This application focuses on trypanosomatid protozoa of the genus Leishmania, the causative agent of leishmaniasis. More than 20 species of Leishmania parasites are able to infect and cause disease in humans and their epidemiological features involve a considerable range of reservoir hosts and insect vectors, suggesting specific adaptations. Leishmaniasis is the second biggest parasitic killer following malaria, with a significant impact on deterioration of social and economic conditions. There is no vaccine available and current therapeutic regimens have serious limitations. The Leishmania (Viannia) subgenus represents a distinct phylogenetic and evolutionary group of Leishmania. Despite the prevalence of these parasites in Central and South America and their association with cutaneous and mucocutaneous disease, their mechanisms of virulence and pathogenesis have not been extensively studied. The Leishmania life cycle entails two morphologically distinct forms: transmission to the vertebrate host is initiated by flagellated metacyclic promastigotes via the bite of an infected female sandfly vector. In the mammalian host, Leishmania are obligate intracellular parasites that replicate within late endosomal/lysosomal compartments of macrophages and may be persistent for months or years. This proposal builds on the availability of a robust murine model for L. (V.) panamensis chronic infection, as well as promastigote and infectious axenic amastigote in vitro cultures. We propose to study differentiation at the molecular level by monitoring the transcriptional landscape using deep-sequencing technologies (RNA-Seq) and examining translation features of mRNA by "ribosome profiling". Traditionally, DNA microarrays were used to survey global patterns and changes in gene expression. Recent pioneering experiments have introduced RNA-Seq, a methodology employing next generation sequencing, i.e. massive parallel sequencing of cDNA. We will also explore potential translation regulatory mechanism(s) by implementing the newly-established "ribosome profiling" methodology, which correlates ribosome occupancy on mRNA with relative mRNA translation efficiencies. The proposed studies will further our understanding of L. (V.) panamensis biology, enhance our understanding of the genome coding capacity of the subgenus Viannia, contribute to determine the possible impact of translational control in Leishmania and have the potential to identify genes important for macrophage infection. The identified genes could be of interest as potential immunotherapeutic and pharmacological targets for treatment and disease control.

Public Health Relevance

Parasitic protozoa are a major cause of global infectious diseases and thus, represent one of the most serious threats to public health. Among these are African trypanosomes, the causative agents of African trypanosomiasis or sleeping sickness in humans and a wasting and fatal disease (Nagana) in cattle, domestic pigs and other farm animals causing a profound effect on the economy of much of the continent. Unless treated, African sleeping sickness is always fatal;no vaccine has been approved and there is a very limited arsenal of drugs with generally severe shortcomings, such as high toxicity and emerging resistance

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Research Grants (R03)
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Pathogenic Eukaryotes Study Section (PTHE)
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Mcgugan, Glen C
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Yale University
Public Health & Prev Medicine
Schools of Medicine
New Haven
United States
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