PerspectiveGenetics

Themes and Variations in Apicomplexan Parasite Biology

Science  01 Jul 2005:
Vol. 309, Issue 5731, pp. 72-73
DOI: 10.1126/science.1115252

The eukaryotic phylum Apicomplexa comprises more than 5000 species of parasitic protozoa (1), including the Plasmodium parasites responsible for malaria. Toxoplasma gondii is well known as a source of congenital neurological birth defects, while Cryptosporidium and Cyclospora (along with Toxoplasma) have emerged as opportunistic infections associated with immunosuppressive conditions (including AIDS), and as sources of human infection through contaminated food or water supplies. Many apicomplexan parasites are also of veterinary importance, including Babesia, Eimeria, Neospora, Sarcocystis, and Theileria. Theileria parva and T. annulata are cattle pathogens, responsible for East Coast fever and theileriosis. Acute lymphoproliferative disease or anemia can lead to death, imposing significant constraints on cattle-farming in sub-Saharan Africa (2).

Theileria parasites are also of considerable biological interest, as the only eukaryotic pathogens known to transform lymphocytes (3). Parasite sporozoites invade lymphocytes, escape from the invasion vacuole, interact with the host cell cytoskeleton (4), and alter cellular signaling pathways (5) through mechanisms that are incompletely understood. Further insight into their fascinating biology comes from two reports in this issue, by Gardner et al. on page 134 (6) and Pain et al. on page 131 (7), that describe effectively complete genome sequences for T. parva and T. annulata, respectively.

The availability of two Theileria genomes, along with numerous sequences for other apicomplexans (8-13), provides a rich trove of data for comparative analysis (see the Table) (14). Consistent with observations in other parasites, the Theileria genome is reduced in both metabolic complexity and size (~4000 genes, 8.4 Mb) relative to the genomes of other eukaryotes. Absent genes suggest metabolic deficiencies in the synthesis of purines, polyamines, fatty acids, and porphyrin, among other pathways (6). The parasites are able to carry out glycolysis, and probably the tricarboxylic acid cycle, although how these pathways are linked is unclear. Moderate levels of synteny are observed between Theileria and Plasmodium genomes (6).

Apicomplexan parasites pursue diverse life-history strategies, infecting virtually all animals, from mollusks to mammals (1). Some parasite life cycles are relatively simple, involving only a single host (see the figure), whereas others require sexual recombination in a vector species for transmission. Some parasites are specialists, restricted to particular species and tissues, whereas others are generalists. For example, Plasmodium falciparum, which causes the most lethal form of malaria, infects only great apes (including humans), and is transmitted only by anopheline mosquitoes. In contrast, T. gondii can infect almost any tissue of warm-blooded animals, causing disease in immunodeficient hosts (including AIDS patients and human and animal fetuses).

The complex life-cycle stages of apicomplexan parasite infection are characterized by persistent themes, with subtle variations. Extracellular “zoite” forms are usually motile, and include an “apical complex” that gives the phylum its name, including organelles associated with host cell attachment, invasion, and establishment of an intracellular “parasitophorous vacuole” (15). Theileria sporozoites and merozoites are unusual in being nonmotile, and appear to invade host cells passively, in an orientation-independent manner (4). Consistent with these observations, organelles usually found in the apical complex are modified: The distinctive cytoskeletal “conoid” (16) is absent; the micronemes (17), whose secretion is associated with cell adhesion, are altered or absent; and the apicoplast (18, 19), a secondary endosymbiotic organelle that may play a role in establishing the parasitophorous vacuole, shows reduced function. Theileria has retained the rhoptries, however; these secretory organelles (17) are also part of the apical complex, and are suspected to function in modifying the parasite's intracellular home for survival (20). In the case of Theileria, rhoptry secretion coincides with lysis of the invasion compartment, releasing parasites into the host cell cytoplasm (3, 4).

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In addition to the insights that they provide into basic metabolic pathways, genome sequences also highlight phylogenetically restricted genes, which are often linked to distinctive aspects of organismal biology. Large families of surface antigens are commonly found in pathogen genomes, and are likely to play an important role in antigenic variation and immune evasion (12-14, 21, 22). Plasmodium genomes even encode proteins targeted into the infected red blood cell (23, 24). These include variable surface antigens that mediate cytoadherence and sequestration of P. falciparum-infected red blood cells within capillaries of the brain and placenta, leading to severe disease and death (22). Expanded numbers of transporters and extensive horizontal gene transfer in the Cryptosporidium genome (12-14, 25) may reflect the extreme need for nutrient salvage in this parasite, and provide several attractive targets for this untreatable opportunistic pathogen that afflicts immunosuppressed individuals. Expanded families of secreted Theileria proteins may play a role in evading immune recognition or regulating host cell transformation, highlighting targets for drug or vaccine development (2). Several individual genes specific to the Theileria genome are also suggestive of roles in modulating the host cell cytoskeleton and the immune response (6, 7).

Parasite life cycles compared.

Concentric circles diagram the differentiation of various apicomplexan parasites, as they traverse multiple stages of their complex life cycle. Radial lines indicate distinct invasion events, in which parasites enter new host cells (broken lines correspond to invasion events that do not require entering a new tissue type). Sporozoites enter the mammalian cells indicated in the upper left sector. Theileria transforms lympohocytes to induce a life-threatening lymphoma; other sporozoites produce little pathogenesis, although the hepatocytic stages of some Plasmodium species may lie dormant for long periods of time. Merozoites (called tachyzoites in Toxoplasma) enter new cells, where they may propagate indefinitely (except for Cryptosporidium), causing significant anemia or tissue destruction. Toxoplasma-infected cells can also differentiate into latent bradyzoite tissue cysts, particularly in muscle and brain. The pink-shaded region at the bottom indicates sexual stages in ticks (Theileria), mosquitoes (Plasmodium), or cats (Toxoplasma), although Toxoplasma bradyzoites may also be transmitted without sexual recombination, via carnivory. Cryptosporidium requires no vector species for transmission. The outermost shape depicts a generic merozoite, with rhoptries of the apical complex at the top.

Overall, the range and depth of genomic-scale data sets available for multiple apicomplexan parasite species provide an extraordinarily rich resource for studying the evolution and function of eukaryotic cells, organelles, and host-pathogen interactions.

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