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Hemoglobin degradation by Plasmodium is a massive catabolic process within the parasite food vacuole that is important for the organism’s survival in its host erythrocyte. A proteolytic pathway is responsible for generating amino acids from hemoglobin. Each of the enzymes involved has its own peculiarities to be exploited for development of antimalarial agents that will starve the parasite or result in build-up of toxic intermediates. There are a number of unanswered questions concerning the cell biology, biochemistry and metabolic roles of this crucial pathway.

Iron metabolism is essential for cell function and potentially toxic because iron can catalyze oxygen radical production. Malaria-attributable anemia and iron deficiency anemia coincide as being treatable diseases in the developing world. In absolute amounts, more than 95% of Plasmodium metal biochemistry occurs in the acidic digestive vacuole where heme released from hemoglobin catabolism forms heme crystals. The antimalarial quinolines interfere with crystallization. Despite the completion of the Plasmodium genome, many ‘gene gaps’ exist in components of the metal pathways described in mammalian or yeast cells. Present evidence suggests that parasite bioavailable iron originates from a labile erythrocyte cytosolic pool rather than from abundant heme iron. Indeed the parasite has to make its own heme within two separate organelles, the mitochondrion and the apicomplast. Paradoxically, despite the abundance of iron within the erythrocyte, iron chelators are cytocidal to the Plasmodium parasite. Hemozoin has become a sensitive biomarker for laser desorption mass spectrometry detection of Plasmodium infection in both mice and humans.

Membrane transport proteins are integral membrane proteins that mediate the passage across the membrane bilayer of specific molecules and/or ions. Such proteins serve a diverse range of physiological roles, mediating the uptake of nutrients into cells, the removal of metabolic wastes and xenobiotics (including drugs), and the generation and maintenance of transmembrane electrochemical gradients. In this chapter we review the present state of knowledge of the membrane transport mechanisms underlying the cell physiology of the intraerythrocytic malaria parasite and its host cell, considering in particular physiological measurements on the parasite and parasitized erythrocyte, the annotation of transport proteins in the Plasmodium genome, and molecular methods used to analyze transport protein function.

The Plasmodium ookinete is the developmental stage of the malaria parasite that invades the mosquito midgut. The ookinete faces two physical barriers in the midgut which it must traverse to become an oocyst: the chitin- and protein-containing peritrophic matrix; and the midgut epithelial cell. This chapter will consider basic aspects of ookinete biology, molecules known to be involved in midgut invasion, and cellular processes of the ookinete that facilitate parasite invasion. Detailed knowledge of these mechanisms may be exploitable in the future towards developing novel strategies of blocking malaria transmission.

Malaria parasites are transmitted by the bite of an infected mosquito, but even efficient vector species possess multiple mechanisms that together destroy most of the parasites present in an infection. Variation between individual mosquitoes has allowed genetic analysis and mapping of loci controlling several resistance traits, and the underlying mechanisms of mosquito response to infection are being described using genomic tools such as transcriptional and proteomic analysis. Malaria infection imposes fitness costs on the vector, but various forms of resistance inflict their own costs, likely leading to an evolutionary tradeoff between infection and resistance. Plasmodium development can be successfully completed only in compatible mosquito-parasite species combinations, and resistance also appears to have parasite specificity. Studies of Drosophila , where genetic variation in immunocompetence is pervasive in wild populations, offer a comparative context for understanding coevolution of the mosquito-malaria relationship. More broadly, plants also possess systems of pathogen resistance with features that are structurally conserved in animal innate immunity, including insects, and genomic datasets now permit useful comparisons of resistance models even between such diverse organisms.

An evolution in modern malaria research occurred with the completion of the Plasmodium falciparum genome project and the onset and application of novel post-genomic technologies. Corresponding with these technological achievements are improvements in accessing and purifying parasite material from ‘hard-to-reach’ stages of malaria development. Characterization of gene and protein expression in the infectious sporozoite and subsequent liver-stage parasite development is critical to identify novel pre-erythrocytic drug and vaccine targets as well as to understand the basic biology of this deadly parasite. Both transcriptional and proteomic analyses on these stages and the remaining stages of development will assist in the ‘credentialing process’ of the complete malaria genome.