Filarial parasites afflict hundreds of millions of individuals worldwide, and represent significant public health problems in many of the poorest countries in the world. The currently available drugs used to combat these infections have several drawbacks, including the need for very long chemotherapeutic courses and the potential for the development of resistance. As a result, the development of new drugs to treat these infections is an important goal in the field of filariasis research. Most of the human filarial parasite species harbor an endosymbiotic bacterium of the genus Wolbachia. These endo-bacteria are essential, as elimination of the endosymbiont leads to sterilization of the adult female parasite. However, the antibiotic regimens that have been used to rid the parasites of the endosymbiont are of very long duration and require the use of a drug whose use is very limited. Thus, the need exists for the development of new chemotherapeutic approaches that can practically exploit the vulnerability of the human filarial parasites to the loss of the Wolbachia endosymbiont. Previous biochemical and genetic studies have established that communication between the host and Wolbachia endobacterium is essential for the Wolbachia to maintain itself and for it to spread throughout the host population. The overall goal of this proposal will be to identify the proteins that are involved in this endosymbiotic relationship and then to establish the functional networks of the genes involved in the process.
The specific aims of the project are: 1. To map the interactome of the endosymbiont and its host. 2. To identify B. malayi nuclear-encoded genes involved in the endosymbiotic interaction. 3. To develop genetic regulatory and functional networks of parasite genes involved in the endosymbiotic relationship. The diseases caused by filarial parasites afflict hundreds of millions of individuals worldwide, and represent significant public health and socio-economic problems in many of the poorest countries in the world. Because of the public health importance of filarial infections, the international community has been supporting various filariasis control programs for over thirty years. The cumulative expenses of these programs now total in the hundreds of millions of dollars. However, progress in the elimination of the human filaria has been hampered by the paucity of efficient tools to combat these infections. The one tool that is really lacking is a method to kill or permanently sterilize the adult female parasites. Without such a tool, the control programs must maintain a high degree of pressure on the parasite population for the effective lifespan of the adult female parasite, a period which can extend to 12 years or more. Recent studies indicated that an intracellular bacterium in these parasites is essential for parasite reproduction and that elimination of this bacterium from the parasite results in sterility of the female worm. This program, if successful will suggest new drug targets that may be used to kill this bacterium, thereby sterilizing the female parasite and giving humanity a potent new tool to use against these parasites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072465-03
Application #
7803612
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Joy, Deirdre A
Project Start
2008-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
3
Fiscal Year
2010
Total Cost
$404,048
Indirect Cost
Name
University of South Florida
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Melnikow, Elena; Xu, Shulin; Liu, Jing et al. (2013) A potential role for the interaction of Wolbachia surface proteins with the Brugia malayi glycolytic enzymes and cytoskeleton in maintenance of endosymbiosis. PLoS Negl Trop Dis 7:e2151
Liu, Canhui; Enright, Tracy; Tzertzinis, George et al. (2012) Identification of genes containing ecdysone response elements in the genome of Brugia malayi. Mol Biochem Parasitol 186:38-43
Liu, Canhui; Kelen, Patrick Vander; Ghedin, Elodie et al. (2011) Analysis of transcriptional regulation of tetracycline responsive genes in Brugia malayi. Mol Biochem Parasitol 180:106-11
Melnikow, Elena; Xu, Shulin; Liu, Jing et al. (2011) Interaction of a Wolbachia WSP-like protein with a nuclear-encoded protein of Brugia malayi. Int J Parasitol 41:1053-61
Ghedin, Elodie; Hailemariam, Tiruneh; DePasse, Jay V et al. (2009) Brugia malayi gene expression in response to the targeting of the Wolbachia endosymbiont by tetracycline treatment. PLoS Negl Trop Dis 3:e525