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Translational repression (TR) of mRNAs plays an important role in sexual differentiation and gametogenesis in multicellular eukaryotes. We show here that TR and mRNA turnover are key influences on stage specific gene expression in the protozoan Plasmodium. The DDX6 class RNA helicase, DOZI (development of zygote inhibited), is found in cytoplasmic bodies of female, blood stage gametocytes in a complex with mRNA species known to be translationally repressed. Genetic disruption of pbdozi inhibits the formation of translationally quiescent mRNPs and targets these and other (>350 different) transcripts to the degradation pathway rather than directing them to translating polysomes, preventing zygote development prior to meiosis in the mosquito. Thus TR is essential in malaria parasite development. A full catalogue of the proteins and processes associated with DOZI (the first described malaria parasite TR-effector protein) might lead to novel approaches to prevent parasite development.

The malaria parasite kills several million people each year, many of them young children in sub-Saharan Africa. A forty-year effort to develop either a subunit or attenuated whole-organism vaccine has met with little success. However, as Andy Waters and colleagues discuss in their Perspective, a new study in mice using genetically attenuated sporozoites of a rodent malaria parasite has yielded a promising protective response in vaccinated animals. The Perspective authors discuss the possibility of developing a human malaria vaccine based on this strategy.

Genetic manipulation of malaria parasites would revolutionize the study of this group of pathogens and have implications for vaccine and drug development. This report describes the stable, drug-selectable genetic transformation of the clinically relevant intracellular blood stages of a malaria parasite. A plasmid transfection vector carrying the gene locus that encodes a drug-resistant form of the bifunctional enzyme dihydrofolate reductase-thymidylate synthase from the rodent malaria parasite Plasmodium berghei was constructed. Derivatives of this vector were introduced into merozoites of P. berghei by electroporation, and parasites were selected for successful transformation in the rodent host on the basis of resistance to pyrimethamine. The plasmids were present in a circular, unrearranged form that replicated episomally to an observed maximum of 15 copies per cell in drug-resistant populations.

Several insects, particularly mosquitoes, are responsible for the transmission of many viral, protozoan, and even worm infections. Previously, insects were considered passive pathogen carriers. But sophisticated cross-talk exists between the pathogen effectors and the immune system of the insect vector. As in vertebrates, the insect's first line of defense is a sophisticated innate immune response (IIR), employing pattern recognition molecules to detect pathogens and shape the antipathogen response. IIR involves humoral and cellular responses ( 1 ), including phagocytic cells and complement-like systems, which result in the activation of effector molecules—for example, thioester-containing protein 1 (TEP1) ( 2 )—that cause lysis or encapsulation of the parasite through melanization. IIR may also trigger free-radical release, causing lethal damage to the pathogen. Despite a fairly detailed picture of how a mosquito responds to pathogen infection ( 3 , 4 ), parasite targets and mechanisms of mosquito immune evasion by parasites are largely unknown. On page 984 of this issue, Molina-Cruz et al. ( 5 ) identify a gene in the human malarial parasite, Plasmodium falciparum , that mediates evasion of the mosquito IIR.

Plasmodium falciparum , the most deadly of the human malaria parasites, continues to ravage rural areas of the developing world. As Waters highlights in his Perspective, high-throughput technology is coming to the rescue with the publication here ( Le Roch et al .) and elsewhere of the gene expression profiles (transcriptomes) of P. falciparum at different stages of its life cycle. These transcriptome data sets should contribute to identifying new targets for drug and vaccine development.

Phenotypic heterogeneity in the repetitive portion of a human malaria circumsporozoite (CS) protein, a major target of candidate vaccines, has been found. Over 14% of clinical cases of uncomplicated Plasmodium vivax malaria at two sites in western Thailand produced sporozoites immunologically distinct from previously characterized examples of the species. Monoclonal antibodies to the CS protein of other P. vivax isolates and to other species of human and simian malarias did not bind to these nonreactive sporozoites, nor did antibodies from monkeys immunized with a candidate vaccine made from the repeat portion of a New World CS protein. The section of the CS protein gene between the conserved regions I and II of a nonreactive isolate contained a nonapeptide repeat, Ala-Asn-Gly-Ala-Gly-Asn-Gln-Pro-Gly, identical at only three amino acid positions with published nonapeptide sequences. This heterogeneity implies that a P. vivax vaccine based on the CS protein repeat of one isolate will not be universally protective.