We have defined the pattern of transcription of the developmentally regulated rRNA genes of Plasmodium species. We have found that upregulation of one of the genes relates to the differentiation of the sporozoite as a unit within the oocyst. We have also discovered a previously undescribed rDNA unit that is expressed only during oocyst development in the mosquito abdomen, but never carried to the thorax in mature sporozoites. Molecular modeling of the oocyst gene reveals that it would suppress UGA termination; hence, its presence in the translation apparatus would result in fundamental changes in the pattern of translation products that occur during development. We consider the elucidation of the characteristics of this switch of importance with regard to understanding translational control in the parasite. To more directly study the ribosomal rRNAs, we have studied the susceptibility of parasites to both cytoplasmic and organellular ribosome inhibitory drugs. We have shown characteristically different effects of the drugs. We have also produced resistant mutants to one of the cytoplasmic ribosome inhibitors, anisomycin. In separate studies, we have continued our work with attenuated lines of human and rodent malarias. Auxotrophic lines of parasites have been cloned and their developmental characteristics studied. Auxotrophic mutants of both species of parasite have been defined by their dependency on either exogenous pyrimidines or para-aminobenzoic acid. These should prove useful in the study of both the biochemistry of parasites and the development of immunity to parasites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000208-15
Application #
5200412
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
1995
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Oakley, Miranda S; Majam, Victoria; Mahajan, Babita et al. (2009) Pathogenic roles of CD14, galectin-3, and OX40 during experimental cerebral malaria in mice. PLoS One 4:e6793
Raj, Dipak Kumar; Mu, Jianbing; Jiang, Hongying et al. (2009) Disruption of a Plasmodium falciparum multidrug resistance-associated protein (PfMRP) alters its fitness and transport of antimalarial drugs and glutathione. J Biol Chem 284:7687-96
McCutchan, Thomas F (2008) Beyond bed nets. Science 319:33
Oakley, Miranda S; McCutchan, Thomas F; Anantharaman, Vivek et al. (2008) Host biomarkers and biological pathways that are associated with the expression of experimental cerebral malaria in mice. Infect Immun 76:4518-29
Grim, K Christiana; McCutchan, Thomas; Sullivan, Margery et al. (2008) Unidentified Plasmodium species in Australian black swans (Cygnus atratus) hatched and raised in North America. J Zoo Wildl Med 39:216-20
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McCutchan, Thomas F (2008) Is a monkey malaria from Borneo an emerging human disease? Future Microbiol 3:115-8
Li, Jian; Zhang, Yanhui; Sullivan, Margery et al. (2007) Typing Plasmodium yoelii microsatellites using a simple and affordable fluorescent labeling method. Mol Biochem Parasitol 155:94-102
Oakley, Miranda S M; Kumar, Sanjai; Anantharaman, Vivek et al. (2007) Molecular factors and biochemical pathways induced by febrile temperature in intraerythrocytic Plasmodium falciparum parasites. Infect Immun 75:2012-25
Rathore, Dharmendar; Nagarkatti, Rana; Jani, Dewal et al. (2005) An immunologically cryptic epitope of Plasmodium falciparum circumsporozoite protein facilitates liver cell recognition and induces protective antibodies that block liver cell invasion. J Biol Chem 280:20524-9

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