Trypanosoma cruzi, the causative agent of Chagas'heart disease affects several million individuals causing significant morbidity and mortality, yet it remains incurable. T. cruzi modulates the gene expression profiles of a few extracellular matrix proteins to facilitate infection. One of the genes up-regulated early during infection by the parasite is host thrombospondin-1 (TSP-1), a matricellular protein. TSP-1 binds specifically to the surface of invasive forms of T. cruzi trypomastigotes and knockdown of host TSP-1 by RNA interference causes significant inhibition of T. cruzi infection. We hypothesize that the trypomastigote form of T. cruzi up- regulates host TSP-1 that interacts with trypanosome surface receptor(s) to enhance the infection of heart cells. The long-term goal of this research is to understand the molecular mechanisms that allow T. cruzi to infect heart cells, so that specific molecular intervention strategies can be developed to prevent infection of heart cells. The hypothesis will be tested by experiments based on these specific aims: 1. To clone and characterize the novel T. cruzi TSP-1 binding molecule. We will use affinity chromatography, MALDITOF-MS, PCR and purification of recombinant proteins approaches to identify, clone and characterize the trypomastigote receptor that is important in the process of T. cruzi infection;2. To determine the in vivo role of TSP-1 gene in the process of T. cruzi infection using TSP-1 KO mice model.

Public Health Relevance

In this project, we propose to identify and characterize a novel receptor on the surface of infectious T. cruzi trypomastigotes that binds specifically with host thrombospondin-1. This research is significant to public health because it will provide a molecular understanding of one of the first steps of infection of heart cells by infectious trypomastigotes, which will facilitate the development of specific molecular intervention strategies to prevent Chagas'heart disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Pilot Research Project (SC2)
Project #
5SC2AI083925-03
Application #
8013618
Study Section
Special Emphasis Panel (ZGM1-MBRS-7 (GC))
Program Officer
Mcgugan, Glen C
Project Start
2009-02-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2011
Total Cost
$143,585
Indirect Cost
Name
Meharry Medical College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
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