of two clades that are as divergent as distinct species and Sutherland et al (2010) have proposed to designate them as sub-species: P.o. curtisi and P.o. wallikeri.

Similarly, molecular analyses indicate that some morphological variants of P. malariae are distinct parasites related to P. malariae and P. brasilianum. P. brasilianum is a simian parasite of the South and Central America that is often speculated to have originated from humans as a result of colonization of the New World.

In addition, humans naturally infected with the simian parasite P. knowlesi have been identified in Malaysia. Nearly all of the cases identified by microscopy as P. malariae were determined to be P. knowlesi by PCR. Four fatalities associated with P. knowlesi infection were also reported from Malysia. Humans infected with P. knowlesi may not be such an rare occurance and may be widespread in Malaysia and perhaps other parts of southeast Asia (Cox-Singh and Singh, 2008).

The four major human Plasmodium species are found in tropical and subtropical regions throughout the world and exhibit overlapping geographical distributions. Differences between the species include:

• blood-stage morphology
• minor life cycle variations
• P. vivax and P. ovale exhibit the hypnozoite stage and can cause true relapses (see discussion of hypnozoites and relapses in main document)
• trophozoite- and schizont-infected erythrocytes of P. falciparum sequester in the microvasuculature and are not found in the peripheral circulation (see discussion of cytoadherence in main document)
• host erythrocyte preference
• P. vivax and P. ovale prefer reticulocytes (immature erythrocytes)
• P. malariae prefers senescent erythrocytes
• P. falciparum exhibits no preference
• disease and clinical manifestation

The older designations (Table) for the various types of malaria reflect the differences in the diseases caused by the different Plasmodium species. P. falciparum causes the most severe disease, hence the malignant designation. This increase morbidity and mortalilty correlates with the higher parasitemia associated with P. falciparum infections and the complications arising from sequestration (see Pathogenesis and Cerebral Malaria). Factors contributing to the higher parasitemias include: large number of merozoites per schizont, lack of host erythrocyte preference, and the immune evasion (ie, spleen avoidance) provided by sequestration. Tertian and quartan refer to the differences in the periodicity of paroxysms (see discussion of paroxysms). Tertian patterns exhibit 48 hour periodicities and quartan refers to a 72 hour periodicity. (Note that in Roman counting the first attack is on day one followed of a symptom-free day and then the next attack on day three.) The species also exhibit other differences in disease severity and duration (see Table in main document).

Morphological Differences

The blood-stage parasites of human Plasmodium species exhibit differences in their morphology and modify the host erythrocyte differently (see Table and Figure). These differences can be used to distinguish the four species. (See life cycle for description of blood-stage forms.)

P. falciparum blood smears are characterized by the presence of young trophozoites (ie, rings) in the absence of mature trophozoites and schizonts. The ring stages of P. falciparum tend to be slightly smaller than the other species and are generally more numerous. Multiply infected erythrocytes and appliqué forms are seen more often in P. falciparum than in the other species. The crescent-shaped gametocytes of P. falciparum are very distinctive, but tend to only appear late in the infection.

The most distinctive features of P. vivax are the enlarged infected erythrocytes and the appearance of granules, called 'Schüffner's dots', over the erythrocyte cytoplasm. These granules are manifestation of caveola-vesicle complexes that form on the erythrocyte membrane. The growing trophozoite of P. vivax often has an ameboid apearance and the schizonts can have more than 20 merozoites.

P. ovale also exhibits Schüffner's dots and an enlarged erythrocyte, making it difficult to distinguish from P. vivax. In general, P. ovale is a more compact parasite than P. vivax. This compactness is most evident in the growing trophozite stage and fewer merozoites are found per schizont. P. ovale also has more of a tendency to form elongated host erythrocytes.

P. malariae is characterized by a compact parasite (all stages) and does not alter the host erythrocyte or cause enlargment. Elongated trophozoites stretching across the erythrocyte, called band forms, are sometimes observed. Schizonts will typically have 8-10 merozoites that are often arranged in a rosette pattern with a clump of pigment in the center.

The ring forms of all four species are very similar and difficult to distinguish. P. falciparum rings tend to be a little smaller and more numerous than the other species. The presence of a large number of rings in the absence of more mature stages, as well as multiply-infected erythrocytes, is highly suggestive of P. falciparum. Erythrocytes infected with P. vivax and P. ovale are enlarged and exhibit Schüffner's dots as the rings mature into trophozoites. The trophozoites of P. vivax are often ameboid, whereas P. ovale tends to be more compact. The P. malariae trophozoite is very compact and the host erythrocyte is not enlarged. Mature asexual forms of P. falciparum are rarely found in the peripheral circulation. The typical number of merozoites produced per schizont is: P. vivax 14-20 (up to 24), P. ovale 6-12 (up to 18), P. malariae 8-10 (up to 12), and P. falciparum 16-24 (up to 36). P. falciparum exhibits crescent-shaped gametocytes whereas the other species are all round to oval. P. vivax and P. ovale gametocytes are in enlarged erythrocytes with Schüffner's dots and are difficult to distinguish from each other. P. malariae gametocytes do not modify the host erythrocyte. Gametocytes can be distinguished from trophozoites by their large size (nearly filling the erythrocyte) and a single nucleus. Mature microgametocytes tend to stain lighter than macrogametocytes and have a more diffuse nucleus. (pdf file of this figure and legend)

Molecular Biology and Evolution

Parasites can be viewed as either 'heirlooms', which have evolved from parasites of the ancestors of the current hosts, or as 'gifts' from another animal sharing the same habaitat. Both of these processes appeared to have played a role in the evolution of malaria parasites. It has long been noted that many of the primate malaria parasites share features with the human parasites suggesting an heirloom type of evolution. However, the human parasite species are quite different indicating that they have different evolutionary pathways.

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