: The kinetoplastid protozoan parasite Trypanosoma cruzi causes Chagas'disease in humans, a chronic and debilitating condition affecting several million individuals in Latin America. Since the vertebrate stages of T. cruzi are obligate intracellular parasites, elucidation of host-pathogen interactions required for establishment of infection is crucial to understanding mechanisms of T. cruzi pathogenesis. Our preliminary findings highlight the parasitophorous vacuole as a transitional point the T. cruzi intracellular life cycle, linking early signaling and cellular changes regulating formation and maturation of the vacuole to downstream changes in gene expression evoked upon emergence of parasites from the vacuole. We will carry out a detailed analysis of the process of T. cruzi vacuole formation, maturation and disruption the molecular and cellular levels. Using the induction of IFNb gene expression as a sensitive reporter for host cell transcriptional responses elicited by vacuole egress by T. cruzi, we will define the host cell signaling pathways required to trigger this response. Finally, we will employ DNA microarray analysis to further characterize host transcriptional responses to T. cruzi with the specific goal of determining which changes are elicited as a primary response to T. cruzi infection versus the majority of secondary, tertiary, responses elicited by soluble factors released from T. cruzi-infected cells. Little is known regarding the molecular and cellular events required to shape a permissive host cell environment for intracellular growth and survival of this pathogen. The multi-faceted approach we propose to examine these early events will provide molecular detail currently lacking in our understanding of the T. cruzi infective process. It is the understanding of these basic processes that will guide our efforts toward effective prevention and control of Chagas'disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047960-09
Application #
7559702
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Mcgugan, Glen C
Project Start
2000-07-15
Project End
2010-06-30
Budget Start
2009-01-01
Budget End
2010-06-30
Support Year
9
Fiscal Year
2009
Total Cost
$305,094
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Chessler, Anne-Danielle C; Caradonna, Kacey L; Da'dara, Akram et al. (2011) Type I interferons increase host susceptibility to Trypanosoma cruzi infection. Infect Immun 79:2112-9
Costales, Jaime A; Daily, Johanna P; Burleigh, Barbara A (2009) Cytokine-dependent and-independent gene expression changes and cell cycle block revealed in Trypanosoma cruzi-infected host cells by comparative mRNA profiling. BMC Genomics 10:252
Chessler, Anne-Danielle C; Unnikrishnan, Meera; Bei, Amy K et al. (2009) Trypanosoma cruzi triggers an early type I IFN response in vivo at the site of intradermal infection. J Immunol 182:2288-96
Chessler, Anne-Danielle C; Ferreira, Ludmila R P; Chang, Tun-Han et al. (2008) A novel IFN regulatory factor 3-dependent pathway activated by trypanosomes triggers IFN-beta in macrophages and fibroblasts. J Immunol 181:7917-24
Petersen, Christine A; Krumholz, Katherine A; Burleigh, Barbara A (2005) Toll-like receptor 2 regulates interleukin-1beta-dependent cardiomyocyte hypertrophy triggered by Trypanosoma cruzi. Infect Immun 73:6974-80
Unnikrishnan, Meera; Burleigh, Barbara A (2004) Inhibition of host connective tissue growth factor expression: a novel Trypanosoma cruzi-mediated response. FASEB J 18:1625-35
Burleigh, B A (2004) Probing Trypanosoma cruzi biology with DNA microarrays. Parasitology 128 Suppl 1:S3-10
Woolsey, Aaron M; Burleigh, Barbara A (2004) Host cell actin polymerization is required for cellular retention of Trypanosoma cruzi and early association with endosomal/lysosomal compartments. Cell Microbiol 6:829-38
Petersen, Christine A; Burleigh, Barbara A (2003) Role for interleukin-1 beta in Trypanosoma cruzi-induced cardiomyocyte hypertrophy. Infect Immun 71:4441-7
Woolsey, Aaron M; Sunwoo, Lisa; Petersen, Christine A et al. (2003) Novel PI 3-kinase-dependent mechanisms of trypanosome invasion and vacuole maturation. J Cell Sci 116:3611-22

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